- Departments & Programs
- Medical Library
- Clinical Trials
- Cancer Information
- Medical Education
Genetics of Breast and Ovarian Cancer (PDQ®)
- High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes
- Low- and Moderate-Penetrance Genes Associated With Breast and/or Ovarian Cancer
- Psychosocial Issues in Inherited Breast Cancer Syndromes
- Changes to This Summary (03/04/2013)
- About This PDQ Summary
- Get More Information From NCI
Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.
Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.
Among women, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and it is the second leading cause of cancer deaths after lung cancer. In 2013, an estimated 234,580 new cases will be diagnosed, and 40,030 deaths from breast cancer will occur. The incidence of breast cancer, particularly for estrogen receptor–positive cancers occurring after age 50 years, is declining and has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy (HRT) following early reports from the Women’s Health Initiative. Ovarian cancer is the ninth most common cancer, with an estimated 22,240 new cases in 2013, but is the fifth most deadly, with an estimated 14,030 deaths in 2013. (Refer to the PDQ summaries on Breast Cancer Treatment and Ovarian Epithelial Cancer Treatment for more information on breast cancer and ovarian cancer rates, diagnosis, and management.)
A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history (see the Family History as a Risk Factor for Breast Cancer and the Family History as a Risk Factor for Ovarian Cancer sections below), and by the observation of some families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with an inheritance of autosomal dominant cancer susceptibility. Formal studies of families (linkage analysis) have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes as the cause of inherited cancer risk in many families. (Refer to the PDQ summary Cancer Genetics Overview for more information on linkage analysis.) Mutations in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.
Family History as a Risk Factor for Breast Cancer
In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree relative (FDR) or a second-degree relative with breast cancer. The risk conferred by a family history of breast cancer has been assessed in both case-control and cohort studies, using volunteer and population-based samples, with generally consistent results. In a pooled analysis of 38 studies, the relative risk (RR) of breast cancer conferred by an FDR with breast cancer was 2.1 (95% confidence interval [CI], 2.0–2.2). Risk increases with the number of affected relatives, age at diagnosis, and the number of affected male relatives. (Refer to the Penetrance of mutations section of this summary for a discussion of familial risk in women from families with BRCA1/BRCA2 mutations who themselves test negative for the family mutation.)
Family History as a Risk Factor for Ovarian Cancer
Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an odds ratio (OR) of 3.1 for the risk of ovarian cancer associated with at least one FDR with ovarian cancer.
Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition
Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics:
- Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.
- Both males and females can inherit and transmit an autosomal dominant cancer predisposition. A male who inherits a cancer predisposition can still pass the altered gene on to his sons and daughters.
Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 mutations and of Cowden syndrome due to PTEN mutations. Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia (AT) gene and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with Lynch syndrome, basal cell nevus (Gorlin) syndrome (OMIM), and multiple endocrine neoplasia type 1 (MEN1) (OMIM). Germline mutations in the genes responsible for those syndromes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.
The family characteristics that suggest hereditary breast and ovarian cancer predisposition include the following:
- Multiple cancers within a family.
- Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).
- Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast cancer and ovarian cancer in the same individual).
- Cases of male breast cancer.
Figure 1 and Figure 2 depict some of the classic inheritance features of a deleterious BRCA1 and BRCA2 mutation, respectively. (Refer to the Standard Pedigree Nomenclature figure in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for definitions of the standard symbols used in these pedigrees.)
There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers from those occurring in noncarriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2/neu receptor-negative and have a basal phenotype. BRCA1-associated ovarian cancers are more likely to be high-grade and of serous histopathology. (Refer to the Pathology of breast cancer and Pathology of ovarian cancer sections of this summary for more information.)
Difficulties in Identifying a Family History of Breast and Ovarian Cancer Risk
When using family history to assess risk, the accuracy and completeness of family history data must be taken into account. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than on the maternal side and thus may be more difficult to obtain. When comparing self-reported information with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.
Other Risk Factors for Breast Cancer
Other risk factors for breast cancer include age, reproductive and menstrual history, hormone therapy, radiation exposure, mammographic breast density, alcohol intake, physical activity, anthropometric variables, and a history of benign breast disease. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) These factors, including their role in the etiology of breast cancer among BRCA1/BRCA2 mutation carriers, are considered in more detail in other reviews. Brief summaries are given below, highlighting, where possible, the effect of these risk factors in women who are genetically susceptible to breast cancer. (Refer to the Clinical management of BRCA mutation carriers section of this summary for more information about their effects in BRCA1/BRCA2 mutation carriers.)
Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years. In women with a genetic susceptibility, breast cancer, and to a lesser degree, ovarian cancer, tends to occur at an earlier age than in sporadic cases.
Reproductive and menstrual history
In general, breast cancer risk increases with early menarche and late menopause and is reduced by early first full-term pregnancy. In BRCA1 and BRCA2 mutation carriers, results have been conflicting and may be gene dependent. No consistent significant associations have been observed. Evidence suggests that reproductive history may be differentially associated with breast cancer subtype (i.e., triple-negative vs. ER-positive breast cancers). In contrast to ER-positive breast cancers, parity has been positively associated with triple-negative disease, with no association with ages at menarche and menopause.
Oral contraceptives (OCs) may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with OC use did not vary in relationship to a family history of breast cancer.
OCs are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers. Although the data are not entirely consistent, a meta-analysis concluded that there was no significant increased risk of breast cancer with OC use in BRCA1/BRCA2 mutation carriers. However, use of OCs formulated before 1975 was associated with an increased risk of breast cancer (summary relative risk [SRR], 1.47; 95% CI, 1.06–2.04). (Refer to the Reproductive factors section in the Clinical management of BRCA mutation carriers section of this summary for more information.)
Hormone replacement therapy
Data exist from both observational and randomized clinical trials regarding the association between postmenopausal HRT and breast cancer. A meta-analysis of data from 51 observational studies indicated a RR of breast cancer of 1.35 (95% CI, 1.21–1.49) for women who had used HRT for 5 or more years after menopause. The Women's Health Initiative (WHI), a randomized controlled trial (NCT00000611) of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined HRT or placebo, was halted early because health risks exceeded benefits. Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR, 1.24; 95% CI, 1.02–1.5, P <. 001) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Women’s Study in the United Kingdom. The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR, 0.77; 95% CI, 0.59–1.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk.
The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors.  The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/BRCA2 mutations. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk. The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has been studied only in the context of bilateral risk-reducing oophorectomy, in which short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk. (Refer to the Hormone replacement therapy in BRCA1/BRCA2 mutation carriers section of this summary for more information.)
Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear.
Preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 or BRCA2 mutations, and in association with germline ATM and TP53 mutations.
The possibility that genetic susceptibility to breast cancer occurs via a mechanism of radiation sensitivity raises questions about radiation exposure. It is possible that diagnostic radiation exposure, including mammography, poses more risk in genetically susceptible women than in women of average risk. Therapeutic radiation could also pose carcinogenic risk. A cohort study of BRCA1 and BRCA2 mutation carriers treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of mutation carriers. Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of radiation exposure, including, but not limited to, mammography, in BRCA1 and BRCA2 mutation carriers have had conflicting results. A large European study showed a dose-response relationship of increased risk with total radiation exposure, but this was primarily driven by nonmammographic radiation exposure before age 20 years. (Refer to the Mammography section in the High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes section of this summary for more information about radiation.)
The risk of breast cancer increases by approximately 10% for each 10 g of daily alcohol intake (approximately one drink or less) in the general population. Prior studies of BRCA1/BRCA2 mutation carriers have found no increased risk associated with alcohol consumption.
Physical activity and anthropometry
Weight gain and being overweight are commonly recognized risk factors for breast cancer. In general, overweight women are most commonly observed to be at increased risk of postmenopausal breast cancer and at reduced risk of premenopausal breast cancer. Sedentary lifestyle may also be a risk factor. These factors have not been systematically evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing mutations, but one study suggested a reduced risk of cancer associated with exercise among BRCA1 and BRCA2 mutation carriers.
Benign breast disease and mammographic density
Benign breast disease (BBD) is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer). There may also be an association between BBD and family history of breast cancer.
An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram, and breast density is likely to have a genetic component in its etiology.
Other risk factors, including those that are only weakly associated with breast cancer and those that have been inconsistently associated with the disease in epidemiologic studies (e.g., cigarette smoking), may be important in women who are in specific genotypically defined subgroups. For example, some studies have suggested that certain N-acetyl transferase alleles may influence female smokers’ risk of developing breast cancer. One study  found a reduced risk of breast cancer among BRCA1/BRCA2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.
Other Risk Factors for Ovarian Cancer
Factors that increase risk of ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and use of OCs. (Refer to the PDQ summary on Prevention of Ovarian Cancer for more information.) Relatively few studies have addressed the effect of these risk factors in women who are genetically susceptible to ovarian cancer. (Refer to the Reproductive factors section of this summary for more information.)
Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote, even in hereditary cancer families.
Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers. Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid. Evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.
Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk, including in BRCA1/BRCA2 mutation carriers. Ovarian cancer risk is reduced more than 90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy (RRSO). In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer. (Refer to the Risk-reducing salpingo-oophorectomy section of this summary for more information about these studies.)
Use of OCs for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population.  A majority of, but not all, studies also support OCs being protective among BRCA1/ BRCA2 mutation carriers. A meta-analysis of 18 studies including 13,627 BRCA mutation carriers reported a significantly reduced risk of ovarian cancer (SRR, 0.50; 95% CI, 0.33–0.75) associated with OC use. (Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.)
Models for Prediction of Breast Cancer Risk
Models to predict an individual’s lifetime risk of developing breast cancer are available. In addition, models exist to predict an individual’s likelihood of having a BRCA1 or BRCA2 mutation. (Refer to the Models for prediction of the likelihood of a BRCA1 or BRCA2 mutation section of this summary for more information about these models.) Not all models can be appropriately applied for all patients. Each model is appropriate only when the patient’s characteristics and family history are similar to the study population on which the model was based. Different models may provide widely varying risk estimates for the same clinical scenario, and the validation of these estimates has not been performed for many models. Table 1 summarizes the salient aspects of two of the common risk assessment models and is designed to aid in choosing the model that best applies to a particular individual.
The Claus model  and the Gail model  are widely used in research studies and clinical counseling. Both have limitations, and the risk estimates derived from the two models may differ for an individual patient. Several other models, which include more detailed family history information, are also in use and are discussed below.Table 1. Characteristics of the Gail and Claus ModelsaGail Model (Breast Cancer Risk Assessment Tool)bClaus ModelFDR = First-degree relative; SDR = second-degree relative.aAdapted from Domchek et al., Rubenstein et al., and Rhodes.bModified based on periodic updates.Data derived from Breast Cancer Detection Demonstration Project Study Cancer and Steroid Hormone Study Study population 2,852 cases, aged ≥35 y 4,730 cases, aged 20–54 y In situ and invasive cancer Invasive cancer 3,146 controls 4,688 controls Caucasian Caucasian Annual breast screeningNot routinely screened Family history characteristics FDRs with breast cancer FDRs or SDRs with breast cancer Age of onset in relatives Other characteristics Current age Current age Age at menarche Age at first live birth Number of breast biopsies Atypical hyperplasia in breast biopsy Race (included in the most current version of the Gail model) StrengthsIncorporates: Incorporates: Risk factors other than family history Paternal and maternal history Age at onset of breast cancer Family history of ovarian cancer Limitations Underestimates risk in hereditary families May underestimate risk in hereditary families Number of breast biopsies without atypical hyperplasia may cause inflated risk estimates May not be applicable to all combinations of affected relatives Does not include risk factors other than family history Does not incorporate: Paternal family history of breast cancer or any family history of ovarian cancer Age at onset of breast cancer in relatives All known risk factors for breast cancer  Best application For individuals with no family history of breast cancer or one FDR with breast cancer, aged ≥50 y For individuals with no more than two FDRs or SDRs with breast cancer For determining eligibility for chemoprevention studies
The Gail and the Claus models will significantly underestimate breast cancer risk in women from families with hereditary breast cancer susceptibility syndromes. Generally, the Claus or the Gail models should not be the sole model used for families with one or more of the following characteristics:
- Three individuals with breast or ovarian cancer (especially when one or more breast cancers are diagnosed before age 50 years).
- A woman who has both breast and ovarian cancer.
- Ashkenazi Jewish ancestry with at least one case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).
The Gail model is the basis for the Breast Cancer Risk Assessment Tool, a computer program that is available from the National Cancer Institute by calling the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237 or TTY at 1-800-332-8615). This version of the Gail model estimates only the risk of invasive breast cancer. The Gail model has been found to be reasonably accurate at predicting breast cancer risk in large groups of white women who undergo annual screening mammography; however, reliability varies based on the cohort studied. Risk can be overestimated in:
Risk could be underestimated in the lowest risk strata. Earlier studies  suggested risk was overestimated in younger women and underestimated in older women. More recent studies  using the modified Gail model (which is currently used) found it performed well in all age groups. Further studies are needed to establish the validity of the Gail model in minority populations. Recently, modifications have been made to the Breast Cancer Risk Assessment Tool incorporating data from the Women’s Contraceptive and Reproductive Experiences (CARE) study. This study of more than 1,600 African American women with invasive breast cancer and more than 1,600 controls was used to develop a breast cancer risk assessment model with improved race-specific calibration. Additional information for seven common low-penetrance breast cancer susceptibility alleles has not been shown to improve model performance significantly.
A study of 491 women aged 18 to 74 years with a family history of breast cancer compared the most recent Gail model to the Claus model in predicting breast cancer risk. The two models were positively correlated (r = .55). The Gail model estimates were higher than the Claus model estimates for most participants. Presentation and discussion of both the Gail and Claus models risk estimates may be useful in the counseling setting.
The Tyrer-Cuzick model incorporates both genetic and nongenetic factors. A three-generation pedigree is used to estimate the likelihood that an individual carries either a BRCA1/BRCA2 mutation or a hypothetical low penetrance gene. In addition, the model incorporates personal risk factors such as parity, body mass index, height, and age at menarche, menopause, HRT use, and first live birth. Both genetic and nongenetic factors are combined to develop a risk estimate. Although powerful, the model at the current time is less accessible to primary care providers than the Gail and Claus models. The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model examines family history to estimate breast cancer risk and also incorporates both BRCA1/BRCA2 and non-BRCA1/BRCA2 genetic risk factors.
Other risk assessment models incorporating breast density have been developed but are not ready for clinical use. In the future, additional models may be developed or refined to include such factors as breast density and other biomarkers.1American Cancer Society.: Cancer Facts and Figures 2013. Atlanta, Ga: American Cancer Society, 2013. Available online. Last accessed May 2, 2013.2Ravdin PM, Cronin KA, Howlader N, et al.: The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 356 (16): 1670-4, 2007.3Yang Q, Khoury MJ, Rodriguez C, et al.: Family history score as a predictor of breast cancer mortality: prospective data from the Cancer Prevention Study II, United States, 1982-1991. Am J Epidemiol 147 (7): 652-9, 1998.4Colditz GA, Willett WC, Hunter DJ, et al.: Family history, age, and risk of breast cancer. Prospective data from the Nurses' Health Study. JAMA 270 (3): 338-43, 1993.5Slattery ML, Kerber RA: A comprehensive evaluation of family history and breast cancer risk. The Utah Population Database. JAMA 270 (13): 1563-8, 1993.6Johnson N, Lancaster T, Fuller A, et al.: The prevalence of a family history of cancer in general practice. Fam Pract 12 (3): 287-9, 1995.7Pharoah PD, Day NE, Duffy S, et al.: Family history and the risk of breast cancer: a systematic review and meta-analysis. Int J Cancer 71 (5): 800-9, 1997.8Bevier M, Sundquist K, Hemminki K: Risk of breast cancer in families of multiple affected women and men. Breast Cancer Res Treat 132 (2): 723-8, 2012.9Stratton JF, Pharoah P, Smith SK, et al.: A systematic review and meta-analysis of family history and risk of ovarian cancer. Br J Obstet Gynaecol 105 (5): 493-9, 1998.10Lindor NM, McMaster ML, Lindor CJ, et al.: Concise handbook of familial cancer susceptibility syndromes - second edition. J Natl Cancer Inst Monogr (38): 1-93, 2008.11Kerber RA, Slattery ML: Comparison of self-reported and database-linked family history of cancer data in a case-control study. Am J Epidemiol 146 (3): 244-8, 1997.12Parent ME, Ghadirian P, Lacroix A, et al.: The reliability of recollections of family history: implications for the medical provider. J Cancer Educ 12 (2): 114-20, 1997 Summer.13Key TJ, Verkasalo PK, Banks E: Epidemiology of breast cancer. Lancet Oncol 2 (3): 133-40, 2001.14Hankinson S, Hunter D: Breast cancer. In: Adami H, Hunter D, Trichopoulos D, eds.: Textbook of Cancer Epidemiology. New York, NY: Oxford University Press, 2002, pp 301-39.15Narod SA: Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2 (2): 113-23, 2002.16Feuer EJ, Wun LM, Boring CC, et al.: The lifetime risk of developing breast cancer. J Natl Cancer Inst 85 (11): 892-7, 1993.17Antoniou AC, Shenton A, Maher ER, et al.: Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 8 (6): R72, 2006.18Jernström H, Lerman C, Ghadirian P, et al.: Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 354 (9193): 1846-50, 1999.19Kotsopoulos J, Lubinski J, Lynch HT, et al.: Age at first birth and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 105 (2): 221-8, 2007.20Phipps AI, Chlebowski RT, Prentice R, et al.: Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. J Natl Cancer Inst 103 (6): 470-7, 2011.21Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 347 (9017): 1713-27, 1996.22Iodice S, Barile M, Rotmensz N, et al.: Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer 46 (12): 2275-84, 2010.23Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 350 (9084): 1047-59, 1997.24Writing Group for the Women's Health Initiative Investigators.: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288 (3): 321-33, 2002.25Chlebowski RT, Hendrix SL, Langer RD, et al.: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289 (24): 3243-53, 2003.26Beral V; Million Women Study Collaborators.: Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362 (9382): 419-27, 2003.27Anderson GL, Limacher M, Assaf AR, et al.: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291 (14): 1701-12, 2004.28Schuurman AG, van den Brandt PA, Goldbohm RA: Exogenous hormone use and the risk of postmenopausal breast cancer: results from The Netherlands Cohort Study. Cancer Causes Control 6 (5): 416-24, 1995.29Steinberg KK, Thacker SB, Smith SJ, et al.: A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 265 (15): 1985-90, 1991.30Sellers TA, Mink PJ, Cerhan JR, et al.: The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 127 (11): 973-80, 1997.31Stanford JL, Weiss NS, Voigt LF, et al.: Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 274 (2): 137-42, 1995.32Colditz GA, Egan KM, Stampfer MJ: Hormone replacement therapy and risk of breast cancer: results from epidemiologic studies. Am J Obstet Gynecol 168 (5): 1473-80, 1993.33Gorsky RD, Koplan JP, Peterson HB, et al.: Relative risks and benefits of long-term estrogen replacement therapy: a decision analysis. Obstet Gynecol 83 (2): 161-6, 1994.34Rebbeck TR, Friebel T, Wagner T, et al.: Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 23 (31): 7804-10, 2005.35Helzlsouer KJ, Harris EL, Parshad R, et al.: Familial clustering of breast cancer: possible interaction between DNA repair proficiency and radiation exposure in the development of breast cancer. Int J Cancer 64 (1): 14-7, 1995.36Helzlsouer KJ, Harris EL, Parshad R, et al.: DNA repair proficiency: potential susceptiblity factor for breast cancer. J Natl Cancer Inst 88 (11): 754-5, 1996.37Abbott DW, Thompson ME, Robinson-Benion C, et al.: BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair. J Biol Chem 274 (26): 18808-12, 1999.38Abbott DW, Freeman ML, Holt JT: Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst 90 (13): 978-85, 1998.39Easton DF: Cancer risks in A-T heterozygotes. Int J Radiat Biol 66 (6 Suppl): S177-82, 1994.40Kleihues P, Schäuble B, zur Hausen A, et al.: Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 150 (1): 1-13, 1997.41Pierce LJ, Strawderman M, Narod SA, et al.: Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 18 (19): 3360-9, 2000.42Narod SA, Lubinski J, Ghadirian P, et al.: Screening mammography and risk of breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Lancet Oncol 7 (5): 402-6, 2006.43Andrieu N, Easton DF, Chang-Claude J, et al.: Effect of chest X-rays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators' Group. J Clin Oncol 24 (21): 3361-6, 2006.44Goldfrank D, Chuai S, Bernstein JL, et al.: Effect of mammography on breast cancer risk in women with mutations in BRCA1 or BRCA2. Cancer Epidemiol Biomarkers Prev 15 (11): 2311-3, 2006.45Gronwald J, Pijpe A, Byrski T, et al.: Early radiation exposures and BRCA1-associated breast cancer in young women from Poland. Breast Cancer Res Treat 112 (3): 581-4, 2008.46Pijpe A, Andrieu N, Easton DF, et al.: Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK). BMJ 345: e5660, 2012.47Smith-Warner SA, Spiegelman D, Yaun SS, et al.: Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 279 (7): 535-40, 1998.48Hamajima N, Hirose K, Tajima K, et al.: Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 87 (11): 1234-45, 2002.49McGuire V, John EM, Felberg A, et al.: No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages <50 years. Cancer Epidemiol Biomarkers Prev 15 (8): 1565-7, 2006.50Dennis J, Ghadirian P, Little J, et al.: Alcohol consumption and the risk of breast cancer among BRCA1 and BRCA2 mutation carriers. Breast 19 (6): 479-83, 2010.51McTiernan A: Behavioral risk factors in breast cancer: can risk be modified? Oncologist 8 (4): 326-34, 2003.52King MC, Marks JH, Mandell JB, et al.: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302 (5645): 643-6, 2003.53Chen J, Pee D, Ayyagari R, et al.: Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density. J Natl Cancer Inst 98 (17): 1215-26, 2006.54Dupont WD, Page DL, Parl FF, et al.: Long-term risk of breast cancer in women with fibroadenoma. N Engl J Med 331 (1): 10-5, 1994.55Boyd NF, Byng JW, Jong RA, et al.: Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 87 (9): 670-5, 1995.56Byrne C, Schairer C, Wolfe J, et al.: Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 87 (21): 1622-9, 1995.57Pankow JS, Vachon CM, Kuni CC, et al.: Genetic analysis of mammographic breast density in adult women: evidence of a gene effect. J Natl Cancer Inst 89 (8): 549-56, 1997.58Boyd NF, Lockwood GA, Martin LJ, et al.: Mammographic densities and risk of breast cancer among subjects with a family history of this disease. J Natl Cancer Inst 91 (16): 1404-8, 1999.59Vachon CM, King RA, Atwood LD, et al.: Preliminary sibpair linkage analysis of percent mammographic density. J Natl Cancer Inst 91 (20): 1778-9, 1999.60Ambrosone CB, Freudenheim JL, Graham S, et al.: Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA 276 (18): 1494-501, 1996.61Brunet JS, Ghadirian P, Rebbeck TR, et al.: Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes. J Natl Cancer Inst 90 (10): 761-6, 1998.62Ghadirian P, Lubinski J, Lynch H, et al.: Smoking and the risk of breast cancer among carriers of BRCA mutations. Int J Cancer 110 (3): 413-6, 2004.63Whittemore AS, Harris R, Itnyre J: Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 136 (10): 1184-203, 1992.64John EM, Whittemore AS, Harris R, et al.: Characteristics relating to ovarian cancer risk: collaborative analysis of seven U.S. case-control studies. Epithelial ovarian cancer in black women. Collaborative Ovarian Cancer Group. J Natl Cancer Inst 85 (2): 142-7, 1993.65Amos CI, Struewing JP: Genetic epidemiology of epithelial ovarian cancer. Cancer 71 (2 Suppl): 566-72, 1993.66Modan B, Hartge P, Hirsh-Yechezkel G, et al.: Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 345 (4): 235-40, 2001.67Brinton LA, Lamb EJ, Moghissi KS, et al.: Ovarian cancer risk after the use of ovulation-stimulating drugs. Obstet Gynecol 103 (6): 1194-203, 2004.68Rodriguez C, Patel AV, Calle EE, et al.: Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 285 (11): 1460-5, 2001.69Riman T, Dickman PW, Nilsson S, et al.: Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J Natl Cancer Inst 94 (7): 497-504, 2002.70Lacey JV Jr, Mink PJ, Lubin JH, et al.: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288 (3): 334-41, 2002.71Anderson GL, Judd HL, Kaunitz AM, et al.: Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 290 (13): 1739-48, 2003.72Tortolero-Luna G, Mitchell MF: The epidemiology of ovarian cancer. J Cell Biochem Suppl 23: 200-7, 1995.73Hankinson SE, Hunter DJ, Colditz GA, et al.: Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA 270 (23): 2813-8, 1993.74Rutter JL, Wacholder S, Chetrit A, et al.: Gynecologic surgeries and risk of ovarian cancer in women with BRCA1 and BRCA2 Ashkenazi founder mutations: an Israeli population-based case-control study. J Natl Cancer Inst 95 (14): 1072-8, 2003.75Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002.76Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.77Narod SA, Risch H, Moslehi R, et al.: Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 339 (7): 424-8, 1998.78Narod SA, Sun P, Ghadirian P, et al.: Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet 357 (9267): 1467-70, 2001.79Whittemore AS, Balise RR, Pharoah PD, et al.: Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer 91 (11): 1911-5, 2004.80McGuire V, Felberg A, Mills M, et al.: Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations. Am J Epidemiol 160 (7): 613-8, 2004.81Ready K, Litton JK, Arun BK: Clinical application of breast cancer risk assessment models. Future Oncol 6 (3): 355-65, 2010.82Amir E, Freedman OC, Seruga B, et al.: Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst 102 (10): 680-91, 2010.83Gail MH, Mai PL: Comparing breast cancer risk assessment models. J Natl Cancer Inst 102 (10): 665-8, 2010.84Claus EB, Risch N, Thompson WD: Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73 (3): 643-51, 1994.85Claus EB, Risch N, Thompson WD: The calculation of breast cancer risk for women with a first degree family history of ovarian cancer. Breast Cancer Res Treat 28 (2): 115-20, 1993.86Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81 (24): 1879-86, 1989.87Domchek SM, Eisen A, Calzone K, et al.: Application of breast cancer risk prediction models in clinical practice. J Clin Oncol 21 (4): 593-601, 2003.88Rubinstein WS, O'Neill SM, Peters JA, et al.: Mathematical modeling for breast cancer risk assessment. State of the art and role in medicine. Oncology (Huntingt) 16 (8): 1082-94; discussion 1094, 1097-9, 2002.89Rhodes DJ: Identifying and counseling women at increased risk for breast cancer. Mayo Clin Proc 77 (4): 355-60; quiz 360-1, 2002.90Gail MH, Costantino JP, Pee D, et al.: Projecting individualized absolute invasive breast cancer risk in African American women. J Natl Cancer Inst 99 (23): 1782-92, 2007.91Schonfeld SJ, Pee D, Greenlee RT, et al.: Effect of changing breast cancer incidence rates on the calibration of the Gail model. J Clin Oncol 28 (14): 2411-7, 2010.92Bondy ML, Lustbader ED, Halabi S, et al.: Validation of a breast cancer risk assessment model in women with a positive family history. J Natl Cancer Inst 86 (8): 620-5, 1994.93Spiegelman D, Colditz GA, Hunter D, et al.: Validation of the Gail et al. model for predicting individual breast cancer risk. J Natl Cancer Inst 86 (8): 600-7, 1994.94Rockhill B, Spiegelman D, Byrne C, et al.: Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst 93 (5): 358-66, 2001.95Costantino JP, Gail MH, Pee D, et al.: Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst 91 (18): 1541-8, 1999.96Bondy ML, Newman LA: Breast cancer risk assessment models: applicability to African-American women. Cancer 97 (1 Suppl): 230-5, 2003.97Gail MH: Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast cancer risk. J Natl Cancer Inst 100 (14): 1037-41, 2008.98Gail MH: Value of adding single-nucleotide polymorphism genotypes to a breast cancer risk model. J Natl Cancer Inst 101 (13): 959-63, 2009.99McTiernan A, Kuniyuki A, Yasui Y, et al.: Comparisons of two breast cancer risk estimates in women with a family history of breast cancer. Cancer Epidemiol Biomarkers Prev 10 (4): 333-8, 2001.100Tyrer J, Duffy SW, Cuzick J: A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 23 (7): 1111-30, 2004.101Antoniou AC, Pharoah PP, Smith P, et al.: The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 91 (8): 1580-90, 2004.102Barlow WE, White E, Ballard-Barbash R, et al.: Prospective breast cancer risk prediction model for women undergoing screening mammography. J Natl Cancer Inst 98 (17): 1204-14, 2006.103Tice JA, Cummings SR, Ziv E, et al.: Mammographic breast density and the Gail model for breast cancer risk prediction in a screening population. Breast Cancer Res Treat 94 (2): 115-22, 2005.
High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes
BRCA1 and BRCA2
Epidemiologic studies have clearly established the role of family history as an important risk factor for both breast and ovarian cancer. After gender and age, a positive family history is the strongest known predictive risk factor for breast cancer. However, it has long been recognized that in some families, there is hereditary breast cancer, which is characterized by an early age of onset, bilaterality, and the presence of breast cancer in multiple generations in an apparent autosomal dominant pattern of transmission (through either the maternal or paternal lineage), sometimes including tumors of other organs, particularly the ovary and prostate gland. It is now known that some of these “cancer families” can be explained by specific mutations in single cancer susceptibility genes. The isolation of several of these genes, which when mutated are associated with a significantly increased risk of breast/ovarian cancer, makes it possible to identify individuals at risk. Although such cancer susceptibility genes are very important, highly penetrant germline mutations are estimated to account for only 5% to 10% of breast cancers overall.
A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families. The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by studies of large kindreds with multiple affected individuals, and has led to the identification of several susceptibility genes, including BRCA1, BRCA2, TP53, PTEN/MMAC1, and STK11. Other genes, such as the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, have been associated with an increased risk of ovarian cancer, but have not been consistently associated with breast cancer.
In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21. The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed. The BRCA1 gene (OMIM) was subsequently identified by positional cloning methods and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Germline mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance of mutations section of this summary for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with mutations in BRCA1; however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with mutations in BRCA2.
A second breast cancer susceptibility gene, BRCA2, was localized to the long arm of chromosome 13 through linkage studies of 15 families with multiple cases of breast cancer that were not linked to BRCA1. Mutations in BRCA2 (OMIM) are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer. (Refer to the Penetrance of mutations section of this summary for more information.) BRCA2 is a large gene with 27 exons that encode a protein of 3,418 amino acids. While not homologous genes, both BRCA1 and BRCA2 have an unusually large exon 11 and translational start sites in exon 2. Like BRCA1, BRCA2 appears to behave like a tumor suppressor gene. In tumors associated with both BRCA1 and BRCA2 mutations, there is often loss of the wild-type (nonmutated) allele.
Mutations in BRCA1 and BRCA2 appear to be responsible for disease in 45% of families with multiple cases of breast cancer only and in up to 90% of families with both breast and ovarian cancer.
BRCA1 and BRCA2 function
Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function, although some missense mutations cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from mutation carriers, deletion of the normal allele results in loss of all function, leading to the classification of BRCA1 and BRCA2 as tumor suppressor genes. In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitination, chromatin remodeling, and cell cycle control.
Mutations in BRCA1 and BRCA2
Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described. Approximately one in 400 to 800 individuals in the general population may carry a pathogenic germline mutation in BRCA1 or BRCA2. The mutations that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that BRCA1 and BRCA2 are tumor suppressor genes. While a small number of these mutations have been found repeatedly in unrelated families, most have not been reported in more than a few families.
Mutation-screening methods vary in their sensitivity. Methods widely used in research laboratories, such as single-stranded conformational polymorphism (SSCP) analysis and conformation-sensitive gel electrophoresis (CSGE), miss nearly a third of the mutations that are detected by DNA sequencing. In addition, large genomic alterations such as translocations, inversions, or large deletions or insertions are missed by most of the techniques, including direct DNA sequencing, but testing for these are commercially available. Such rearrangements are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are less frequently seen in BRCA2 and in individuals of Ashkenazi Jewish descent.
Variants of uncertain significance
Germline deleterious mutations in the BRCA1/BRCA2 genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for BRCA1 or BRCA2; therefore, the classification of nucleotide changes to predict their functional impact as deleterious or benign relies on imperfect data. The majority of accepted deleterious mutations result in protein truncation and/or loss of important functional domains. However, 10% to 15% of all individuals undergoing genetic testing with full sequencing of BRCA1 and BRCA2 will not have a clearly deleterious mutation detected but will have a variant of uncertain (or unknown) significance (VUS). Variants of uncertain significance may cause substantial challenges in counseling, particularly in terms of cancer risk estimates and risk management. Clinical management of such patients needs to be highly individualized and must take into consideration factors such as the patient’s personal and family cancer history, in addition to sources of information to help characterize the VUS as benign or deleterious. Thus an improved classification and reporting system may be of clinical utility.
African Americans appear to have a higher rate of VUS. A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratories, Inc., over a 3-year period. Among subjects who had no clearly deleterious mutation, 13% had VUS defined as “missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins.” The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of subjects with no clear deleterious mutations had sequence alterations that were once considered VUS, but were reclassified as a polymorphism, or occasionally as a deleterious mutation. In a 2009 study of data from Myriad, 16.5% of individuals of African ancestry had VUS, the highest rate among all ethnicities. Over time, the rate of changes classified as VUS has decreased in all ethnicities, largely due to improved mutation classification algorithms. VUS continue to be reclassified as additional information is accumulated. Such information may impact the continuing care of affected individuals.
A number of methods for discriminating deleterious from neutral VUS exist and others are in development  including integrated methods (see below). Interpretation of VUS is greatly aided by efforts to track VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. In general, a VUS observed in individuals who also have a deleterious mutation, especially when the same VUS has been identified in conjunction with different deleterious mutations, is less likely to be in itself deleterious, although there are rare exceptions. As an adjunct to the clinical information, models to interpret VUS have been developed, based on sequence conservation, biochemical properties of amino acid changes, incorporation of information on pathologic characteristics of BRCA1- and BRCA2-related tumors (e.g., BRCA1-related breast cancers are usually estrogen receptor [ER]–negative), and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins. When attempting to interpret a VUS, all available information should be examined.
Population estimates of the likelihood of having a BRCA1 or BRCA2 mutation
Statistics regarding the percentage of individuals found to be BRCA mutation carriers among samples of women and men with a variety of personal cancer histories regardless of family history are provided below. These data can help determine who might best benefit from a referral for cancer genetic counseling and consideration of genetic testing but cannot replace a personalized risk assessment, which might indicate a higher or lower mutation likelihood based on additional personal and family history characteristics.
In some cases, the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect, wherein a mutation identified in a contemporary population can be traced back to a small group of founders isolated by geographic, cultural, or other factors. Most notably, two specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews. However, other founder mutations have been identified in African Americans and Hispanics. The presence of these founder mutations has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. For example, it is estimated that up to 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.
Among the general population, the likelihood of having any BRCA mutation is as follows:
- General population (excluding Ashkenazim): about 1 in 400 (~0.25%).
- Women with breast cancer (any age): 1 in 50 (2%).
- Women with breast cancer (younger than 40 years): 1 in 10 (10%).
- Men with breast cancer (any age): 1 in 20 (5%).
- Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10%–15%).
Among Ashkenazi Jewish individuals, the likelihood of having any BRCA mutation is as follows:
- General Ashkenazi Jewish population: 1 in 40 (2.5%).
- Women with breast cancer (any age): 1 in 10 (10%).
- Women with breast cancer (younger than 40 years): 1 in 3 (30%–35%).
- Men with breast cancer (any age): 1 in 5 (19%).
- Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%–41%).
Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1  and BRCA2  mutations in various ethnic groups. The prevalence of BRCA1 mutations in breast cancer patients by ethnic group was 3.5% in Hispanics, 1.3% to 1.4% in African Americans, 0.5% in Asian Americans, 2.2% to 2.9% in non-Ashkenazi Caucasians, and 8.3% to 10.2% in Ashkenazi Jewish individuals. The prevalence of BRCA2 mutations by ethnic group was 2.6% in African Americans and 2.1% in Caucasians.
A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%. Another study of 108 women with fallopian tube cancer identified mutations in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall). Estimates of the frequency of fallopian tube cancer in BRCA mutation carriers are limited by the lack of precision in the assignment of site of origin for high-grade, metastatic, serous carcinomas at initial presentation.
Clinical criteria and models for prediction of the likelihood of a BRCA1 or BRCA2 mutation
Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer. Personal characteristics associated with an increased likelihood of a BRCA1 and/or BRCA2 mutation include the following:
- Breast cancer diagnosed at an early age. (Some studies use age 40 years, while others use age 50 years as a cutoff.)
- Ovarian cancer.
- Bilateral breast cancer.
- A history of both breast and ovarian cancer.
- Breast cancer diagnosed in a male at any age.
- Triple-negative breast cancer diagnosed in women younger than 50 years.
- Ashkenazi Jewish background.
Family history characteristics associated with an increased likelihood of carrying a BRCA1 and/or BRCA2 mutation include the following:
- Multiple cases of breast cancer.
- Both breast and ovarian cancer.
- One or more breast cancers in male family members.
- Ashkenazi Jewish background.
Clinical criteria for identifying individuals who may have a BRCA1 or BRCA2 mutation
Several professional organizations and expert panels, including the American Society of Clinical Oncology, the National Comprehensive Cancer Network (NCCN), the American Society of Human Genetics, the American College of Medical Genetics, the U.S. Preventive Services Task Force, and the Society of Gynecologic Oncologists, have developed clinical criteria that can be helpful to health care providers in identifying individuals who may have a BRCA1 or BRCA2 mutation.
Models for prediction of the likelihood of a BRCA1 or BRCA2 mutation
Many models have been developed to predict the probability of identifying germline BRCA1/BRCA2 mutations in individuals or families. These models include those using logistic regression, genetic models using Bayesian analysis (BRCAPRO and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA]), and empiric observations, including the Myriad prevalence tables. Two of the earliest models predicted only for BRCA1 mutations and are not clinically useful at this time. More recently, using complex segregation analysis, a polygenetic model (BOADICEA) examining both breast cancer risk and the probability of having a BRCA1 or BRCA2 mutation has been published. Even among experienced providers, the use of prediction models has been shown to increase the power to discriminate which patients are most likely to be identified as BRCA1/BRCA2 mutation carriers. The power of several of the models has been compared in different studies, and currently there is no one model that is consistently superior to others. Most models do not include other cancers seen in the BRCA1 and BRCA2 spectrum such as pancreatic cancer and prostate cancer. Interventions that decrease the likelihood that an individual will develop cancer (such as oophorectomy and mastectomy) may influence the ability to predict BRCA1 and BRCA2 mutation status. One study has shown that the risk models are sensitive to the amount of family history data available and do not perform as well with limited family information.
The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families. There have been variable results in the performance of the BRCAPRO model among Hispanics, and both the BRCAPRO model and Myriad tables underestimated the proportion of mutation carriers in an Asian American population. Further information is needed to determine which model performs best in each ethnic group.
The inclusion of breast tumor markers, such as ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu), has been shown to improve the performance of BRCAPRO and BOADICEA.Table 2. Characteristics of Common Models for Estimating the Likelihood of a BRCA 1/2 MutationMyriad Prevalence Tables BRCAPRO BOADICEA Tyrer-Cuzick AJ = Ashkenazi Jewish; BOADICEA = Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm; FDR = first-degree relatives; SDR = second-degree relatives. MethodEmpiric data from Myriad Genetics based on family and personal history reported on requisition formsStatistical modelStatistical modelStatistical modelFeatures of the ModelProband may or may not have breast or ovarian cancer Proband may or may not have breast or ovarian cancerProband may or may not have breast or ovarian cancerProband must be unaffected Considers age of breast cancer diagnosis as <50 y, >50 y Considers exact age at breast and ovarian cancer diagnosis Considers exact age at breast and ovarian cancer diagnosis Also includes reproductive factors and body mass index to estimate breast cancer risk Considers breast cancer in ≥1 affected relative only if diagnosed <50 y Considers prior genetic testing in family (i.e., BRCA1/BRCA2 mutation–negative relatives) Includes all FDR and SDR with and without cancer Considers ovarian cancer in ≥1 relative at any age Considers oophorectomy status Includes AJ ancestry Includes AJ ancestry Includes all FDR and SDR with and without cancer Very easy to use Includes AJ ancestry LimitationsSimplified/limited consideration of family structureRequires computer software and time-consuming data entry Requires computer software and time-consuming data entryDesigned for individuals unaffected with breast cancer Early age of breast cancer onset Incorporates only FDR and SDR; may need to change proband to best capture risk and to account for disease in the paternal lineage Incorporates only FDR and SDR; may need to change proband to best capture risk May overestimate risk in bilateral breast cancer  May perform better in Caucasians than minority populations 
Genetic testing for BRCA1 and BRCA2 mutations has been available to the public since 1996. As more individuals have undergone testing, risk assessment models have improved. This, in turn, gives providers better data to estimate an individual patient’s risk of carrying a mutation. There remains an art to risk assessment. There are factors that might limit the ability to provide an accurate risk assessment (i.e., small family size, paucity of women, or ethnicity) including the specific circumstances of the individual patient (such as history of disease or prophylactic surgeries).
Penetrance of mutations
The proportion of individuals carrying a mutation who will manifest the disease is referred to as penetrance. For adult-onset diseases, penetrance is usually dependent upon the individual carrier's age and sex. For example, the penetrance for breast cancer in female BRCA1/BRCA2 mutation carriers is often quoted by age 50 years (generally premenopausal) and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual mutation carrier's risk of cancer involves some level of imprecision.
Numerous studies have estimated breast and ovarian cancer penetrance in BRCA1 and BRCA2 mutation carriers. Risk of both breast and ovarian cancer is consistently estimated to be higher in BRCA1 than in BRCA2 mutation carriers. Results from two large meta-analyses are shown in Table 3. One study  analyzed pooled pedigree data from 22 studies involving 289 BRCA1 and 221 BRCA2 mutation–positive individuals. Index cases from these studies had female breast cancer, male breast cancer, or ovarian cancer but were unselected for family history. A subsequent study  combined penetrance estimates from the previous study and nine others that included an additional 734 BRCA1 and 400 BRCA2 mutation–positive families. The estimated cumulative risks of breast cancer by age 70 years in these two meta-analyses were 55% to 65% for BRCA1 and 45% to 47% for BRCA2 mutation carriers. Ovarian cancer risks were 39% for BRCA1 and 11% to 17% for BRCA2 mutation carriers.Table 3. Estimated Cumulative Breast and Ovarian Cancer Risks in BRCA1 and BRCA2 Mutation Carriers StudyBreast cancer risk (%) by age 70 y (95% CI) Ovarian cancer risk (%) by age 70 y (95% CI) CI = confidence interval.BRCA1BRCA2BRCA1BRCA2Antoniou et al. 65 (44–78) 45 (31–56) 39 (18–54) 11 (2.4–19) Chen et al. 55 (50–59) 47 (42–51) 39 (34–45) 17 (13–21)
While the cumulative risks of cancer by age 70 years are higher for BRCA1 than BRCA2 mutation carriers, the relative risks (RR) of breast cancer decline with age more in BRCA1 mutation carriers. Studies of penetrance for carriers of specific individual mutations are not usually large enough to provide stable estimates, but numerous studies of the Ashkenazi founder mutations have been conducted. One group of researchers analyzed the subset of families with one of the Ashkenazi founder mutations from their larger meta-analyses and found that the estimated penetrance for the individual mutations was very similar to the corresponding estimates among all mutation carriers.
One study provided prospective 10-year risks of developing cancer among asymptomatic carriers at various ages. Nonetheless, making precise penetrance estimates in an individual carrier is difficult.
Risk-reducing salpingo-oophorectomy and/or use of oral contraceptives have been shown to alter risk. (Refer to the Risk-reducing salpingo-oophorectomy section and the Oral contraceptives section of this summary for more information.) Other environmental factors being studied include reproductive and hormonal factors. Genetic modifiers of penetrance of breast cancer and ovarian cancer are increasingly under study but are not clinically useful at this time. While the average breast cancer and ovarian cancer penetrances may not be as high as initially estimated, they are substantial, both in relative and absolute terms, particularly in women born after 1940. A higher risk before age 50 years has been consistently seen in more recent birth cohorts, and additional studies will be required to further characterize potential modifying factors to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.
Cancers other than female breast/ovarian
Female breast and ovarian cancers are clearly the dominant cancers associated with BRCA1 and BRCA2. BRCA mutations also confer an increased risk of fallopian tube and primary peritoneal carcinomas. One large study from a familial registry of BRCA1 mutation carriers has found a 120-fold relative risk of tubal cancer among BRCA1 mutation carriers compared with the general population. The risk of primary peritoneal cancer among BRCA mutation carriers with intact ovaries is increased but remains poorly quantified, despite a residual risk of 3% to 4% in the 20 years following risk-reducing salpingo-oophorectomy. (Refer to the Risk-reducing salpingo-oophorectomy section in the Ovarian cancer section of this summary for more information.)
Pancreatic, male breast, and prostate cancers have also been consistently associated with BRCA mutations, particularly with BRCA2. Other cancers have been associated in some studies. The strength of the association of these cancers with BRCA mutations has been more difficult to estimate because of the lower numbers of these cancers observed in mutation carriers.
Men with BRCA2 mutations, and to a lesser extent BRCA1 mutations, are at increased risk of breast cancer with lifetime risks estimated at 5% to 10% and 1% to 2%, respectively. Men carrying BRCA2 mutations, and to a lesser extent BRCA1 mutations, have an approximately threefold to sevenfold increased risk of prostate cancer. BRCA2-associated prostate cancer also appears to be more aggressive. (Refer to the BRCA1 and BRCA2 section in the PDQ summary on Genetics of Prostate Cancer for more information.)
Studies of familial pancreatic cancer (FPC)  and unselected series of pancreatic cancer  have also supported an association with BRCA2, and to a lesser extent, BRCA1. Overall, it appears that between 3% to 15% of families with FPC may have germline BRCA2 mutations, with risks increasing with more affected relatives. Similarly, studies of unselected pancreatic cancers have reported BRCA2 mutation frequencies between 3% to 7%, with these numbers approaching 10% in those of Ashkenazi Jewish descent. The lifetime risk of pancreatic cancer in BRCA2 carriers is estimated to be 3% to 5%  compared with an estimated lifetime risk of 0.5% by age 70 years in the general population. Other cancers associated with BRCA2 mutations in some, but not all, studies include melanoma, biliary cancers, and head and neck cancers, but these risks appear modest (<5% lifetime) and are less well studied.Table 4. Spectrum of Cancers in BRCA1 and BRCA2 Mutation CarriersCancer Sites BRCA1 Mutation CarrierBRCA2 Mutation CarrieraRefer to the PDQ summary on Genetics of Prostate Cancer for more information about the association of BRCA1 and BRCA2 with prostate cancer. +++ Multiple studies demonstrated association and are relatively consistent.++ Multiple studies and the predominance of the evidence are positive.+ May be an association, predominantly single studies; smaller limited studies and/or inconsistent but weighted toward positive.Strength of EvidenceMagnitude of Absolute RiskStrength of EvidenceMagnitude of Absolute RiskBreast (female)+++High+++HighOvary, fallopian tube, peritoneum+++High+++ModerateBreast (male)+Undefined+++LowPancreas++Very Low+++LowProstatea+Undefined+++High
The first Breast Cancer Linkage Consortium study investigating cancer risks reported an excess of colorectal cancer in BRCA1 carriers (RR, 4.1; 95% CI, 2.4–7.2). This finding was supported by some, but not all, family-based studies. However, unselected series of colorectal cancer that have been exclusively performed in the Ashkenazi Jewish population have not shown elevated rates of BRCA1 or BRCA2 mutations. Taken together, the data suggest little, if any, increased risk of colorectal cancer, and possibly only in specific population groups. Therefore, at this time, BRCA1 mutation carriers should adhere to population-screening recommendations for colorectal cancer.
No increased prevalence of hereditary BRCA mutations was found among 200 Jewish women with endometrial carcinoma or 56 unselected women with uterine papillary serous carcinoma. (Refer to the Risk-reducing salpingo-oophorectomy section in the Ovarian cancer section of this summary for more information.)
Cancer risk in individuals who test negative for a known familial BRCA1/BRCA2 mutation
There is conflicting evidence as to the residual familial risk among women who test negative for the BRCA1/BRCA2 mutation segregating in the family. An initial study based on prospective evaluation of 353 women who tested negative for the BRCA1 mutation segregating in the family found that five incident breast cancers occurred during more than 6,000 person-years of observation, for a lifetime risk of 6.8%, a rate similar to the general population. A report that the risk may be as high as fivefold in women who tested negative for the BRCA1 or BRCA2 mutation in the family  was followed by numerous letters to the editor suggesting that ascertainment biases account for much of this observed excess risk.  Three additional analyses have suggested an approximate 1.5-fold to 2-fold excess risk. Several studies have involved retrospective analyses; all studies have been based on small observed numbers of cases and have been of uncertain statistical and clinical significance. No cases of ovarian cancer have been reported in these studies.
Results from numerous other prospective studies have found no increased risk. A study of 375 women who tested negative for a known familial mutation in BRCA1 or BRCA2 reported two invasive breast cancers, two in situ breast cancers, and no ovarian cancers diagnosed, with a mean follow-up of 4.9 years. Four invasive breast cancers were expected, whereas two were observed. Another study of similar size but longer follow-up (395 women and 7,008 person-years of follow-up) also found no statistically significant overall increase in breast cancer risk among mutation-negative women (observed/expected [O/E], 0.82; 95% CI, 0.39–1.51), although women who had at least one first-degree relative with breast cancer had a nonsignificant increased risk (O/E, 1.33; 95% CI, 0.41–2.91). A study of 160 BRCA1 and 132 BRCA2 mutation–positive families from the Breast Cancer Family Registry found no evidence for increased risk among noncarriers in these families. In a large study of 722 mutation-negative women from Australia in whom six invasive breast cancers were observed after a median follow-up of 6.3 years, the standardized incidence ratio (SIR) was not significantly elevated (SIR, 1.14; 95% CI, 0.51–2.53). Based on the currently available data, it appears that women testing negative for known familial BRCA1/BRCA2 mutations can adhere to general population screening guidelines unless they have sufficient additional risk factors, such as a personal history of atypical hyperplasia of the breast or family history of breast cancer in relatives who do not carry the familial mutation.
Breast and ovarian cancer risk in breast cancer families without detectable BRCA1/BRCA2 mutations
The majority of families with site-specific breast cancer test negative for BRCA1/BRCA2 and have no features consistent with Cowden syndrome or Li-Fraumeni syndrome. Three studies using population-based and clinic-based approaches have demonstrated no increased risk of ovarian cancer in such families. Although ovarian cancer risk was not increased, breast cancer risk remained elevated.
Role of BRCA1 and BRCA2 in sporadic cancer
Given that germline mutations in BRCA1 or BRCA2 lead to a very high probability of developing breast and/or ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Although somatic mutations in BRCA1 and BRCA2 are not common in sporadic breast and ovarian cancer tumors, there is increasing evidence that downregulation of BRCA1 protein expression may play a role in these tumor types. Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter. Similar findings have not been reported for BRCA2 mutations, although the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer. Approximately 10% to 15% of sporadic breast cancers appear to have BRCA1 promoter hypermethylation, and even more have downregulation of BRCA1 by other mechanisms. Basal-type breast cancers (ER-negative, PR-negative, HER2-negative, and cytokeratin 5/6–positive) more commonly have BRCA1 dysregulation than other tumor types. BRCA1-related tumor characteristics have also been associated with constitutional methylation of the BRCA1 promoter. In a study of 255 breast cancers diagnosed before age 40 years in women without germline BRCA1 mutations, methylation of BRCA1 in peripheral blood was observed in 31% of women whose tumors had multiple BRCA1-associated pathological characteristics (e.g., high mitotic index and growth pattern including multinucleated cells) compared with less than 4% methylation in controls. (Refer to the BRCA1 pathology section for more information.) Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer, and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease. Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.
Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. None of the studies have had sufficient numbers of mutation-positive individuals to make definitive conclusions, and the findings are probably not sufficiently established to use in individual risk assessment and management. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629. This is the region of the gene containing the BRCA1 C-terminal (BRCT) repeat, which has been shown to specifically interact with RAD51. A study of 164 families with BRCA2 mutations collected by the Breast Cancer Linkage Consortium confirmed the initial finding. Mutations within the ovarian cancer cluster region were associated with an increased risk of ovarian cancer and a decreased risk of breast cancer in comparison to families with mutations on either side of this region. In addition, a study of 356 families with protein-truncating BRCA1 mutations collected by the Breast Cancer Linkage Consortium reported breast cancer risk to be lower with mutations in the central region (nucleotides 2,401–4,190) compared with surrounding regions. Ovarian cancer risk was significantly reduced with mutations 3’ to nucleotide 4,191. These observations have generally been confirmed in subsequent studies. Studies in Ashkenazim, in whom substantial numbers of families with the same mutation can be studied, have also found higher rates of ovarian cancer in carriers of the BRCA1:185delAG mutation, in the 5' end of BRCA1, compared with carriers of the BRCA1:5382insC mutation in the 3' end of the gene. The risk of breast cancer, particularly bilateral breast cancer, and the occurrence of both breast and ovarian cancer in the same individual, however, appear to be higher in BRCA1:5382insC mutation carriers compared with carriers of BRCA1:185delAG and BRCA2:6174delT mutations. Ovarian cancer risk is considerably higher in BRCA1 mutation carriers, and it is uncommon before age 45 years in BRCA2:6174delT mutation carriers.
Pathology of breast cancer
Several studies evaluating pathologic patterns seen in BRCA1-associated breast cancers have suggested an association with adverse pathologic and biologic features. These findings include higher than expected frequencies of medullary histology, high histologic grade, areas of necrosis, trabecular growth pattern, aneuploidy, high S-phase fraction, high mitotic index, and frequent TP53 mutations. In a large international series of 3,797 BRCA1 mutation carriers, the median age at breast cancer diagnosis was 40 years. Of breast tumors arising in BRCA1 carriers, 78% were ER-negative; 79% were PR-negative; 90% were HER2-negative; and 69% were triple-negative. These findings were consistent with multiple smaller series. In addition, the proportion of ER-negative tumors significantly decreased as the age at breast cancer diagnosis increased.
There is considerable, but not complete, overlap between the triple-negative and basal-like subtype cancers, both of which are common in BRCA1-associated breast cancer,  particularly in women diagnosed before age 50 years. A small proportion of BRCA1-related breast cancers are ER-positive, which are associated with later age of onset. These ER-positive cancers have clinical behavior features that are "intermediate" between ER-negative BRCA1 cancers and ER-positive sporadic breast cancers, raising the possibility that there may be a unique mechanism by which they develop.
The prevalence of germline BRCA1 mutations in women with triple-negative breast cancer is significant, both in women undergoing clinical genetic testing (and thus selected in large part for family history) and in unselected triple-negative patients, with mutations reported in 11% to 35%. The highest rate reported was in a clinic-based series in women younger than 30 years with high-grade triple-negative breast cancer. In this small, highly selected population, 35% had BRCA1 mutations. Notably, studies have demonstrated a high rate of BRCA1 mutations in unselected women with triple-negative breast cancer, particularly in those diagnosed before age 50 years. One study examined 308 individuals with triple-negative breast cancer; BRCA1 mutations were present in 45. Mutations were seen both in women unselected for family history (11 of 58; 19%) and in those with family history (26 of 111; 23%). A group of researchers reported results of BRCA1/2 testing in 77 unselected patients with triple-negative breast cancer. Of these, 15 (19.5%) had either a germline BRCA1 (n = 11; 14%) or BRCA2 (n = 3; 4%) mutation or a somatic BRCA1 (n = 1) mutation. The median age at cancer diagnosis was 45 years in BRCA1 mutation carriers and 53 years in noncarriers (P = .005). Interestingly, this study also demonstrated a lower risk of relapse in those with BRCA1 mutation–associated triple-negative breast cancer than in those with nonmutated triple-negative breast cancer, although this study was limited by its size. A second study examining clinical outcomes in BRCA1-associated versus non-BRCA1-associated triple-negative breast cancer showed no difference, although there was a trend toward more brain metastases in those with BRCA1-associated breast cancer. In both of these studies, all but one BRCA1 mutation carrier received chemotherapy. A subsequent study of 199 patients with triple-negative breast cancer recruited through a community oncology practice identified 21 BRCA mutations (10.6%), of which 13 were in BRCA1 and 8 were in BRCA2.
It has been hypothesized that many BRCA1 tumors are derived from the basal epithelial layer of cells of the normal mammary gland, which account for 3% to 15% of unselected invasive ductal cancers. If the basal epithelial cells of the breast represent the breast stem cells, the regulatory role suggested for wild-type BRCA1 may partly explain the aggressive phenotype of BRCA1-associated breast cancer when BRCA1 function is damaged. Further studies are needed to fully appreciate the significance of this subtype of breast cancer within the hereditary syndromes.
The most accurate method for identifying basal-like breast cancers is through gene expression studies, which have been used to classify breast cancers into biologically- and clinically-meaningful groups. This technology has also been shown to correctly differentiate BRCA1- and BRCA2-associated tumors from sporadic tumors in a high proportion of cases. Notably, among a set of breast tumors studied by gene expression array to determine molecular phenotype, all tumors with BRCA1 alterations fell within the basal tumor subtype; however, this technology is not in routine use due to its high cost. Instead, immunohistochemical markers of basal epithelium have been proposed to identify basal-like breast cancers, which are typically negative for ER, progesterone receptor, and HER2, and stain positive for cytokeratin 5/6, or epidermal growth factor receptor. Based on these methods to measure protein expression, a number of studies have shown that the majority of BRCA1-associated breast cancers are positive for basal epithelial markers.
There is growing evidence that preinvasive lesions are a component of the BRCA phenotype. The Breast Cancer Linkage Consortium initially reported a relative lack of an in situ component in BRCA1-associated breast cancers, also seen in two subsequent studies of BRCA1/BRCA2 carriers. However, in a study of 369 ductal carcinoma in situ (DCIS) cases, BRCA1 and BRCA2 mutations were detected in 0.8% and 2.4%, respectively, which is only slightly lower than previously reported prevalence in studies of invasive breast cancer patients. A retrospective study of breast cancer cases in a high-risk clinic found similar rates of preinvasive lesions, particularly DCIS, among 73 BRCA-associated breast cancers and 146 mutation-negative cases. A study of Ashkenazi Jewish women, stratified by whether they were referred to a high-risk clinic or were unselected, showed similar prevalence of DCIS and invasive breast cancers in referred patients compared with one-third lower DCIS cases among unselected subjects. Similarly, data about the prevalence of hyperplastic lesions have been inconsistent, with reports of increased and decreased prevalence. Similar to invasive breast cancer, DCIS diagnosed at an early age and/or with a family history of breast and/or ovarian cancer is more likely to be associated with a BRCA1/BRCA2 mutation.
Overall evidence suggests DCIS is part of the BRCA1/BRCA2 spectrum, particularly BRCA2; however, the prevalence of mutations in DCIS patients, unselected for family history, is less than 5%.
The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well-characterized than that of BRCA1, although they are generally positive for ER and PR. A large international series of 2,392 BRCA2 mutation carriers found that only 23% of tumors arising in BRCA2 mutation carriers were ER-negative; 36% were PR-negative; 87% were HER2-negative; and 16% were triple-negative. A report from Iceland found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors than in sporadic controls; however, a single BRCA2 founder mutation (999del5) accounts for nearly all hereditary breast cancer in this population, thus limiting the generalizability of this observation. A large case series from North America and Europe described a greater proportion of BRCA2-associated tumors with continuous pushing margins, fewer tubules and lower mitotic counts. Other reports suggest that BRCA2-related tumors include an excess of lobular and tubulolobular histology. In summary, histologic characteristics associated with BRCA2 mutations have been inconsistent.
Pathology of ovarian cancer
Ovarian cancer arising in women with BRCA1 and BRCA2 mutations is more likely to be invasive serous adenocarcinoma and less likely to be mucinous or borderline. Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease. Approximately 60% of sporadic ovarian cancers have serous histology, but a survey of all published data shows that 94% of BRCA1-related ovarian cancers have this type of histology. Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/BRCA2 carriers in a Dutch case-control study. In contrast to high-grade serous ovarian cancer, low-grade serous ovarian cancer is not likely to be part of the spectrum of BRCA1- or BRCA2-related ovarian cancer. Both primary ovarian carcinomas and primary peritoneal carcinomas have a higher incidence of somatic TP53 mutations and exhibit relatively aggressive features, including higher grade and p53 overexpression. The histopathologic profile of BRCA2-related ovarian cancer has not been well defined. The finding of differential expression of genes in BRCA1, BRCA2, and sporadic ovarian cancer, using DNA microarray technology, suggests distinct molecular pathways of carcinogenesis that may ultimately distinguish them histologically. Furthermore, there have been data to suggest that BRCA-related ovarian cancers that relapse frequently metastasize to viscera, while relapsed sporadic ovarian cancers commonly remain confined to the peritoneum.
Histopathologic examinations of fallopian tubes removed prophylactically from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that are accompanied by changes in cell-cycle and apoptosis-related proteins, suggesting a premalignant phenotype. Occult carcinomas have been reported in 2% to 11% of the adnexa removed at the time of risk-reducing surgery from BRCA mutation carriers. The majority of these occult carcinomas are seen within the fallopian tube, which has led to the hypothesis that many BRCA-associated ovarian cancers may actually have originated in the fallopian tube. Specifically, the distal segment of the fallopian tube (fimbriae) has been implicated as a common origin for the high-grade serous cancers seen in BRCA mutation carriers based on its close proximity to the ovarian surface and peritoneal cavity and its large surface area.
Clinical management of BRCA mutation carriers
Few data exist on the outcomes of interventions to reduce risk in people with a genetic susceptibility to breast or ovarian cancer. As a result, recommendations for management are primarily based on expert opinion. In addition, as outlined in other sections of this summary, uncertainty is often considerable regarding the level of cancer risk associated with a positive family history or genetic test. In this setting, personal preferences are likely to be an important factor in patients’ decisions about risk reduction strategies.
Screening and Prevention Strategies
Refer to the PDQ summary on Breast Cancer Screening for information on screening in the general population, and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information on levels of evidence related to screening and prevention.
In the general population, evidence for the value of breast self-examination (BSE) is limited. Preliminary results have been reported from a randomized study of BSE being conducted in Shanghai, China. At 5 years, no reduction in breast cancer mortality was seen in the BSE group compared with the control group of women, nor was a substantive stage shift seen in breast cancers that were diagnosed. (Refer to the PDQ summary on Breast Cancer Screening for more information.)
Little direct prospective evidence exists regarding BSE in individuals with an increased risk of breast cancer. In the Canadian National Breast Screening Study, women with first-degree relatives with breast cancer had statistically significantly higher BSE competency scores than those without a family history. In a study of 251 high-risk women at a referral center, five breast cancers were detected by self-examination less than a year after a previous screen (as compared with one cancer detected by clinician exam and 11 cancers detected as a result of mammography). Women in the cohort were instructed in self-examination, but it is not stated whether the interval cancers were detected as a result of planned self-examination or incidental discovery of breast masses. In another series of BRCA1/BRCA2 mutation carriers, four of nine incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting the potential value of self-examination. A task force convened by the Cancer Genetics Studies Consortium has recommended “monthly self-examination beginning early in adult life (e.g., by age 18–21 years) to establish a regular habit and allow familiarity with the normal characteristics of breast tissue. Education and instruction in self-examination are recommended.”
Level of evidence: 5
Clinical breast examination
Few prospective data exist regarding clinical breast examination (CBE).
The Cancer Genetics Studies Consortium task force concluded, “As with self-examination, the contribution of clinical examination may be particularly important for women at inherited risk of early breast cancer.” They recommended that female carriers of a BRCA1 or BRCA2 high-risk mutation undergo annual or semiannual clinical examinations beginning at age 25 to 35 years.
In the general population, strong evidence suggests that regular mammography screening of women aged 50 to 59 years leads to a 25% to 30% reduction in breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.) For women who begin mammographic screening at age 40 to 49 years, a 17% reduction in breast cancer mortality is seen, which occurs 15 years after the start of screening. Observational data from a cohort study of more than 28,000 women suggest that the sensitivity of mammography is lower for young women. In this study, the sensitivity was lowest for younger women (aged 30–49 years) who had a first-degree relative with breast cancer. For these women, mammography detected 69% of breast cancers diagnosed within 13 months of the first screening mammography. By contrast, sensitivity for women younger than 50 years without a family history was 88% (P = .08). For women aged 50 years and older, sensitivity was 93% at 13 months and did not vary by family history. Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers. Subsequent observational studies have found that the positive predictive value (PPV) of mammography increases with age and is highest among older women and among women with a family history of breast cancer. Higher PPVs may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity. One study found an association between the presence of pushing margins (a histopathologic description of a pattern of invasion) and false-negative mammograms in 28 women, 26 of whom had a BRCA1 mutation and two of whom had a BRCA2 mutation. Pushing margins, characteristic of medullary histology, are associated with an absence of fibrotic reaction. In addition, rapid tumor doubling times may lead to tumors presenting shortly after an apparently normal study. In one study, mean tumor doubling time in BRCA1/BRCA2 carriers was 45 days, compared with 84 days in noncarriers. Another study that evaluated mammographic breast density in women with BRCA mutations found no association between mutation status and mammographic density; however, in both carriers and noncarriers, increased breast density was associated with increased breast cancer risk.
The randomized Canadian National Breast Screening Study-2 (NBSS2) compared annual CBE plus mammography to CBE alone in women aged 50 to 59 years from the general population. Both groups were given instruction in BSE. Although mammography detected smaller primary invasive tumors and more invasive and ductal carcinomas in situ (DCIS) than CBE, the breast cancer mortality rates in the CBE-plus-mammography group and the CBE- alone group were nearly identical, and compared favorably with other breast cancer screening trials. After a mean follow-up of 13 years (range 11.3–16.0 years), the cumulative breast cancer mortality ratio was 1.02 (95% confidence interval [CI] = 0.78–1.33). One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE.
Digital mammography refers to the use of a digital detector to find and record x-ray images. This technology improves contrast resolution, and has been proposed as a potential strategy for improving the sensitivity of mammography. A screening study comparing digital with routine mammography in 6,736 examinations of women aged 40 years and older found no difference in cancer detection rates; however, digital mammography resulted in fewer recalls. In another study (ACRIN-6652) comparing digital mammography to plain-film mammography in 42,760 women, the overall diagnostic accuracy of the two techniques was similar. When receiver operating characteristic curves were compared, digital mammography was more accurate in women younger than 50 years, in women with radiographically dense breasts, and in premenopausal or perimenopausal women.
In a prospective study of 251 individuals with BRCA mutations who received uniform recommendations regarding screening and risk-reducing, or prophylactic, surgery, annual mammography detected breast cancer in six women at a mean of 20.2 months after receipt of BRCA results. The Cancer Genetics Studies Consortium task force has recommended for female carriers of a BRCA1 or BRCA2 high-risk mutation, “annual mammography, beginning at age 25 to 35 years. Mammograms should be done at a consistent location when possible, with prior films available for comparison.” Data from prospective studies on the relative benefits and risks of screening with an ionizing radiation tool versus CBE or other nonionizing radiation tools would be useful.
Certain observations have led to the concern that BRCA mutation carriers may be more prone to radiation-induced breast cancer than women without mutations. The BRCA1 and BRCA2 proteins are known to be important in cellular mechanisms of DNA damage repair, including those involved in repairing radiation-induced damage. Some studies have suggested intermediate radiation sensitivity in cells that are heterozygous for a BRCA mutation, but this is not consistent and varies by experimental system and endpoint.
Two studies failed to find convincing evidence of an association between ionizing radiation exposure and breast cancer risk in BRCA1 and BRCA2 mutation carriers.  In contrast, two large international studies found evidence of an increased breast cancer risk due to chest x-rays  or estimates of total exposure to diagnostic radiation. A large international case-control study of 1,601 mutation carriers described an increased risk of breast cancer (hazard ratio [HR], 1.54) among women who were ever exposed to chest x-rays, with risk being highest in women aged 40 years and younger, born after 1949, and exposed to x-rays only before age 20 years. Some of the subjects in this study were also included in a larger, more comprehensive analysis of mutation carriers from three European centers. In that study of 1,993 BRCA1 and BRCA2 mutation carriers from the United Kingdom, France, and the Netherlands, age-specific total diagnostic radiation exposure (e.g., chest x-rays, mammography, fluoroscopy, and computed tomography) estimates were derived from self-reported questionnaires. Women exposed before age 30 years had an increased risk (HR, 1.90; 95%, CI 1.20–3.00), compared with those never exposed. This risk was primarily driven by nonmammographic radiation exposure in women younger than age 20 years (HR, 1.62; 95% CI, 1.02–2.58).
With the routine use of magnetic resonance imaging (MRI) in BRCA1 and BRCA2 mutation carriers, any potential benefit of mammographic screening must be carefully weighed against potential risks, particularly in young women. One study has suggested that the most cost-effective screening strategy in BRCA1 and BRCA2 mutation carriers may be annual MRI beginning at age 25 years, with alternating MRI and digital mammography (so that each test is done annually but screening occurs every 6 months) beginning at age 30 years. NCCN currently recommends annual mammography and MRI screening beginning at age 25 years.
Magnetic resonance imaging
Because of the relative insensitivity of mammography in women with an inherited risk of breast cancer, a number of screening modalities have been proposed and investigated in high-risk women, including BRCA mutation carriers. Several studies have described the experience with breast MRI screening in women at risk of breast cancer, including descriptions of relatively large multi-institutional trials. Several considerations must be kept in mind when reviewing these reports:
- The studies are variable in terms of the underlying population being studied, equipment and signal processing protocols, the manner of reporting results, and the manner in which sensitivity and specificity are calculated.
- The different screening tests (MRI and mammogram with or without ultrasound) are performed nearly simultaneously in these studies, and the screening modalities are compared to each other. Therefore, sensitivity is defined somewhat differently in these studies than in the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) of follow-up and outcome reporting.
- The number of screening rounds is limited, and the distinction between prevalent (first round) and incident cancer detection rates is often unclear.
Despite these caveats, the reported studies consistently demonstrate that breast MRI is more sensitive than either mammography or ultrasound for the detection of hereditary breast cancer. The results of six large studies are presented in Table 5, Summary of MRI Screening Studies in Women at Hereditary Risk of Breast Cancer. Most cancers in these programs were screen detected with only 6% of cancers presenting in the interval between screenings. The sensitivity of MRI (as defined by the study methodology) ranged from 71% to 100%. Of the combined studies, 77% of the cancers were identified by MRI, and 42% were identified by mammography.
Concerns have been raised about the reduced specificity of MRI compared with other screening modalities. In one study, after the initial MRI screen, 16.5% of the patients were recalled for further evaluation, and 7.6% of subjects were recommended to undergo a short-interval follow-up examination at 6 months. These rates declined significantly during later screening rounds, with fewer than 10% of the subjects recalled for more detailed MRI and fewer than 3% recommended to have short interval follow-up. In a second study, Magnetic Resonance Imaging for Breast Screening (MARIBS), the recall rate for additional evaluation was 10.7% per year. The benign biopsy rates in the first study were 11% at first round, 6.6% at second round, and 4.7% at third round. In the MARIBS study, the aggregate surgical biopsy rate was 9 per 1,000 screening episodes, though this may underestimate the burden because follow-up ultrasounds, core-needle biopsies, and fine-needle aspirations have not been included in the numerator of the MARIBS calculation. The PPV of MRI has been calculated differently in the various series and fluctuates somewhat, depending on whether all abnormal examinations or only the examinations that result in a biopsy are counted in the denominator. Generally, the PPV of a recommendation for tissue sampling (as opposed to further investigation) is in the range of 50% in most series.
These trials appear to establish that MRI is superior to mammography in the detection of hereditary breast cancer, and that women participating in these trials including annual MRI screening were less likely to have a cancer missed by screening. However, mammography identifies some cancers, particularly DCIS, that are not identified by MRI. While MRI does appear to be more sensitive than mammogram, it is unknown whether MRI screening results in a survival benefit or even in downstaging compared with mammography alone. One screening study demonstrated that patients were more likely to be diagnosed with small tumors and node-negative disease than women in two nonrandomized control groups. However, a randomized study of screening with or without MRI using tumor stage or mortality as an endpoint has not been performed. Despite the apparent sensitivity of MRI screening, some women in MRI-based programs will nevertheless develop life-threatening breast cancer. In a prospective study of 51 BRCA1 and 41 BRCA2 mutation carriers screened with yearly mammograms and MRIs (of whom 80 had prophylactic oophorectomy), 11 breast cancers (9 invasive and 2 DCIS) were detected. Six cancers were first detected on MRI, three were first detected by mammogram, and two were interval cancers. All breast cancers occurred in BRCA1 mutation carriers, suggesting a continued high risk of BRCA1-related breast cancer following oophorectomy in the short term. These results suggest that surveillance and prevention strategies may have differing outcomes in BRCA1 and BRCA2 mutation carriers. The American Cancer Society and NCCN have recommended the use of annual MRI screening for women at hereditary risk of breast cancer.
An additional question regarding the timing of mammography and MRI is whether they should be done simultaneously or in an alternating fashion (so that while each test is done annually, screening occurs every 6 months). One study has suggested that the most cost-effective screening strategy in BRCA1 and BRCA2 mutation carriers may be annual MRI beginning at age 25 years, with alternating MRI and digital mammography beginning at age 30 years.Table 5. Summary of Magnetic Resonance Imaging (MRI) Screening Studies in Women at Hereditary Risk of Breast Cancer SeriesRijnsburger Warner MARIBS Kuhl Weinstein Sardanelli TotalsaBased upon the first 1,909 women screened.bIncludes patients with invasive cancer only and patients with both invasive and in situ cancers.cIncludes only 75 cancers detected in women who underwent both mammographic and MRI screening.dRestricted to studies in which ultrasound was performed.N PatientsOverall2,1572366496876095014,839BRCA1/BRCA2 Carriers59423612065443301,389N Screening Episodes6,2534571,8811,6791,59211,862N CancersBaseline 22a1320100065Subsequent97915171852208Invasiveb78162981144186In situ199697858Annual Incidence10.4/1,00019/1,000Detected at Planned Screening782133271849226 (83%)N Detected by Each ModalityMammography31c814972594 (42%)MRI51c1727251242174 (77%)Ultrasoundd71032646 (41%)Follow-up Median of 4.9 yMinimum of 1 y2–7 yMedian of 29.09 mo2 y3 y
Level of evidence: 3
Several studies have reported instances of breast cancer detected by ultrasound that were missed by mammography, as discussed in one review. In a pilot study of ultrasound as an adjunct to mammography in 149 women with moderately increased risk based on family history, one cancer was detected, based on ultrasound findings. Nine other biopsies of benign lesions were performed. One was based on abnormalities on both mammography and ultrasound, and the remaining eight were based on abnormalities on ultrasound alone. A large study of 2,809 women with dense breast tissue (ACRIN-6666) demonstrated that ultrasound increased the detection rate due to breast cancer screening from 7.6 per 1,000 with mammography alone to 11.8 per 1,000 for combined mammography and ultrasound. However, ultrasound screening increases false-positive rates and appears to have a limited benefit in combination with MRI. In a multicenter study of 171 women (92% of whom were BRCA1/BRCA2 mutation carriers) undergoing simultaneous mammography, MRI, and ultrasound, no cancers were detected by ultrasound alone. Uncertainties about ultrasound include the effect of screening on mortality, the rate and outcome of false-positive results, and access to experienced breast ultrasonographers.
Level of evidence: None assigned
Other screening modalities
A number of other techniques are under active investigation, including tomosynthesis, contrast-enhanced mammography, thermography, and radionuclide scanning. Additional evidence is needed before these techniques can be incorporated into clinical practice.
In the general population, both subcutaneous mastectomy and simple (total) mastectomy have been used for prophylaxis. Only 90% to 95% of breast tissue is removed with subcutaneous mastectomy. In a total or simple mastectomy, removal of the nipple-areolar complex increases the proportion of breast tissue removed compared with subcutaneous mastectomy. However, some breast tissue is usually left behind with both procedures. The risk of breast cancer following either of these procedures has not been well established.
The effectiveness of risk-reducing mastectomy (RRM) in women with BRCA1 or BRCA2 mutations has been evaluated in several studies. In one retrospective cohort study of 214 women considered to be at hereditary risk by virtue of a family history suggesting an autosomal dominant predisposition, three women were diagnosed with breast cancer after bilateral RRM, with a median follow-up of 14 years. As 37.4 cancers were expected, the calculated risk reduction was 92% (95% CI, 76.6–98.3). In a follow-up subset analysis, 176 of the 214 high-risk women in this cohort study underwent mutation analysis of BRCA1 and BRCA2. Mutations were found in 26 women (18 deleterious, eight variants of uncertain significance). None of those women had developed breast cancer after a median follow-up of 13.4 years. Two of the three women diagnosed with breast cancer after RRM were tested, and neither carried a mutation. The calculated risk reduction among mutation carriers was 89.5% to 100% (95% CI, 41.4%–100%), depending on the assumptions made about the expected numbers of cancers among mutation carriers and the status of the untested woman who developed cancer despite mastectomy. The result of this retrospective cohort study has been supported by a prospective analysis of 76 mutation carriers undergoing RRM and followed prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas eight were identified in women undergoing regular surveillance (HR for breast cancer after RRM, 0 [95% CI, 0–0.36]).
The Prevention and Observation of Surgical End Points (PROSE) study group estimated the degree of breast cancer risk reduction after RRM in BRCA1/BRCA2 mutation carriers. The rate of breast cancer in 105 mutation carriers who underwent bilateral RRM was compared with that in 378 mutation carriers who did not choose surgery. Bilateral mastectomy reduced the risk of breast cancer after a mean follow-up of 6.4 years by approximately 90%.
Another study evaluated the effectiveness of contralateral RRM in affected women with hereditary breast cancer. In a group of 148 BRCA1 or BRCA2 mutation carriers, 79 of whom underwent RRM, the risk of contralateral cancer was reduced by 91% and was independent of the effect of risk-reducing oophorectomy. Survival was better among women undergoing RRM, but this result was apparently associated with higher mortality due to the index cancer or metachronous ovarian cancer in the group not undergoing surgery. More recently, data from ten European centers on 550 women indicated that RRM was highly effective.
Studies describing histopathologic findings in RRM specimens from women with BRCA1 or BRCA2 mutations have been somewhat inconsistent. In two series, proliferative lesions associated with an increased risk of breast cancer (lobular carcinoma in situ, atypical lobular hyperplasia, atypical ductal hyperplasia, DCIS) were noted in 37% to 46% of women with mutations undergoing either unilateral or bilateral RRM. In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of risk-reducing bilateral or contralateral mastectomies performed in known BRCA1 or BRCA2 mutation carriers from Australia, three (6%) cancers were detected at surgery. In a study from Sweden among 100 women with a hereditary risk of breast cancer, unsuspected lesions were found in 13 out of 50 BRCA1/BRCA2 mutation carriers. These findings were not replicated in a third retrospective cohort study. In this study, proliferative fibrocystic changes were noted in none of 11 bilateral mastectomies from patients with deleterious mutations and in only two of seven contralateral unilateral risk-reducing mastectomies in affected mutation carriers.
Although data are sparse, the evidence to date indicates that while a substantial proportion of women with a strong family history of breast cancer are interested in discussing RRM as a treatment option, uptake varies according to culture, geography, health care system, insurance coverage, provider attitudes, and other social factors. For example, in one setting where the providers made one to two field trips to family gatherings for family information sessions and individual counseling, only 3% of unaffected carriers obtained RRM within 1 year of follow-up. Among women at increased risk of breast cancer due to family history, fewer than 10% opted for mastectomy. Selection of this option was related to breast cancer–related worry as opposed to objective risk parameters (e.g., number of relatives with breast cancer). In contrast, in a Dutch study of highly motivated women being followed every 6 months at a high-risk center, more than half (51%) of unaffected carriers opted for RRM. Almost 90% of the RRM surgeries were performed within 1 year of DNA testing. In this study, those most likely to have RRM were women younger than 55 years and with children. In addition, self-perceived risk has been closely linked to interest in RRM.
Assuming risk reduction in the range of 90%, a theoretical model suggests that for a group of 30-year-old women with BRCA1 or BRCA2 mutations, RRM would result in an average increased life expectancy of 2.9 to 5.3 years. While these data are useful for public policy decisions, they cannot be individualized for clinical care as they include assumptions that cannot be fully tested. Another study of at-risk women showed a 70% time-tradeoff value, indicating that the women were willing to sacrifice 30% of life expectancy in order to avoid RRM. A cost-effectiveness analysis study estimated that risk-reducing surgery (mastectomy and oophorectomy) is cost-effective compared with surveillance with regard to years of life saved, but not for improved quality of life.
A computer-simulated survival analysis using a Monte Carlo model included breast MRI, mammography, RRM, and risk-reducing salpingo-oophorectomy (RRSO) and examined the impact of each of these on BRCA1 and BRCA2 mutation carriers separately. The most effective strategy was found to be RRSO at age 40 years and RRM at age 25 years, in which case survival at age 70 years approached that of the general population. However, delaying mastectomy until age 40 years, or substituting RRM with screening with breast MRI and mammogram, had little impact on survival estimates. For example, replacing RRM with MRI-based screening in women with RRSO at age 40 years led to a 3% to 5% decrement in survival compared to RRM at age 25 years. The authors have developed an online tool. As with any model, uncertainty remains due to numerous assumptions; however, this provides additional information for women and their providers who are making these difficult decisions.
The Society of Surgical Oncology has endorsed RRM as an option for women with BRCA1/BRCA2 mutations or strong family histories of breast cancer.
Individual psychological factors have an important role in decision-making about RRM by unaffected women. Research is emerging about psychosocial outcomes of RRM. (Refer to the Psychosocial Outcome Studies section of this summary for more information.)
Level of evidence: 3aii
Risk-reducing salpingo-oophorectomy (RRSO)
In the general population, removal of both ovaries has been associated with a reduction in breast cancer risk of up to 75%, depending on parity, weight, and age at time of artificial menopause. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) A Mayo Clinic study of 680 women at various levels of familial risk found that in women younger than 60 years who had bilateral oophorectomy, the likelihood of breast cancers developing was reduced for all risk groups. Ovarian ablation, however, is associated with important side effects such as hot flashes, impaired sleep habits, vaginal dryness, dyspareunia, and increased risk of osteoporosis and heart disease. A variety of strategies may be necessary to counteract the adverse effects of ovarian ablation.
In support of early small studies, a retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (HR, 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR, 0.04; 95% CI, 0.01–0.16) after RRSO. A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend. With RRSO, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74). A prospective multicenter study of 1,079 women followed for a median of 30 to 35 months found that while RRSO was associated with reductions in breast cancer risk in both BRCA1 and BRCA2 mutation carriers, the risk reduction was more pronounced in BRCA2 carriers (HR, 0.28; 95% CI, 0.08–0.92). A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in BRCA1/BRCA2 mutation carriers confirmed that RRSO was associated with a significant reduction in breast cancer risk (overall: HR, 0.49; 95% CI, 0.37–0.65; BRCA1: HR, 0.47; 95% CI, 0.35–0.64; BRCA2: HR, 0.47; 95% CI, 0.26–0.84).
In addition to the reduction in incidence of both breast and ovarian cancer, a prospective multicenter cohort study of 2,482 BRCA1/BRCA2 mutation carriers has reported an association of RRSO with a reduction in all-cause mortality (HR, 0.40; 95% CI, 0.26–0.61), breast cancer–specific mortality (HR, 0.44; 95% CI, 0.26–0.76), and ovarian cancer–specific mortality (HR, 0.21; 95% CI, 0.06–0.80).
Level of evidence: 3ai
Tamoxifen (a synthetic antiestrogen) increases breast-cell growth inhibitory factors and concomitantly reduces breast-cell growth stimulatory factors. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP-P-1), a prospective, randomized, double-blind trial, compared tamoxifen (20 mg/day) with placebo for 5 years. Tamoxifen was shown to reduce the risk of invasive breast cancer by 49%. The protective effect was largely confined to estrogen receptor–positive breast cancer, which was reduced by 69%. The incidence of estrogen receptor–negative cancer was not significantly reduced. Similar reductions were noted in the risk of preinvasive breast cancer. Reductions in breast cancer risk were noted both among women with a family history of breast cancer and in those without a family history. An increased incidence of endometrial cancers and thrombotic events occurred among women older than 50 years. Interim data from two European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months  or 70 months, respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used hormone replacement therapy (HRT). These trials varied considerably in study design and populations. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
A substudy of the NSABP-P-1 trial evaluated the effectiveness of tamoxifen in preventing breast cancer in BRCA1/BRCA2 mutation carriers older than 35 years. BRCA2-positive women benefited from tamoxifen to the same extent as BRCA1/BRCA2 mutation–negative participants; however, tamoxifen use among healthy women with BRCA1 mutations did not appear to reduce breast cancer incidence. These data must be viewed with caution in view of the small number of mutation carriers in the sample (8 BRCA1 carriers and 11 BRCA2 carriers).
Level of evidence: 1
In contrast to the very limited data on primary prevention in BRCA1 and BRCA2 mutation carriers with tamoxifen, several studies have found a protective effect of tamoxifen on the risk of contralateral breast cancer. In one study involving approximately 600 BRCA1/BRCA2 mutation carriers, tamoxifen use was associated with a 51% reduction in contralateral breast cancer. An update to this report examined 285 BRCA1/BRCA2 mutation carriers with bilateral breast cancer and 751 BRCA1/BRCA2 mutation carriers with unilateral breast cancer (40% of these patients were included in their initial study). Tamoxifen was associated with a 50% reduction in contralateral breast cancer risk in BRCA1 mutation carriers and a 58% reduction in BRCA2 mutation carriers. Tamoxifen did not appear to confer benefit in women who had undergone an oophorectomy, although the numbers in this subgroup were quite small. Another study involving 160 BRCA1/BRCA2 mutation carriers demonstrated that tamoxifen use following treatment of breast cancer with lumpectomy and radiation was associated with a 69% reduction in the risk of contralateral breast cancer. These studies are limited by their retrospective, case-control designs and the absence of information regarding estrogen-receptor status in the primary tumor.
The STAR trial (NSABP-P-2) included more than 19,000 women and compared 5 years of raloxifene versus tamoxifen in reducing the risk of invasive breast cancer.  There was no difference in incidence of invasive breast cancer at a mean follow-up of 3.9 years; however, there were fewer noninvasive cancers in the tamoxifen group. The incidence of thromboembolic events and hysterectomy was significantly lower in the raloxifene group. Detailed quality of life data demonstrate slight differences between the two arms. Data regarding efficacy in BRCA1 or BRCA2 mutation carriers are not available.
The effect of tamoxifen on ovarian cancer risk was studied in 714 BRCA1 mutation carriers. All subjects had a prior history of breast cancer; use of tamoxifen was not associated with an increased risk of subsequent ovarian cancer (OR, 0.78; 95% CI, 0.46–1.33).
Level of evidence: 1
Pregnancy and lactation
In the general population, breast cancer risk increases with early menarche and late menopause, and is reduced at early first full-term pregnancy. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) In the Nurses’ Health Study, these were risk factors among women who did not have a mother or sister with breast cancer. Among women with a family history of breast cancer, pregnancy at any age appeared to be associated with an increase in risk of breast cancer, persisting to age 70 years.
One study evaluated risk modifiers among 333 female carriers of a BRCA1 high-risk mutation. In women with known mutations of the BRCA1 gene, early age at first live birth and parity of three or more have been associated with a lowered risk of breast cancer. A relative risk (RR) of 0.85 was estimated for each additional birth, up to five or more; however, increasing parity appeared to be associated with an increased risk of ovarian cancer. In a case-control study from New Zealand, investigators noted no difference in the impact of parity upon the risk of breast cancer between women with a family history of breast cancer and those without a family history.
Studies of the effect of pregnancy on breast cancer risk have revealed complex results and the relationship with parity has been inconsistent and may vary between BRCA1 and BRCA2 mutation carriers. Parity has more consistently been associated with a reduced risk of breast cancer in BRCA1 mutation carriers. Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.
Level of evidence: 4aii
In the general population, breastfeeding has been associated with a slight reduction in breast cancer risk in a few studies, including a large collaborative reanalysis of multiple epidemiologic studies, and at least one study suggests that it may be protective in BRCA1 mutation carriers. In a multicenter breast cancer case-control study of 685 BRCA1 and 280 BRCA2 mutation carriers with breast cancer and 965 mutation carriers without breast cancer drawn from multiple-case families, among BRCA1 mutation carriers, breastfeeding for one year or more was associated with approximately a 45% reduced risk of breast cancer. No such reduced risk was observed among BRCA2 mutation carriers. A second study failed to confirm this association.
There is no consistent evidence that the use of oral contraceptives (OCs) increases the risk of breast cancer in the general population. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
Although several smaller studies have reported a slightly increased risk of breast cancer with OC use in BRCA1/BRCA2 mutation carriers, a meta-analysis concluded that the associated risk is not significant with more recent OC formulations. However, OCs formulated before 1975 were associated with an increased risk of breast cancer. A large proportion of patients upon which this meta-analysis was based were drawn from three large studies summarized in Table 6.Table 6. Oral Contraceptive (OC) Use and Breast Cancer Risk in BRCA1/BRCA2 Mutation Carriers Brohet 2007a Haile 2006b,c  Narod 2002b  CI = confidence interval.aReports risk estimates in the form of hazard ratios with 95% confidence intervals.bReports risk estimates in the form of odds ratios with 95% confidence intervals.cRisk estimates restricted to BRCA mutation carriers younger than 40 years.Study Population BRCA1 Carriers with Breast CancerN = 597 N = 195; diagnosis < age 50 y N = 981 BRCA2 Carriers with Breast CancerN = 249 N = 128; diagnosis < age 50 yN = 330 Ever Use OCBRCA11.47 [CI 1.13–1.91] 0.64 [CI 0.35–1.16]1.38 [CI 1.11–1.72] P = .003a BRCA2 1.49 [Cl 0.8–2.7] 1.29 [Cl 0.61–2.76]0.94 [Cl 0.72–1.24] Age Use < 20 yBRCA11.41 [Cl 0.99–2.01] 0.84 [Cl 0.45–1.55]1.36 [Cl 1.11–1.67] P = .003 BRCA21.25 [Cl 0.57–2.74] 1.64 [Cl 0.77–3.46]Not reported Total DurationBRCA1<9 y: 1.51 [Cl 1.1–2.08] <5 y: 0.61 [Cl 0.31–1.17] <10 y: 1.36 [Cl 1.11–167] P = .003 BRCA2<9 y: 2.27 [Cl 1.1–4.65] <5 y: 0.79 [Cl 0.26–2.37]<10 y: 0.82 [Cl 0.56–1.91]Use Before Full-term PregnancyBRCA1>4 y: 1.49 [Cl 1.05–2.11] >4 y: 0.69 [Cl 0.41–1.16] Not evaluatedBRCA2>4 y: 2.58 [Cl 1.21–5.49] >4 y: 2.08 [Cl 1.02–4.25] trend per y: 1.11; P trend = .01Use Before 1975 BRCA11.48 [Cl 1.11–1.98] Excluded patients who used OC before 1975 1.42 [Cl 1.17–1.75] P < .001 BRCA21.36 [Cl 0.71–2.58] Use After 1975 BRCA11.57 [Cl 1.11–2.22] 0.65 [Cl 0.36–1.19] Not evaluatedBRCA21.53 [Cl 0.75–3.12] 1.21 [Cl 0.56–2.58]
When counseling patients about contraceptive options and preventive actions, the potential impact of OC use upon the risk of breast cancer and ovarian cancer and other health-related effects of OCs need to be considered. A number of important issues remain unresolved, including the potential differences between BRCA1 and BRCA2 mutation carriers, effect of age and duration of exposure, and effect of OCs on families with highly penetrant early-onset breast cancer.
Level of evidence: 3aii
(Refer to the Oral contraceptives section in the Chemoprevention section of this summary for a discussion of OC use and ovarian cancer in this population.)
Hormone replacement therapy
Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with HRT in the general population. The Women’s Health Initiative (WHI) was a randomized controlled trial of approximately 160,000 postmenopausal women that investigated the risks and benefits of dietary interventions and hormone therapy to reduce the incidence of heart disease, breast cancer, colorectal cancer, and fractures. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits. One of the adverse outcomes prompting closure was a significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150) breast cancers (RR, 1.24; 95% CI, 1.02–1.50; P < .001) in women randomly assigned to receive estrogen and progestin. Results of a follow-up study suggest that the recent reduction in breast cancer incidence, especially among women aged 50 to 69 years, is predominantly related to decrease in use of combined estrogen plus progestin HRT. HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.
Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased  or unaffected by a family history of breast cancer; risk did not vary by family history in the meta-analysis. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/BRCA2 mutations. Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.
Hormone replacement therapy in BRCA1/BRCA2 mutation carriers
The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 mutation has been examined in two studies. In a prospective study of 462 BRCA1 or BRCA2 mutation carriers, bilateral risk-reducing salpingo-oophorectomy (RRSO) (n = 155) was significantly associated with breast cancer risk reduction overall (HR, 0.40; 95% CI, 0.18–0.92). Using mutation carriers without bilateral RRSO or HRT as the comparison group, HRT use (n = 93) did not significantly alter the reduction in breast cancer risk associated with bilateral RRSO (HR, 0.37; 95% CI, 0.14–0.96). In a matched case-control study of 472 postmenopausal women with BRCA1 mutations, HRT use was associated with an overall reduction in breast cancer risk (odds ratio [OR], 0.58; 95% CI, 0.35–0.96; P = .03). A nonsignificant reduction in risk was observed both in women who had undergone bilateral oophorectomy and in those who had not. Women taking estrogen alone had an OR of 0.51 (95% CI, 0.27–0.98; P = .04), while the association with estrogen and progesterone was not statistically significant (OR, 0.66; 95% CI, 0.34–1.27; P = .21). Especially given the differences in estimated risk associated with HRT between observational studies and the WHI, these findings should be confirmed in randomized prospective studies, but they suggest that HRT in BRCA1/BRCA2 mutation carriers neither increases breast cancer risk nor negates the protective effect of oophorectomy.
Level of evidence: 3aii
Refer to the PDQ summary on Ovarian Cancer Screening for information on screening in the general population and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information on levels of evidence related to screening and prevention. The latter also outlines the five requirements that must be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice.
In the general population, clinical examination of the ovaries has neither the specificity nor the sensitivity to reliably identify early ovarian cancer. No data exist regarding the benefit of clinical examination of the ovaries (bimanual pelvic examination) in women at inherited risk of ovarian cancer.
Level of evidence: None assigned
In the general population, transvaginal ultrasound (TVUS) appears to be superior to transabdominal ultrasound in the preoperative diagnosis of adnexal masses. Both techniques have lower specificity in premenopausal women than in postmenopausal women due to the cyclic menstrual changes in premenopausal ovaries (e.g., transient corpus luteum cysts) that can cause difficulty in interpretation. The randomized prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO-1) found no reduction in mortality with the annual use of combined TVUS and cancer antigen (CA) 125 in screening asymptomatic postmenopausal women at general-population risk of ovarian cancer.
Data are limited regarding the potential benefit of TVUS in screening women at inherited risk of ovarian cancer. A number of retrospective studies have reported experience with ovarian cancer screening in high-risk women using TVUS with or without CA 125. However, there is little uniformity in the definition of high-risk criteria and compliance with screening, and in whether cancers detected were incident or prevalent. One of the largest reported studies included 888 BRCA1/BRCA2 mutation carriers who were screened annually with TVUS and CA 125. Ten women developed ovarian cancer; five of the ten developed interval cancers after normal screening results within 3 to 10 months before diagnosis. Five of the ten ovarian cancers were screen-detected incident cases, which had normal screening results within 6 to 14 months before diagnosis. Of these five cases, four were stage IIIB or IV.
A similar study reported the results of annual TVUS and CA 125 in a cohort of 312 high-risk women (152 BRCA1/BRCA2 mutation carriers). Of the four cancers that were detected due to abnormal TVUS and CA 125, all four patients were symptomatic, and three had advanced-stage disease. Annual screening of BRCA1/BRCA2 mutation carriers with pelvic ultrasound, TVUS, and CA 125 failed to detect early-stage ovarian cancer among 241 BRCA1/BRCA2 mutation carriers in a study from the Netherlands. Three cancers were detected over the course of the study, all advanced stage IIIC disease. Finally, a study of 1,100 moderate- and high-risk women who underwent annual TVUS and CA 125 reported that ten of 13 ovarian tumors were detected due to screening. Only five of ten were stage I or II. There are limited data related to the efficacy of semiannual screening with TVUS and CA 125.
The first prospective study of TVUS and CA 125 with survival as the primary outcome was completed in 2009. Of the 3,532 high-risk women screened, 981 were BRCA mutation carriers, of which 49 developed ovarian cancer. The 5- and 10-year survival was 58.6% (95% CI, 50.9–66.3) and 36% (95% CI, 27–45), respectively, and there was no difference in survival between carriers and noncarriers. A major limitation of the study was the absence of a control group. Despite limitations, this study suggests that annual surveillance by TVUS and CA 125 level appear to be ineffective in detecting tumors at an early stage to substantially influence survival.
Level of evidence: 4
Serum CA 125
Serum CA 125 screening for ovarian cancer in high-risk women has been evaluated in combination with TVUS in a number of retrospective studies, as described in the previous section.
The National Institutes of Health (NIH) Consensus Statement on Ovarian Cancer recommended against routine screening of the general population for ovarian cancer with serum CA 125. (Refer to the Combined CA-125 and TVU section in the PDQ summary on Ovarian Cancer Screening for more information.) The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA 125 screening every 6 to 12 months, beginning at age 35 years. The Cancer Genetics Studies Consortium task force has recommended that female carriers of a deleterious BRCA1 mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years. Both recommendations are based solely on expert opinion and best clinical judgment.
Level of evidence: 5
Other candidate ovarian cancer biomarkers
The need for effective ovarian cancer screening is particularly important for women carrying mutations in BRCA1 and BRCA2, and the mismatch repair genes (e.g., MLH1, MSH2, MSH6, PMS2), disorders in which the risk of ovarian cancer is high. There is a special sense of urgency for BRCA1 mutation carriers, in whom cumulative lifetime risks of ovarian cancer may exceed 40%.
Thus, it is expected that many new ovarian cancer biomarkers (either singly or in combination) will be proposed as ovarian cancer screening strategies during the next 5 to 10 years. While this is an active area of research with a number of promising new biomarkers in early development, at present, none of these biomarkers alone or in combination have been sufficiently well studied to justify their routine clinical use for screening purposes, either in the general population or in women at increased genetic risk.
Before addressing information related to emerging ovarian cancer biomarkers, it is important to consider the several steps that are required to develop and, more importantly, validate a new biomarker. One useful framework is that published by the National Cancer Institute Early Detection Research Network investigators. They indicated that the goal of a cancer-screening program is to detect tumors at an early stage so that treatment is likely to be successful. The gold standard by which such programs are judged is whether the death rate from the cancer for which screening is performed is reduced among those being screened. In addition, the screening test must be sufficiently noninvasive and inexpensive to allow widespread use in the population to be screened. Maintaining high test specificity (i.e., few false-positive results) is essential for a population screening test, because even a low false-positive rate results in many people having to undergo unnecessary and costly diagnostic procedures and psychological stress. It is likely that the use of several such cancer biomarkers in combination will be required for a screening test to be both sensitive and specific.
Furthermore, a clinically useful test must have a high PPV (a parameter derived from sensitivity, specificity and disease prevalence in the screened population). Practically speaking, a biomarker with a PPV of 10% implies that ten surgical procedures would be required to identify one case of ovarian cancer; the remaining nine surgeries would represent false-positive test findings. In general, the ovarian cancer research community considers biomarkers with a PPV less than 10% to be clinically unacceptable, given the morbidity related to bilateral salpingo-oophorectomy. Finally, it is important to keep in mind that while novel biomarkers may be present in the sera of women with advanced ovarian cancer (which comprise the vast majority of cases analyzed in the early phases of biomarker development), they may or may not be detectable in women with early stage disease, which is essential if the screening test is to be clinically useful.
It has been suggested that there are five general phases in biomarker development and validation:
- Phase I — Preclinical exploratory studies
- Identify potentially discriminating biomarkers.
- Usually done by comparing gene over- or under-expression in the tumor compared with normal tissue.
- Since many exploratory analyses in large numbers of genes are performed at this stage, one or more may seem to have good discriminating ability between cancers and normal tissue by random chance alone.
- Phase 2 — Clinical assay development for clinical disease
- Develop a clinical assay that can be obtained on noninvasively obtained samples (e.g., a blood specimen).
- Often the test targets the protein product of one of the genes found to be of interest in phase I.
- The goal is to describe the performance characteristics of the assay for distinguishing between subjects with and without cancer. At this point, the assay should be in its final configuration and remain stable throughout the following phases.
- IMPORTANT: Since the case subjects in a phase 2 study already have cancer, with assay results obtained at the time of disease diagnosis, one cannot determine if disease can be detected early with a given biomarker.
- Phase 3 — Retrospective longitudinal repository studies
- Compare clinical specimens collected from cancer case subjects before their clinical diagnosis with specimens from subjects who have not developed cancer.
- Evaluate, as a function of time before clinical diagnosis, the biomarker’s ability to detect preclinical disease.
- Define the criteria for a positive screening test in preparation for phase 4.
- Explore the influence of other patient characteristics (e.g., age, gender, smoking status, medication use) on the ability of the biomarker to discriminate between those with and without preclinical disease.
- Phase 4 — Prospective screening studies
- Determine the operating characteristics of the biomarker-based screening test in a population for which the test is intended.
- Measure the detection rate (number of abnormal tests among all those with the disease) and the false-positive rate (the number of abnormal tests among all those who do not have the disease).
- Evaluate whether the cancers detected by the test are being found at an early stage, a point at which treatment is more likely to be curative.
- Assess whether the test is acceptable in a population of persons for whom it is intended. Will subjects comply with the test schedule and results?
- Phase 5 — Cancer control studies
- Ideally, conduct randomized controlled clinical trials in clinically relevant populations, in which one arm is subjected to screening and appropriate intervention if screen-positive, while the other arm is not screened.
- Determine whether the death rate of the cancer being screened for is reduced among those who use the screening test.
- Obtain information about the costs of screening and treatment of screen-detected cancers.
Finally, for a validated biomarker test to be considered appropriate for use in a particular population, it must have been evaluated in that specific population without prior selection of known positives and negatives. In addition, the test must demonstrate clinical utility, that is, a positive net balance of benefits and risks associated with the application of the test. These may include improved health outcomes and net psychosocial and economic benefits.
Ovarian cancer poses a unique challenge relative to the potential impact of false-positive test results. There are no reliable noninvasive diagnostic tests for early stage disease, and clinically-significant early stage cancer may not be grossly visible at the time of exploratory surgery. Consequently, it is likely that some patients will only be reassured that their abnormal test does not indicate the presence of cancer by having their ovaries and fallopian tubes surgically removed and examined microscopically. High test specificity (i.e., a very low false-positive rate) is required to avoid unnecessary surgery and induction of premature menopause in false positive women.
Variations on CA 125
CA 125 plus an ovarian cancer symptom index
An ovarian cancer symptom index for predicting the presence of cancer was evaluated in 75 cases and 254 high-risk controls (BRCA mutation carriers or women with a strong family history of breast and ovarian cancer). Women had a positive symptom index if they reported any of the predefined symptoms (bloating or increase in abdominal size, abdominal or pelvic pain, and difficulty eating or feeling full quickly) more than 12 times per month occurring only within the prior 12 months. CA 125 values greater than 30 U/mL were considered abnormal. The symptom index independently predicted the presence of ovarian cancer, after controlling for CA 125 levels (P < .05). The combination of an elevated CA 125 and a positive symptom index correctly identified 89.3% of the cases. The symptom index correlated with the presence of cancer in 50% of the affected women who did not have elevated CA 125 levels, but 11.8% of the high-risk controls without cancer also had a positive symptom index. The authors suggested that a composite index including both CA 125 and the symptom index had better performance characteristics than either test used alone, and that this strategy might be used as a first screen in a multi-step screening program. Additional test performance validation and determination of clinical utility are required in unselected screening populations.
Level of evidence: 5
Risk of ovarian cancer algorithm
A novel modification of CA 125 screening is based on the hypothesis that rising CA 125 levels over time may provide better ovarian cancer screening performance characteristics than simply classifying CA 125 as normal or abnormal based on an arbitrary cut-off value. This has been implemented in the form of the risk of ovarian cancer algorithm (ROCA), an investigational statistical model that incorporates serial CA 125 test results and other covariates into a computation which produces an estimate of the likelihood that ovarian cancer is present in the screened subject. The first report of this strategy, based on reanalysis of 5,550 average-risk women from the Stockholm Ovarian Cancer screening trial, suggested that ovarian cancer cases and controls could be distinguished with 99.7% sensitivity, 83% specificity, and a PPV of 16%. That PPV represents an eightfold increase over the 2% PPV reported with a single measure of CA 125. This report was followed by applying the ROCA to 33,621 serial CA 125 values obtained from the 9,233 average-risk postmenopausal women in a prospective British ovarian cancer screening trial. The area under the receiver operator curve increased from 84% to 93% (P = .01) for ROCA compared with a fixed CA 125 cutoff. These observations represented the first evidence that preclinical detection of ovarian cancer might be improved using this screening strategy. A prospective study of 13,000 normal volunteers aged 50 years and older in England used serial CA 125 values and the ROCA to stratify participants into low, intermediate, and elevated risk subgroups. Each had its own prescribed management strategy, including TVUS and repeat CA 125 either annually (low risk) or at 3 months (intermediate risk). Using this protocol, ROCA was found to have a specificity of 99.8% and a PPV of 19%.
Two prospective trials in England utilized the ROCA. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) randomly assigned normal-risk women to either (1) no screening, (2) annual ultrasound, or (3) multimodal screening (N = 202,638; accrual completed; follow-up ends in 2014), and the U.K. Familial Ovarian Cancer Screening Study (UKFOCSS) targeted high-risk women (accrual completed). There are also two high-risk cohorts using the ROCA under evaluation in the United States: the Cancer Genetics Network ROCA Study (N = 2,500; follow-up complete; analysis underway) and the Gynecologic Oncology Group Protocol 199 (GOG-0199; enrollment complete; follow-up ends in late 2011). Thus, additional data regarding the utility of this currently investigational screening strategy will become available within the next few years.
Level of evidence: 4
Miscellaneous new markers
A wide array of new candidate ovarian cancer biomarkers has been described during the past decade, including HE4; mesothelin; kallikreins 6, 10, and 11; osteopontin; prostasin; M-CSF; OVX1; lysophosphatidic acid; vascular endothelial growth factor (VEGF) B7-H4; and interleukins 6 and 8, to name just a few. These have been singly studied, in combination with CA 125, or in various other permutations. Most of the study populations are relatively small and comprise highly-selected known ovarian cancer cases and healthy controls of the type evaluated in early biomarker development phases 1 and 2. Results have not been consistently replicated in multiple studies; presently, none are considered ready for widespread clinical application.
Level of evidence: 5
Initially, mass spectroscopy of serum proteins was combined with complex analytic algorithms to identify protein patterns that might distinguish between ovarian cancer cases and controls. This approach assumed that pattern recognition alone would be sufficient to permit such discrimination, and that identification of the specific proteins responsible for the patterns identified was not required. Subsequently, this strategy has been modified, using similar laboratory tools, to identify finite numbers of specific known serum markers that may be used in place of, or in conjunction with, CA 125 measurements for the early detection of cancer. These studies  have generally been small case-control studies that are limited by sample size and the number of early-stage cancer cases included. Further evaluation is needed to determine whether any additional markers identified in this fashion have clinical utility for the early detection of ovarian cancer in the unselected clinical population of interest.
Level of evidence: 5
Because individual biomarkers have not met the criteria for an effective screening test, it has been suggested that it may be necessary to combine multiple ovarian cancer biomarkers in order to obtain satisfactory screening test results. This strategy was employed to quantitatively analyze six serum biomarkers (leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA 125), using a multiplex, bead-based platform. A similar assay was available commercially under the trade name OvaSure until its voluntary withdrawal from the market by the manufacturer.[Response to FDA Warning Letter]
The cases in this study were newly-diagnosed ovarian cancer patients who had blood collected just prior to surgery: 36 were stage I and II; 120 were stage III and IV. The controls were healthy age-matched individuals who had not developed ovarian cancer within 6 months of blood draw. Neither cases nor controls in this study were well characterized regarding their familial and or genetic risk status, but they have been suggested to comprise a high-risk population. First, 181 controls and 113 ovarian cancer cases were tested to determine the initial panel of biomarkers that best discriminated between cases and controls (training set). The resulting panel was applied to an additional 181 controls and 43 ovarian cancer cases (test set). Pooling both early- and late-stage ovarian cancer across the combined training and test sets, performance characteristics were reported as a sensitivity of 95.3% and a specificity of 99.4%, with a PPV of 99.3% and a negative predictive value of 99.2%, using a formula that assumed an ovarian cancer prevalence of about 50%, as seen in the highly selected research population.
In order to avoid biases which may make test performance appear to be better than it really is, it is worth noting that combining training and test populations in analyses of this sort is generally not recommended. The most appropriate prevalence to use is the disease prevalence in the unselected population to be screened. The prevalence of ovarian cancer in the general population is 1 in 2,500. In a recently published correction to their manuscript, the authors assumed that the prevalence of ovarian cancer in the screened population was 1/2,500 (0.04%) and recalculated the PPV to be only 6.5%. On that basis the investigators have retracted their claim that this test is suitable for population screening. If this test were used in patients at increased risk of ovarian cancer, the actual prevalence in such a target population is likely to be higher than that observed in the general population, but well below the assumed 50% figure used in the published analysis. This revised PPV of 6.5% indicates that approximately 1 in 15 women with a positive test would in fact have ovarian cancer, and only a fraction of those with ovarian cancer would be stages I or II. The remaining 14 positive tests would represent false-positives, and these women would be at risk of exposure to needless anxiety and potentially morbid diagnostic procedures, including bilateral salpingo-oophorectomy.
Viewed in the context of the criteria previously described, this assay would be classified as phase 2 in its development. While this appears to be a promising avenue of ovarian cancer screening research, additional validation is required, particularly in an unselected population representative of the clinical screening population of interest. A recent position statement by the Society of Gynecologic Oncologists regarding this assay indicated “it is our opinion that additional research is needed to validate the test’s effectiveness before offering it to women outside of the context of a research study conducted with appropriate informed consent under the auspices of an Institutional Review Board.”
Level of evidence: 5
Numerous studies have found that women at inherited risk of breast and ovarian cancer have a decreased risk of ovarian cancer following risk-reducing salpingo-oophorectomy (RRSO). A retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (HR, 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR, 0.04; 95% CI, 0.01–0.16) after bilateral oophorectomy. A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend. With oophorectomy, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74). A prospective multicenter study of 1,079 women who were followed for a median of 30 to 35 months found that RRSO is highly effective in reducing ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. This study also showed that RRSO was associated with reductions in breast cancer risk in both BRCA1 and BRCA2 mutation carriers; however, the breast cancer risk reduction was more pronounced in BRCA2 carriers (HR, 0.28; 95% CI, 0.08–0.92). In a case-control study in Israel, bilateral oophorectomy was associated with reduced ovarian/peritoneal cancer risks (OR, 0.12; 95% CI, 0.06–0.24). A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in BRCA1/BRCA2 mutation carriers confirmed that RRSO was associated with a significant reduction in risk of ovarian or fallopian tube cancer (HR, 0.21; 95% CI, 0.12–0.39). The study also found a significant reduction in risk of breast cancer (overall: HR, 0.49; 95% CI, 0.37–0.65; BRCA1: HR, 0.47; 95% CI, 0.35–0.64; BRCA2: HR, 0.47; 95% CI, 0.26–0.84).
In addition to a reduction in risk of ovarian and breast cancer, RRSO may also significantly improve overall survival (OS) and breast and ovarian cancer-specific survival. A prospective cohort study of 666 women with germline mutations in BRCA1 and BRCA2 found an HR for overall mortality of 0.24 (95% CI, 0.08–0.71) in women who had RRSO compared with women who did not. This study provides the first evidence to suggest a survival advantage among women undergoing RRSO.
Studies on the degree of risk reduction afforded by RRSO have begun to clarify the spectrum of occult cancers discovered at the time of surgery. Primary fallopian tube cancers, primary peritoneal cancers, and occult ovarian cancers have all been reported. Several case series have reported a prevalence of malignant findings among mutation carriers undergoing risk-reducing oophorectomy. Among studies with 50 or more subjects, prevalence ranged from 2.3% to 11%. Some of the variation in prevalence is likely due to differences in surgical technique, pathologic handling of the tissues, and age at RRSO. In addition to occult cancers, premalignant lesions have also been described in fallopian tube tissue removed for prophylaxis. In one series of 12 women with BRCA1 mutations undergoing risk-reducing surgery, 11 had hyperplastic or dysplastic lesions identified in the tubal epithelium. In several of the cases the lesions were multifocal. These pathologic findings are consistent with the identification of germline BRCA1 and BRCA2 mutations in women affected with both tubal and primary peritoneal cancers. One study suggests a causal relationship between early tubal carcinoma, or tubal intraepithelial carcinoma, and subsequent invasive serous carcinoma of the fallopian tube, ovary or peritoneum. (Refer to the Pathology of ovarian cancer section of this summary for more information.)
These findings support the inclusion of fallopian tube cancers, which account for less than 1% of all gynecologic cancers in the general population, as a component of hereditary ovarian cancer syndrome and necessitate removal of the fallopian tubes at the time of risk-reducing surgery. There is clear evidence that RRSO must include routine collection of peritoneal washings and careful adherence to comprehensive pathologic evaluation of the entire adnexa using serial sectioning.
The peritoneum, however, appears to remain at low risk for the development of a Müllerian-type adenocarcinoma, even after oophorectomy. Of the 324 women from the Gilda Radner Familial Ovarian Cancer Registry who underwent risk-reducing oophorectomy, six (1.8%) subsequently developed primary peritoneal carcinoma. No period of follow-up was specified. Among 238 individuals in the Creighton Registry with BRCA1/BRCA2 mutations who underwent risk-reducing oophorectomy, five subsequently developed intra-abdominal carcinomatosis (2.1%). Of note, all five of these women had BRCA1 mutations. A study of 1,828 women with a BRCA1 or BRCA2 mutation found a 4.3% risk of primary peritoneal cancer at 20 years after RRSO.
Given the current limitations of screening for ovarian cancer and the high risk of the disease in BRCA1 and BRCA2 mutation carriers, NCCN Guidelines recommend RRSO between the ages of 35 and 40 years or upon completion of childbearing, as an effective risk-reduction option. Optimal timing of RRSO must be individualized, but evaluating a woman's risk of ovarian cancer based on mutation status can be helpful in the decision-making process. In a large study of U.S. BRCA1 and BRCA2 families, age-specific cumulative risk of ovarian cancer at age 40 years was 4.7% for BRCA1 mutation carriers and 1.9% for BRCA2 mutation carriers. In a combined analysis of 22 studies of BRCA1 and BRCA2 mutation carriers, risk of ovarian cancer for BRCA1 mutation carriers increases most sharply from age 40 years to age 50 years, while for BRCA2 mutation carriers the risk is low before age 50 years, but increases sharply from age 50 years to age 60 years. In a population-based study of BRCA mutations in ovarian cancer patients, patients with BRCA2 mutations had a significantly later age of onset than patients with BRCA1 mutations (57.3 years [range, 40–72] vs. 52.6 years [range, 31–78]). In summary, women with BRCA1 mutations may consider RRSO for ovarian cancer risk reduction at a somewhat earlier age than women with BRCA2 mutations; however, women with BRCA2 mutations may still consider early RRSO for breast cancer risk reduction.
Studies indicate that removal of the uterus is not necessary as a risk-reducing procedure. No increased BRCA mutation prevalence was seen among 200 Jewish women with endometrial carcinoma or 56 unselected women with uterine papillary serous carcinoma. However, small studies have reported that uterine papillary serous carcinoma may be part of the BRCA-associated spectrum of disease. The cumulative risk of endometrial cancer among BRCA mutation carriers with ER-positive breast cancer treated with tamoxifen may be an additional factor to consider when counseling this population about prophylactic hysterectomy. Hysterectomy might also be considered in young, unaffected BRCA mutation carriers who may want to use HRT but for whom hysterectomy would offer a simplified regimen of estrogen alone. In counseling a BRCA mutation carrier about optimal risk-reducing surgical options, aggregate data suggest that the risk from residual tubal tissue following RRSO is the least compelling reason to suggest hysterectomy. Therefore, in the absence of tamoxifen use or other underlying uterine or cervical problems, hysterectomy is not a routine component of RRSO for BRCA carriers.
For women who are premenopausal at the time of surgery, the symptoms of surgical menopause (e.g., hot flashes, mood swings, weight gain, and genitourinary complaints) can cause a significant impairment in their quality of life. To reduce the impact of these symptoms, providers have often prescribed a time-limited course of systemic HRT after surgery. (Refer to the Hormone replacement therapy in BRCA1/BRCA2 mutation carriers section of this summary for more information.)
Studies have examined the effect of RRSO on quality of life (QOL). One study examined 846 high-risk women of whom 44% underwent RRSO and 56% had periodic screening. Of the 368 BRCA1/BRCA2 mutation carriers, 72% underwent RRSO. No significant differences were observed in QOL scores (as assessed by the Short Form-36) between those with RRSO or screening or compared with the general population; however, women with RRSO had fewer breast and ovarian cancer worries (P < .001), more favorable cancer risk perception (P < .05) but more endocrine symptoms (P < .001) and worse sexual functioning (P < .05). Of note, 37% of women used HRT following RRSO, although 62% were either perimenopausal or postmenopausal. Researchers then examined 450 premenopausal high-risk women who had chosen either RRSO (36%) or screening (64%). Of those in the RRSO group, 47% used HRT. HRT users (n = 77) had fewer vasomotor symptoms than nonusers (n = 87; P < .05), but they had more vasomotor symptoms than women in the screening group (n = 286). Likewise, women who underwent RRSO and used HRT had more sexual discomfort due to vaginal dryness and dyspareunia than those in the screening group (P < .01). Therefore, while such symptoms are improved via HRT use, HRT is not completely effective and additional research is warranted to address these important issues.
The long-term nononcologic effects of RRSO in BRCA1/BRCA2 mutation carriers are unknown. In the general population, RRSO has been associated with increased cardiovascular disease, dementia, death from lung cancer, and overall mortality. When age at oophorectomy has been analyzed, the most detrimental effect has been seen in women who undergo RRSO before age 45 years and do not take estrogen-replacement therapy. BRCA1/BRCA2 mutation carriers undergoing RRSO may have an increased risk of metabolic syndrome. RRSO has also been associated with an improvement in short-term mortality in this population. The benefits related to cancer risk reduction following RRSO are clear, but further data on the long-term nononcologic risks and benefits are needed.
Bilateral salpingectomy has been suggested as an interim procedure to reduce risk in BRCA mutation carriers.There are no data available on the efficacy of salpingectomy as a risk-reducing procedure. The procedure preserves ovarian function and spares the premenopausal patient the adverse effects of a premature menopause. The procedure can be performed using a minimally invasive approach, and a subsequent bilateral oophorectomy could be deferred until the patient approaches menopause. While the data make a compelling argument that some pelvic serous cancers in BRCA mutation carriers originate in the fallopian tube, clearly, some cancers arise in the ovary. Furthermore, bilateral salpingectomy could give patients a false sense of security that they have eliminated their cancer risk as completely as if they had undergone a bilateral salpingo-oophorectomy. A small study of 14 young BRCA mutation carriers documented the procedure as feasible. However, efficacy and impact on ovarian function was not assessed in this study. Future prospective trials are needed to establish the validity of the procedure as a risk-reducing intervention.
OCs have been shown to have a protective effect against ovarian cancer in the general population. Several studies including a large, multicenter case-control study showed a protective effect, while one population-based study from Israel failed to demonstrate a protective effect.
There has been great interest in determining whether a similar benefit extends to women who are at increased genetic risk of ovarian cancer. A multicenter study of 799 ovarian cancer patients with BRCA1 or BRCA2 mutations, and 2,424 control patients without ovarian cancer but with a BRCA1 or BRCA2 mutation, showed a significant reduction in ovarian cancer risk with use of OCs (OR, 0.56; 95% CI, 0.45–0.71). Compared to never use of OCs, duration up to 1 year was associated with an OR of 0.67 (95% CI, 0.50–0.89). The OR for each year of OC use was 0.95 (95% CI, 0.92–0.97) with a maximum observed protection at 3 years to 5 years of use. This study included women from a prior study by the same authors and confirmed the results of that prior study. A population-based case-control study of ovarian cancer did not find a protective benefit of OC use in BRCA1 or BRCA2 mutation carriers, (OR, 1.07 for ≥5 years of use), although they were protective, as expected, among noncarriers (OR, 0.53 for ≥5 years of use). A small population-based case-control study of 36 BRCA1 mutation carriers, however, observed a similar, protective effect in both mutation carriers and noncarriers (OR, approximately 0.5). A multicenter study of subjects drawn from numerous registries observed a protective effect of OCs among the 147 BRCA1 or BRCA2 mutation carriers, with ovarian cancer compared with the 304 matched mutation carriers without cancer (OR, 0.62 for ≥6 years of use). Finally, a meta-analysis of 18 studies including 13,627 BRCA mutation carriers, of whom 2,855 had breast cancer and 1,503 had ovarian cancer, reported a significantly reduced risk of ovarian cancer (summary relative risk, 0.50; 95% CI, 0.33–0.75) associated with OC use. The authors also reported significantly greater risk reductions with longer duration of OC use (36% reduction in risk for each additional 10 years of OC use). There was no association with breast cancer risk and use of OC pills formulated after 1975.
Level of evidence: 3aii
(Refer to the Oral contraceptives section in the Reproductive factors section of this summary for a discussion of OC use and breast cancer in this population.)
It has been suggested that incessant ovulation, with repetitive trauma and repair to the ovarian epithelium, increases the risk of ovarian cancer. In epidemiologic studies in the general population, physiologic states that prevent ovulation have been associated with decreased risk of ovarian cancer. It has also been suggested that chronic overstimulation of the ovaries by luteinizing hormone (LH) plays a role in ovarian cancer pathogenesis. Most of these data derive from studies in the general population, but some information suggests the same is true in women at high risk due to genetic predisposition.
Among the general population, parity decreases the risk of ovarian cancer by 45% compared with nulliparity. Subsequent pregnancies appear to decrease ovarian cancer risk by 15%. Earlier studies of women with BRCA1/BRCA2 mutations showed that parity decreases the risk of ovarian cancer. In a large case-control study, parity was associated with a significant reduction in ovarian cancer risk in women with BRCA1 mutations, OR 0.67 (CI, 0.46–0.96). For each birth, BRCA1 mutation carriers had an OR of 0.87 (CI, 0.79–0.95). In this same study, parity was associated with an increase in ovarian cancer risk in BRCA2 mutation carriers; however, there was no significant trend for each birth, OR 1.08 (CI, 0.90–1.29). Further studies are necessary to define the association of parity and risk of ovarian cancer in BRCA2 mutation carriers, but for BRCA1 carriers, each live birth significantly decreases risk of ovarian cancer, as it does in sporadic ovarian cancer.
Lactation and tubal ligation
In the general population, breast feeding is associated with a decrease in ovarian cancer risk. In BRCA mutation carriers, data are limited. One study found no protective effect with breast feeding. A case-control study among women with BRCA1 or BRCA2 mutations demonstrates a significant reduction in risk of ovarian cancer (OR, 0.39) for women who have had a tubal ligation. This protective effect was confined to those women with mutations in BRCA1 and persists after controlling for OC use, parity, history of breast cancer, and ethnicity. A case-control study of ovarian cancer in Israel found a 40% to 50% reduced risk of ovarian cancer among women undergoing gynecologic surgeries (tubal ligation, hysterectomy, unilateral oophorectomy, ovarian cystectomy, excluding bilateral oophorectomy). The mechanism of protection is uncertain. Proposed mechanisms of action include decreased blood flow to the ovary, resulting in interruption of ovulation and/or ovarian hormone production; occlusion of the fallopian tube, thus blocking a pathway for potential carcinogens; or a reduction in the concentration of uterine growth factors that reach the ovary. (Refer to the PDQ summary on Prevention of Ovarian Cancer for information relevant to the general population.)
Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.
Management of Male BRCA Mutation Carriers
There are data to suggest that men with BRCA gene mutations have an increased risk of various cancers including male breast cancer and prostate cancer (see Table 4). However, clinical guidelines to manage male carriers with BRCA mutations are based on consensus statements and expert opinions because information is limited.
There have been suggestions that BRCA2-associated prostate cancers are associated with aggressive disease phenotype. Specifically, two recent studies have reported the median survival of male BRCA2 carriers with prostate cancer in the range of 4 to 5 years. Furthermore, mortality rate was reported as 60% at 5 years in one of these studies, compared with 2% to 8% reported in the recent European  and North American  PSA screening trials after comparable follow-up. The data have been more limited in BRCA1-associated prostate cancers, however a number of recent studies have suggested an aggressive disease phenotype as well.
The benefits of PSA screening in BRCA carriers are currently unknown; however, there have been suggestions (based on very small studies) that PSA levels at prostate cancer diagnosis may be higher in carriers than non-carriers. These findings suggest that PSA screening may be of potential utility in men with BRCA mutations, especially in view of the aggressive phenotype. Preliminary results of the IMPACT PSA screening study reported a positive predictive value of 47.6% in 21 BRCA2 carriers undergoing biopsy on the basis of elevated PSA. Since screening these men detected clinically significant prostate cancer, the authors suggest that these findings provide rationale for continued screening in such men; however, a survival benefit from such screening has not been shown. Ultimately, it is possible that information on BRCA mutation status in men may inform optimal screening and treatment strategies. Furthermore, recent data that the presence of a germline BRCA2 mutation is an independent prognostic factor for survival in prostate cancer led these authors to conclude that active surveillance may not be the optimal management strategy due to the aggressive disease phenotype.
Screening for male breast cancer in BRCA mutation carriers as suggested by the NCCN clinical practice guidelines  includes breast self-exam training and education, clinical breast exam every 6 to 12 months, and consideration of a baseline mammogram. Annual mammogram is a consideration with the presence of gynecomastia or parenchymal/glandular breast density on baseline study. Furthermore, screening guidelines for prostate cancer include PSA screening and digital rectal exam on an annual basis starting at age 40 years.
Reproductive Considerations in BRCA Mutation Carriers
Refer to the Prenatal diagnosis and preimplantation genetic diagnosis section in the Psychosocial Issues in Inherited Breast Cancer Syndromes section of this summary for more information.
Prognosis of BRCA1- and BRCA2-related breast cancer
BRCA1-related breast cancer
The distinct features of BRCA1-associated breast tumors are important in prognosis. In addition, there appears to be accelerated growth in BRCA1-associated breast cancer, which is suggested by high-proliferation indices and absence of the expected correlation of tumor size with lymph node status. These pathological features are associated with a worse prognosis in breast cancer, and early studies suggested that BRCA1 mutation carriers with breast cancer may have a poorer prognosis compared with sporadic cases. These studies particularly noted an increase in ipsilateral and contralateral second primary breast cancers in BRCA1 mutation carriers. A retrospective cohort study found a 47.4% incidence of contralateral cancer 25 years after the first breast cancer. BRCA1 carriers had a risk 1.6 times higher than BRCA2 carriers, and risk was higher when the first breast cancer occurred before age 40 years. A retrospective cohort study of 496 Ashkenazi Jewish (AJ) breast cancer patients from two centers compared the relative survival among 56 BRCA1/BRCA2 mutation carriers followed for a median of 116 months. BRCA1 mutations were independently associated with worse disease-specific survival. The poorer prognosis was not observed in women who received chemotherapy. A large population-based study of incident cases of breast cancer among women in Israel failed to find a difference in OS for carriers of BRCA1 founder mutations (n = 76) compared with noncarriers (n = 1,189). Similar findings were seen in a European cohort with no differences in disease-free survival in BRCA1-associated breast cancers. Subsequently, a prospective cohort study of 3,220 women from North America and Australia with incident breast cancer (including 93 BRCA1 carriers and 71 BRCA2 carriers) who were followed up for a mean of 7.9 years reported similar outcomes among BRCA1/2 carriers and those with sporadic disease. However, results were based on chemotherapy regimens used in the late 1990s and did not adjust for surgical approach (lumpectomy vs. mastectomy) and effect of oophorectomy.
A group of researchers reported the results of BRCA1/2 testing in 77 unselected patients with triple-negative breast cancer. Of these, 15 (19.5%) had either a germline BRCA1 (n = 11; 14%) or BRCA2 (n = 3; 4%) mutation or a somatic BRCA1 (n = 1) mutation. The median age at cancer diagnosis was 45 years in BRCA1 mutation carriers and 53 years in noncarriers (P = .005). Interestingly, this study also demonstrated a lower risk of relapse in those with BRCA1 mutation–associated triple-negative breast cancer than in nonmutated triple-negative breast cancer, although this study was limited by its size. A second study examining clinical outcome in BRCA1-associated verus non-BRCA1-associated triple-negative breast cancer showed no difference, although there was a trend toward more brain metastases in those with BRCA1-associated breast cancer. In both of these studies, all but one BRCA1 mutation carrier received chemotherapy.
In summary, BRCA1-associated tumors appear to have a prognosis similar to sporadic tumors despite having clinical, histopathologic, and molecular features, which indicate a more aggressive phenotype. BRCA1 mutation carriers who do not receive chemotherapy may have a worse prognosis. However, because most BRCA1-associated breast cancers are triple negative, they are usually treated with adjuvant chemotherapy. Work is ongoing to determine whether BRCA1-associated breast cancers should receive different therapy than sporadic tumors. (Refer to the Role of BRCA1 and BRCA2 in response to systemic therapy section of this summary for more information.)
BRCA2-related breast cancer
Early studies of the prognosis of BRCA2 associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer. A small study reported statistically significant higher OS in BRCA2 mutation carriers with metastatic breast cancer.
Role of BRCA1 and BRCA2 in response to systemic therapy
A growing body of preclinical and clinical literature suggests a differential response of BRCA-related breast cancers to systemic chemotherapy. This is based on the emerging understanding of the functions of these genes in response to DNA damage and mitotic spindle machinery control. As several chemotherapeutic agents target either DNA or mitotic spindle structural integrity, the lack of BRCA functions could alter response to these agents. Intact BRCA1 and BRCA2 are important in DNA repair by homologous recombination. Preclinical studies of BRCA1 and BRCA2 deficient cell lines have suggested increased sensitivity to drugs which cause DNA damage that is repaired by homologous recombination, such as cisplatin, carboplatin and mitomycin C. Conversely, intact BRCA1 may be important for spindle poisons, such as taxanes, to be effective. Preclinical models suggest decreased sensitivity to these drugs in mutated cell lines.
Evidence of the role of BRCA1/BRCA2 mutations in humans is preliminary. A number of small studies have suggested increased clinical response rates, particularly in BRCA1 mutation carriers, but design limitations make it difficult to use these studies to guide clinical recommendations. A small study reported statistically significant higher sensitivity to first-line treatment in BRCA2 mutation carriers with metastatic breast cancer compared with those with sporadic metastatic cancer; conversely, no statistically significant differences were observed for BRCA1 carriers with metastatic breast cancer.
Retrospective and prospective studies  have suggested a higher-than-expected response rate to chemotherapy in BRCA1 mutation carriers receiving neoadjuvant chemotherapy for breast cancer, especially when using cisplatin. Several studies have been published regarding the Polish experience on the use of preoperative chemotherapy in BRCA1 mutation carriers. The largest report  includes data on 102 BRCA1 mutation carriers of which 51 were described in two prior studies.  Women were identified from a registry of 6,903 patients. Those with a Polish founder mutation in BRCA1 (5382insC, C61G, or 4153delA) who had also received preoperative chemotherapy were included. Of these 102 women, 22% had a pathologic complete response (pCR). Twelve women received cisplatin chemotherapy as part of a clinical trial of whom 10 had a pCR (83%). All other patients were examined retrospectively. Of these, 14 received cyclophosphamide, methotrexate, and fluorouracil with one pCR (7%), 25 received doxorubicin and docetaxel with two pCR (8%), and 51 received doxorubicin and cyclophosphamide with 11 pCR (22%). To place this in the context of other available data, several retrospective studies in BRCA1 and BRCA2 mutation carriers typically treated with anthracycline-based chemotherapy have demonstrated clinical complete response rates of 46% to 90% after preoperative chemotherapy, particularly in BRCA1 mutation carriers. A trial of preoperative cisplatin in triple-negative breast cancer patients demonstrated a pCR of 22%; however, both BRCA1 mutation carriers in the study had a pCR.
Thus, the preclinical and clinical data suggesting improved chemotherapy response rates in BRCA1-associated breast cancer are consistent with the emerging understanding of BRCA1 function in DNA-damage response and cell-cycle regulation. While these findings raise the possibility that germline status may influence treatment choices, there is insufficient evidence at this time to support treating mutation carriers with different regimens.
Another specific process to exploit in BRCA1/BRCA2-deficient tumors is the poly (ADP-ribose) polymerase (PARP) pathway. Whereas BRCA1 and BRCA2 are active in the repair of double-stranded DNA breaks by homologous recombination, PARP is involved in the repair of single-stranded breaks by base excision repair. It was hypothesized that inhibiting base excision repair in BRCA1 or BRCA2 deficient cells would lead to enhanced cell death as two separate repair mechanisms would be compromised—the concept of synthetic lethality. In vitro studies have shown that PARP inhibition kills BRCA mutant cells with high specificity.
PARP inhibitors quickly entered clinical trials. A phase I study of an oral PARP inhibitor called olaparib has demonstrated tolerability (with minimal side effects) and activity in BRCA1 and BRCA2 mutation carriers with breast, ovarian, and prostate cancer. Phase II trials in breast cancer have confirmed tolerability and efficacy of olaparib in mutation carriers. Two sequential cohorts of 27 patients, each receiving 400 mg twice daily of olaparib and 100 mg twice daily of olaparib, respectively, were examined. The women had received a median of three prior chemotherapeutic regimens. Responses were seen in both groups. In the 400 mg twice daily group, 41% (11/27) of patients had a RECIST-defined response, and another 44% (12/27) had stable disease. In the 100 mg twice daily group, 22% (6/27) had responses, and 44% (12/27) had stable disease. Although the two doses levels cannot be directly compared as they were not randomized, more responses were seen in the higher dose cohort. Several other PARP inhibitors are in development.
Preclinical models suggest that the combination of PARP inhibitors and chemotherapy may be synergistic; however, such synergy may come at the expense of toxicity. The results of ongoing and recently completed clinical trials are awaited with interest.
(Refer to the Systemic therapy section in the Ovarian Cancer Treatment Strategies section of this summary for more information.)
Breast conservation therapy for BRCA1/BRCA2 mutation carriers
While lumpectomy plus radiation therapy has become standard local-regional therapy for women with early-stage breast cancer, its use in women with a hereditary predisposition for breast cancer who do not choose immediate bilateral mastectomy is more complicated. Initial concerns about the potential for therapeutic radiation to induce tumors or cause excess toxicity in BRCA1/BRCA2 mutation carriers were unfounded.  Despite this, an increased rate of second primary breast cancer exists, which could impact treatment decisions.
Because of the established increased risk of second primary breast cancers, which may be up to 60% in younger women with BRCA1 mutations, some BRCA1/BRCA2 mutation carriers choose bilateral mastectomy at the time of their initial cancer diagnosis. (Refer to the Contralateral breast cancer in BRCA mutation carriers section of this summary for more information.) However, several studies support use of breast conservation therapy as a reasonable option to treat the primary tumor. The risk of ipsilateral recurrence at 10 years has been estimated to be between 10% to 15% and is similar to that seen in noncarriers. Studies with longer follow-up demonstrate risks of ipsilateral breast events at 15 years as high as 24%, largely due to ipsilateral second breast cancers (rather than relapse of the primary tumor).  Although not entirely consistent across studies, radiation therapy, chemotherapy, oophorectomy, and tamoxifen are associated with a decreased risk of ipsilateral events, as is the case in sporadic breast cancer. The risk of contralateral breast cancer does not appear to be different in women undergoing breast conservation therapy versus unilateral mastectomy, suggesting no added risk of contralateral breast cancer from scattered radiation. Finally, no difference in OS at 15 years has been seen between BRCA1/BRCA2 mutation carriers choosing breast conservation therapy and those choosing mastectomy.
Level of evidence: 3a
Contralateral breast cancer in BRCA mutation carriers
As early as 1995, the Breast Cancer Linkage Consortium estimated the risk of contralateral breast cancer (CBC) in BRCA1 mutation carriers to be as high as 60% by age 60 years. This report has been followed by several retrospective studies of various cohorts of women with hereditary patterns of breast cancer in both the United States and Europe. One retrospective cohort study reviewed the records of 91 AJ women diagnosed with breast cancer before the age of 42 years, 30 of whom had a deleterious BRCA1 or BRCA2 mutation. At a median follow-up of 63 months, the rate of CBC was 40% in the mutation carriers compared with 8.2% among noncarriers. Carriers had a shorter median interval between cancers than noncarriers (36 months vs. 63.9 months). The same group reported 5-, 10-, and 15-year probabilities of CBC of 11.9%, 37.6% and 53.2%, respectively, among 87 mutation carriers. Rates of CBC in this clinical cohort did not differ by mutation type (BRCA1 vs. BRCA2) or by age at first diagnosis. A case-control study from the Netherlands compared rates of CBC between 49 women with BRCA1-related breast cancer and 196 breast cancer cases not known to have a BRCA1/BRCA2 mutation (sporadic controls). At 5 years of follow-up, rates of CBC were 20.4% among mutation carriers versus 5.6% among the controls. In an expanded cohort of BRCA1-related breast cancer patients, the risk of CBC was inversely correlated with age at first diagnosis, with the majority of cases of CBC occurring among women whose first breast cancer was diagnosed at or before age 50 years. A similar analysis matching 28 BRCA2 mutation–positive cases with 112 sporadic controls found a fivefold increase in CBC among cases (25% vs. 4.5%). A larger study of members of BRCA1/BRCA2 families in the Netherlands reported similar 10-year risks of CBC for women from BRCA1 and BRCA2 families (34.2% and 29.2%). In another study, 127 patients with early-onset breast cancer (aged ≤42 years) who had been treated with breast-conserving therapy, were genotyped for mutations in BRCA1 and BRCA2. At a median follow-up of 12 years, the rate of contralateral breast cancer among the 22 mutation-positive patients was 42% compared with 9% in the noncarriers. A similar analysis from the Institut Curie in Paris reported a rate of CBC of 37% among mutation carriers compared with 7.3% in noncarriers at a median follow-up of 8.75 years.
In a larger cohort of breast cancer patients (n = 336) from families with documented BRCA1/BRCA2 mutations and 9.2 years of follow-up, the rate of CBC was 28.9% at a mean interval of 5.5 years. Prior oophorectomy was associated with a 59% reduction in the risk of CBC. Another case-control study of mutation carriers and noncarriers identified through ascertainment of women with bilateral breast cancer found that systemic adjuvant chemotherapy reduced CBC risk among mutation carriers (RR, 0.5; 95% CI, 0.2–1.0). Tamoxifen was associated with a nonsignificant risk reduction (RR, 0.7; 95% CI, 0.3–1.8). Similar risk reduction was seen in noncarriers; however, given the higher absolute CBC risk in carriers, there is potentially a greater impact of adjuvant treatment in risk reduction. A high concordance in estrogen receptor status and tumor grade was reported among women from a registry of BRCA1/BRCA2 carriers who had bilateral breast cancer. The German Consortium for Hereditary Breast and Ovarian Cancer estimated the risk of CBC in members of BRCA1 and BRCA2 mutation–positive families. At 25 years following the first breast cancer, the risk of CBC was close to 50% in both BRCA1 and BRCA2 families. The risk was also inversely correlated with age in this study, with the highest risks seen in women whose first breast cancer was before age 40 years.  A comparison of 655 women with BRCA1/BRCA2 mutations undergoing breast-conserving therapy versus those undergoing mastectomy noted that both treatment groups experienced high rates of CBC, exceeding 50% by 20 years of follow up. Rates were significantly higher among women with BRCA1 mutations compared with those with BRCA2 mutations, and among women whose first breast cancer occurred at or before age 35 years. The WECARE study, a large population-based nested case-control study of CBC, reported a 10-year risk of CBC among BRCA1/BRCA2 mutation carriers of 15.9%, compared with a risk of 4.9% among noncarriers. Risks were also inversely related to age at first diagnosis in this study.
Thus, despite differences in study design, study sites, and sample sizes, the data on CBC among women with BRCA1/BRCA2 mutations show several consistent findings:
- The risk at all time points studied is significantly higher than that among sporadic controls.
- The risk continues to rise with time since first breast cancer, and reaches 20% to 30% at 10 years of follow up, and 40% to 50% at 20 years in most studies.
- Some, but not all, studies show an excess of CBC among BRCA1 carriers compared with BRCA2 carriers.
- The risk of CBC is greatest among women whose first breast cancer occurs at a young age.
Refer to the Chemoprevention section of this summary for information about the use of tamoxifen as a risk-reduction strategy for CBC in BRCA mutation carriers.
Prognosis of BRCA1- and BRCA2-related ovarian cancer
Despite generally poor prognostic factors, several studies have found an improved survival among ovarian cancer patients with BRCA mutations. A nationwide, population-based, case-control study in Israel found 3-year survival rates to be significantly better for ovarian cancer patients with BRCA founder mutations, compared with controls. Five-year follow-up in the same cohort showed improved survival for carriers of both BRCA1 and BRCA2 mutations (54 months) versus noncarriers (38 months), which was most pronounced for women with stages III and IV ovarian cancer and for women with high-grade tumors. In a U.S. study of AJ women with ovarian cancer, those with BRCA mutations had a longer median time to recurrence and an overall improved survival, compared with both AJ women with ovarian cancer who did not have a BRCA mutation and two large groups of advanced-stage ovarian cancer clinical trial patients. In a retrospective U.S. hospital-based study, Ashkenazi BRCA mutation carriers had a better response to platinum-based chemotherapy, as measured by response to primary therapy, disease-free survival, and OS, compared with sporadic cases. Similarly, a significant survival advantage was seen in a case-control study among women with non-AJ BRCA mutations. A study from the Netherlands also showed a better response to platinum-based primary chemotherapy in 112 BRCA1/2 carriers than in 220 sporadic ovarian cancer patients. A U.S. population-based study showed improvement in OS in BRCA2, but not in BRCA1, carriers. However, the study included only 12 BRCA2 mutation carriers and 20 BRCA1 mutation carriers. Significantly better OS and progression-free survival were observed in 29 BRCA2 mutation–positive high-grade serous ovarian cancer cases (20 germline, 9 somatic) from The Cancer Genome Atlas study compared with BRCA mutation–negative cases. BRCA1 mutations were not significantly associated with prognosis. Furthermore, a pooled analysis of 26 observational studies that included 1,213 BRCA mutation carriers and 2,666 noncarriers with epithelial ovarian cancer showed more favorable survival in mutation carriers (BRCA1: HR, 0.73; 95% CI, 0.64–0.84; P < .001; BRCA2: HR, 0.49; 95% CI, 0.39–0.61; P < .001). Thus, 5-year survival in both BRCA1 and BRCA2 carriers with epithelial ovarian cancers was better than that observed in noncarriers, with BRCA2 carriers having the best prognosis. A study in Japanese patients found a survival advantage in stage III BRCA1-associated ovarian cancers treated with cisplatin regimens compared with nonhereditary cancers treated in a similar manner.
In contrast, several studies have not found improved OS among ovarian cancer patients with BRCA mutations. A population-based study from Sweden noted an initial survival advantage in BRCA1-associated cases, but this advantage did not persist after 3 or 4 years. Similarly, a case-control study from the Netherlands found an improvement in short-term (up to 5 years) survival among women with familial ovarian cancer compared with sporadic controls, but no difference in longer-term survival. A study from the United Kingdom found a worse survival rate in ovarian cancer patients with a family history of ovarian cancer, whether or not they had a BRCA mutation, compared with sporadic controls. Finally, a case-control study at the University of Iowa failed to find any survival advantage for women with BRCA1 inactivation, whether by germline mutation, somatic mutation, or BRCA1 promoter silencing. In this study, however, cases (women with BRCA1 inactivation) were matched to controls on several variables, including tumor grade and p53 status, thus possibly minimizing any differences between the two groups.
There are compelling data to show improved survival in AJ ovarian cancer patients with BRCA1 or BRCA2 founder mutations; however, further large studies in other populations with appropriate controls are needed to determine whether this survival advantage applies more broadly to all BRCA1- or BRCA2-related ovarian cancers.
PARP pathway inhibitors are currently being studied for the treatment of BRCA1- or BRCA2-deficient ovarian cancers. (Refer to the Role of BRCA1 and BRCA2 in response to systemic therapy section in the Breast Cancer Treatment Strategies section of this summary for more information about PARP inhibitors.) While PARP is involved in the repair of single-stranded breaks by base excision repair, BRCA1 and BRCA2 are active in the repair of double-stranded DNA breaks by homologous combination. Therefore, it was hypothesized that inhibiting base excision repair with PARP inhibition in BRCA1- or BRCA2-deficient tumors leads to enhanced cell death, as two separate repair mechanisms would be compromised – the concept of synthetic lethality.
A phase I study of olaparib, an oral PARP inhibitor, demonstrated tolerability (with minimal side effects) and activity in BRCA1 and BRCA2 mutation carriers with ovarian, breast, and prostate cancers. A phase II trial of two different doses of olaparib demonstrated tolerability and efficacy in recurrent ovarian cancer patients with BRCA1 or BRCA2 mutations. The overall response rate was 33% (11 of 33 patients) in the cohort receiving 400 mg twice daily and 13% (3 of 24 patients) in the cohort receiving 100 mg twice daily. The most frequent side effects were mild nausea and fatigue. Olaparib appears to be most effective in patients who are platinum-sensitive. In addition to ovarian cancer patients with germline BRCA1 or BRCA2 mutations, PARP inhibitors also may be useful in ovarian cancer patients with somatic BRCA1 or BRCA2 mutations or with epigenetic silencing of the genes.
Several additional phase II studies have been published that examined PARP inhibitors in ovarian cancer. In one study, women with BRCA1/2 mutations and recurrent ovarian cancer were randomly assigned to receive liposomal doxorubicin (Doxil) (n = 33), versus olaparib at 200 mg twice daily (n = 32), versus olaparib at 400 mg twice daily (n = 32). This study did not show a difference in progression-free survival between the groups, which was the primary endpoint. Of interest, the liposomal doxorubicin arm had a higher response rate than anticipated, consistent with other studies demonstrating that BRCA1/2-associated ovarian cancers may be more sensitive to liposomal doxorubicin than are sporadic ovarian cancers. Another study demonstrated significant responses to olaparib in recurrent ovarian cancer patients, including patients with a BRCA1/2 mutation (objective response rate [ORR], 41%) and patients without a BRCA1/2 mutation (ORR, 24%). This study emphasizes that certain sporadic ovarian cancers, particularly those of high-grade serous histology, may have properties similar to BRCA1/2 mutation–related tumors.
Another study examined the role of maintenance therapy with the PARP inhibitor olaparib in platinum-sensitive recurrent ovarian cancer (not restricted to BRCA1/2 mutation carriers). In this randomized controlled trial, those who received olaparib maintenance therapy had an improvement in progression-free survival with an HR of 0.35. In BRCA1/2 mutation carriers, the HR was approximately 0.1.
Level of evidence: 3dii
Other High-Penetrance Syndromes Associated with Breast and/or Ovarian Cancer
Lynch syndrome (LS) is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer. The condition is caused by germline mutations in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch mutations. The MLH1 and MSH2 genes are the most common susceptibility genes for LS, accounting for 80% to 90% of observed mutations, followed by MSH6 and PMS2. (Refer to the Lynch syndrome (LS) section in the PDQ summary on Genetics of Colorectal Cancer for more information about this syndrome.)
The lifetime risk of ovarian carcinoma in females with LS is estimated to be up to 12%, and the reported RR of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected LS. Characteristics of LS-associated ovarian cancers may include overrepresentation of the International Federation of Gynecology and Obstetrics stages 1 and 2 at diagnosis (reported as 81.5%), underrepresentation of serous subtypes (reported as 22.9%), and a better 10-year survival (reported as 80.6%) than reported both in population-based series and in BRCA mutation carriers.
The issue of breast cancer risk in LS has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with LS; one of these studies evaluated breast cancer risk in individuals with LS and found that it is not elevated. However, the largest prospective study to date of 446 unaffected mutation carriers from the Colon Cancer Family Registry  who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001). The same group subsequently analyzed data on 764 MMR gene mutation carriers with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59). However, further studies are needed to define absolute risks and age distribution before surveillance guidelines for breast cancer can be developed for MMR mutation carriers.
Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS) (OMIM), in which germline mutations of the TP53 gene (OMIM) on chromosome 17p have been documented. This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma. Tumors in LFS families tend to occur in childhood and early adulthood, and often present as multiple primaries in the same individual. Evidence supports a genotype-phenotype correlation, with an association of the location of the mutation, the kind of cancer that develops, and the age of onset. Brain and adrenal gland tumors were associated with specific sites of missense mutations. Age at onset of breast cancer was 34.6 years in families with a TP53 mutation compared with 42.5 years in those families without a mutation. A germline mutation in the TP53 gene has been identified in more than 50% of families exhibiting this syndrome, and inheritance is autosomal dominant, with a penetrance of at least 50% by age 50 years.
Germline TP53 mutations were identified in 17% (n = 91) of 525 samples submitted to City of Hope laboratories for clinical TP53 testing. All families with a TP53 mutation had at least one family member with a sarcoma, breast cancer, brain cancer, or adrenocortical cancer (core cancers). In addition, all eight individuals with a choroid plexus tumor had a TP53 mutation, as did 14 of the 21 individuals with childhood adrenocortical cancer. In women aged 30 to 49 years who had breast cancer but no family history of other core cancers, no TP53 mutations were found. TP53 mutations are uncommon in women with breast cancer before age 30 years with no other indications for TP53 screening (e.g., a family history of sarcoma). In three studies, the numbers of women with TP53 mutations were 0 (of 95), 1 (of 14), and 2 (of 52).
Located on chromosome 17p, TP53 encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. It is also an active component of programmed cell death. Inactivation of the TP53 gene or disruption of the protein product is thought to allow the persistence of damaged DNA and the possible development of malignant cells. Evidence also exists that patients treated for a TP53-related tumor with chemotherapy or radiation therapy may be at risk of a treatment-related second malignancy. Germline mutations in TP53 are thought to account for fewer than 1% of breast cancer cases. TP53-associated breast cancer is often HER2/neu-positive, in addition to being ER-positive, PR-positive, or both.
One of the more than 50 cancer-related genodermatoses, Cowden syndrome (OMIM) is characterized by multiple hamartomas, an excess of breast cancer, gastrointestinal malignancies, endometrial cancer, and thyroid disease, both benign and malignant. Lifetime estimates for breast cancer among women with Cowden syndrome range from 25% to 50%. As in other forms of hereditary breast cancer, onset is often at a young age and may be bilateral. Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. History or observation of the characteristic skin features raises a suspicion of Cowden syndrome. Central nervous system manifestations include macrocephaly, developmental delay, and dysplastic gangliocytomas of the cerebellum. Germline mutations in the PTEN gene (OMIM), which is located on chromosome 10q23 and encodes a tyrosine phosphatase protein with homology to tensin, are responsible for Cowden syndrome. Loss of heterozygosity at the PTEN locus observed in a high proportion of related cancers suggests that PTEN functions as a tumor suppressor gene. Its defined enzymatic function indicates a role in maintenance of the control of cell proliferation. Disruption of PTEN appears to occur late in tumorigenesis and may act as a regulatory molecule of cytoskeletal function. Although PTEN mutations, which are estimated to occur in 1 in 200,000 individuals, account for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into the signal pathway and the maintenance of normal cell physiology. (Refer to the Major Genes section in the PDQ summary on Genetics of Colorectal Cancer for more information about Cowden syndrome.)
Peutz-Jeghers syndrome (PJS)
PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, and the perioral and buccal regions, and multiple gastrointestinal polyps, both hamartomatous and adenomatous. Germline mutations in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families. (Refer to the Peutz-Jeghers Gene(s) section in the PDQ summary on Genetics of Colorectal Cancer for more information.) The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancy. A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS. Table 7 shows the cumulative risk of these tumors. The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Clinical Practice Guidelines for the Diagnosis of Cancer in Peutz-Jeghers Syndrome in the PDQ summary on Genetics of Colorectal Cancer.
Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in over-estimates of these risks should be considered.Table 7. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified AgeaSiteAge (y)Cumulative Risk (%)bReference(s)GI = Gastrointestinal.aReprinted with permission from Macmillan Publishers Ltd: Gastroenterology , copyright 2010.bAll cumulative risks were increased compared to the general population (P < .05) with the exception of cervix and testes.cGI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.dWesterman et al.: GI cancer does not include pancreatic cancer.eDid not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.Any cancer60–7037–93GI cancerc,d60–7038–66Gynecological cancer60–7013–18Per originStomach6529Small bowel6513Colorectum6539Pancreas65–7011–36Lung65–707–17Breast60–7032–54Uterus659Ovary6521Cervixe6510Testese6591Phipps RF, Perry PM: Familial breast cancer. Postgrad Med J 64 (757): 847-9, 1988.2Sellers TA, Potter JD, Rich SS, et al.: Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer. J Natl Cancer Inst 86 (24): 1860-5, 1994.3Newman B, Austin MA, Lee M, et al.: Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proceedings of the National Academy of Sciences 85(9): 3044-3048, 1988.4Hall JM, Lee MK, Newman B, et al.: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250 (4988): 1684-9, 1990.5Narod SA, Feunteun J, Lynch HT, et al.: Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 338 (8759): 82-3, 1991.6Brose MS, Rebbeck TR, Calzone KA, et al.: Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94 (18): 1365-72, 2002.7Thompson D, Easton DF; Breast Cancer Linkage Consortium.: Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94 (18): 1358-65, 2002.8Risch HA, McLaughlin JR, Cole DE, et al.: Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98 (23): 1694-706, 2006.9Tai YC, Domchek S, Parmigiani G, et al.: Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 99 (23): 1811-4, 2007.10Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994.11Gayther SA, Mangion J, Russell P, et al.: Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15 (1): 103-5, 1997.12Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999.13Liede A, Karlan BY, Narod SA: Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22 (4): 735-42, 2004.14Ding YC, Steele L, Kuan CJ, et al.: Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. Breast Cancer Res Treat 126 (3): 771-8, 2011.15Tonin P, Weber B, Offit K, et al.: Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 2 (11): 1179-83, 1996.16Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993.17Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108 (2): 171-82, 2002.18Narod SA, Foulkes WD: BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4 (9): 665-76, 2004.19An Open Access On-Line Breast Cancer Mutation Data Base [Database]. Bethesda, Md: National Human Genome Research Institute, 2002. Available online. Last accessed February 22, 2013.20Ford D, Easton DF, Peto J: Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 57 (6): 1457-62, 1995.21Whittemore AS, Gong G, John EM, et al.: Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev 13 (12): 2078-83, 2004.22Eng C, Brody LC, Wagner TM, et al.: Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1. J Med Genet 38 (12): 824-33, 2001.23Unger MA, Nathanson KL, Calzone K, et al.: Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Genet 67 (4): 841-50, 2000.24Walsh T, Casadei S, Coats KH, et al.: Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295 (12): 1379-88, 2006.25Palma MD, Domchek SM, Stopfer J, et al.: The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res 68 (17): 7006-14, 2008.26Stadler ZK, Saloustros E, Hansen NA, et al.: Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families. Breast Cancer Res Treat 123 (2): 581-5, 2010.27Judkins T, Rosenthal E, Arnell C, et al.: Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer 118 (21): 5210-6, 2012.28Shannon KM, Rodgers LH, Chan-Smutko G, et al.: Which individuals undergoing BRACAnalysis need BART testing? Cancer Genet 204 (8): 416-22, 2011.29Plon SE, Eccles DM, Easton D, et al.: Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 29 (11): 1282-91, 2008.30Nanda R, Schumm LP, Cummings S, et al.: Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. JAMA 294 (15): 1925-33, 2005.31Frank TS, Deffenbaugh AM, Reid JE, et al.: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20 (6): 1480-90, 2002.32Hall MJ, Reid JE, Burbidge LA, et al.: BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer 115 (10): 2222-33, 2009.33Goldgar DE, Easton DF, Deffenbaugh AM, et al.: Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet 75 (4): 535-44, 2004.34Thompson D, Easton DF, Goldgar DE: A full-likelihood method for the evaluation of causality of sequence variants from family data. Am J Hum Genet 73 (3): 652-5, 2003.35Spearman AD, Sweet K, Zhou XP, et al.: Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol 26 (33): 5393-400, 2008.36Gómez García EB, Oosterwijk JC, Timmermans M, et al.: A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history. Breast Cancer Res 11 (1): R8, 2009.37Goldgar DE, Easton DF, Byrnes GB, et al.: Genetic evidence and integration of various data sources for classifying uncertain variants into a single model. Hum Mutat 29 (11): 1265-72, 2008.38Fleming MA, Potter JD, Ramirez CJ, et al.: Understanding missense mutations in the BRCA1 gene: an evolutionary approach. Proc Natl Acad Sci U S A 100 (3): 1151-6, 2003.39Tavtigian SV, Deffenbaugh AM, Yin L, et al.: Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 43 (4): 295-305, 2006.40Mirkovic N, Marti-Renom MA, Weber BL, et al.: Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition. Cancer Res 64 (11): 3790-7, 2004.41Abkevich V, Zharkikh A, Deffenbaugh AM, et al.: Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet 41 (7): 492-507, 2004.42Couch FJ, Rasmussen LJ, Hofstra R, et al.: Assessment of functional effects of unclassified genetic variants. Hum Mutat 29 (11): 1314-26, 2008.43Chenevix-Trench G, Healey S, Lakhani S, et al.: Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res 66 (4): 2019-27, 2006.44Ostrow KL, McGuire V, Whittemore AS, et al.: The effects of BRCA1 missense variants V1804D and M1628T on transcriptional activity. Cancer Genet Cytogenet 153 (2): 177-80, 2004.45Wu K, Hinson SR, Ohashi A, et al.: Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. Cancer Res 65 (2): 417-26, 2005.46Weitzel JN, Lagos V, Blazer KR, et al.: Prevalence of BRCA mutations and founder effect in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev 14 (7): 1666-71, 2005.47Weitzel JN, Lagos VI, Herzog JS, et al.: Evidence for common ancestral origin of a recurring BRCA1 genomic rearrangement identified in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev 16 (8): 1615-20, 2007.48Mefford HC, Baumbach L, Panguluri RC, et al.: Evidence for a BRCA1 founder mutation in families of West African ancestry. Am J Hum Genet 65 (2): 575-8, 1999.49Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer 83 (10): 1301-8, 2000.50Papelard H, de Bock GH, van Eijk R, et al.: Prevalence of BRCA1 in a hospital-based population of Dutch breast cancer patients. Br J Cancer 83 (6): 719-24, 2000.51Loman N, Johannsson O, Kristoffersson U, et al.: Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst 93 (16): 1215-23, 2001.52Malone KE, Daling JR, Doody DR, et al.: Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 66 (16): 8297-308, 2006.53Newman B, Mu H, Butler LM, et al.: Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 279 (12): 915-21, 1998.54Basham VM, Lipscombe JM, Ward JM, et al.: BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 4 (1): R2, 2002.55Risch HA, McLaughlin JR, Cole DE, et al.: Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68 (3): 700-10, 2001.56Rubin SC, Blackwood MA, Bandera C, et al.: BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing. Am J Obstet Gynecol 178 (4): 670-7, 1998.57Pal T, Permuth-Wey J, Betts JA, et al.: BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 104 (12): 2807-16, 2005.58Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.59King MC, Marks JH, Mandell JB, et al.: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302 (5645): 643-6, 2003.60Gershoni-Baruch R, Dagan E, Fried G, et al.: Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. Eur J Cancer 36 (8): 983-6, 2000.61Hodgson SV, Heap E, Cameron J, et al.: Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer. J Med Genet 36 (5): 369-73, 1999.62Struewing JP, Coriaty ZM, Ron E, et al.: Founder BRCA1/2 mutations among male patients with breast cancer in Israel. Am J Hum Genet 65 (6): 1800-2, 1999.63Hirsh-Yechezkel G, Chetrit A, Lubin F, et al.: Population attributes affecting the prevalence of BRCA mutation carriers in epithelial ovarian cancer cases in Israel. Gynecol Oncol 89 (3): 494-8, 2003.64Moslehi R, Chu W, Karlan B, et al.: BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66 (4): 1259-72, 2000.65Levine DA, Argenta PA, Yee CJ, et al.: Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J Clin Oncol 21 (22): 4222-7, 2003.66John EM, Miron A, Gong G, et al.: Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA 298 (24): 2869-76, 2007.67Vicus D, Finch A, Cass I, et al.: Prevalence of BRCA1 and BRCA2 germ line mutations among women with carcinoma of the fallopian tube. Gynecol Oncol 118 (3): 299-302, 2010.68Aziz S, Kuperstein G, Rosen B, et al.: A genetic epidemiological study of carcinoma of the fallopian tube. Gynecol Oncol 80 (3): 341-5, 2001.69Couch FJ, DeShano ML, Blackwood MA, et al.: BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336 (20): 1409-15, 1997.70Shattuck-Eidens D, Oliphant A, McClure M, et al.: BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA 278 (15): 1242-50, 1997.71Spiegelman D, Colditz GA, Hunter D, et al.: Validation of the Gail et al. model for predicting individual breast cancer risk. J Natl Cancer Inst 86 (8): 600-7, 1994.72Frank TS, Manley SA, Olopade OI, et al.: Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 16 (7): 2417-25, 1998.73Chang-Claude J, Dong J, Schmidt S, et al.: Using gene carrier probability to select high risk families for identifying germline mutations in breast cancer susceptibility genes. J Med Genet 35 (2): 116-21, 1998.74Couch FJ, Hartmann LC: BRCA1 testing--advances and retreats. JAMA 279 (12): 955-7, 1998.75Parmigiani G, Berry D, Aguilar O: Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62 (1): 145-58, 1998.76Ready K, Litton JK, Arun BK: Clinical application of breast cancer risk assessment models. Future Oncol 6 (3): 355-65, 2010.77Amir E, Freedman OC, Seruga B, et al.: Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst 102 (10): 680-91, 2010.78Lakhani SR, Reis-Filho JS, Fulford L, et al.: Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11 (14): 5175-80, 2005.79Kwon JS, Gutierrez-Barrera AM, Young D, et al.: Expanding the criteria for BRCA mutation testing in breast cancer survivors. J Clin Oncol 28 (27): 4214-20, 2010.80Young SR, Pilarski RT, Donenberg T, et al.: The prevalence of BRCA1 mutations among young women with triple-negative breast cancer. BMC Cancer 9: 86, 2009.81Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010.82National Comprehensive Cancer Network.: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2012. Rockledge, PA: National Comprehensive Cancer Network, 2012. Available online with free registration. Last accessed February 04, 2013.83Statement of the American Society of Human Genetics on genetic testing for breast and ovarian cancer predisposition. Am J Hum Genet 55 (5): i-iv, 1994.84U.S. Preventive Services Task Force.: Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 143 (5): 355-61, 2005.85Lancaster JM, Powell CB, Kauff ND, et al.: Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 107 (2): 159-62, 2007.86Evans DG, Eccles DM, Rahman N, et al.: A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet 41 (6): 474-80, 2004.87Apicella C, Dowty JG, Dite GS, et al.: Validation study of the LAMBDA model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women. Clin Genet 72 (2): 87-97, 2007.88Antoniou AC, Pharoah PP, Smith P, et al.: The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 91 (8): 1580-90, 2004.89Struewing JP, Abeliovich D, Peretz T, et al.: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11 (2): 198-200, 1995.90Oddoux C, Struewing JP, Clayton CM, et al.: The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 14 (2): 188-90, 1996.91Warner E, Foulkes W, Goodwin P, et al.: Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91 (14): 1241-7, 1999.92Euhus DM, Smith KC, Robinson L, et al.: Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO. J Natl Cancer Inst 94 (11): 844-51, 2002.93de la Hoya M, Díez O, Pérez-Segura P, et al.: Pre-test prediction models of BRCA1 or BRCA2 mutation in breast/ovarian families attending familial cancer clinics. J Med Genet 40 (7): 503-10, 2003.94Berry DA, Parmigiani G, Sanchez J, et al.: Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst 89 (3): 227-38, 1997.95Barcenas CH, Hosain GM, Arun B, et al.: Assessing BRCA carrier probabilities in extended families. J Clin Oncol 24 (3): 354-60, 2006.96Kang HH, Williams R, Leary J, et al.: Evaluation of models to predict BRCA germline mutations. Br J Cancer 95 (7): 914-20, 2006.97Antoniou AC, Hardy R, Walker L, et al.: Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics. J Med Genet 45 (7): 425-31, 2008.98Katki HA: Incorporating medical interventions into carrier probability estimation for genetic counseling. BMC Med Genet 8: 13, 2007.99Weitzel JN, Lagos VI, Cullinane CA, et al.: Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA 297 (23): 2587-95, 2007.100Oros KK, Ghadirian P, Maugard CM, et al.: Application of BRCA1 and BRCA2 mutation carrier prediction models in breast and/or ovarian cancer families of French Canadian descent. Clin Genet 70 (4): 320-9, 2006.101Vogel KJ, Atchley DP, Erlichman J, et al.: BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model. J Clin Oncol 25 (29): 4635-41, 2007.102Kurian AW, Gong GD, John EM, et al.: Performance of prediction models for BRCA mutation carriage in three racial/ethnic groups: findings from the Northern California Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev 18 (4): 1084-91, 2009.103Kurian AW, Gong GD, Chun NM, et al.: Performance of BRCA1/2 mutation prediction models in Asian Americans. J Clin Oncol 26 (29): 4752-8, 2008.104Biswas S, Tankhiwale N, Blackford A, et al.: Assessing the added value of breast tumor markers in genetic risk prediction model BRCAPRO. Breast Cancer Res Treat 133 (1): 347-55, 2012.105Mavaddat N, Rebbeck TR, Lakhani SR, et al.: Incorporating tumour pathology information into breast cancer risk prediction algorithms. Breast Cancer Res 12 (3): R28, 2010.106Tai YC, Chen S, Parmigiani G, et al.: Incorporating tumor immunohistochemical markers in BRCA1 and BRCA2 carrier prediction. Breast Cancer Res 10 (2): 401, 2008.107Tyrer J, Duffy SW, Cuzick J: A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 23 (7): 1111-30, 2004.108Ready KJ, Vogel KJ, Atchley DP, et al.: Accuracy of the BRCAPRO model among women with bilateral breast cancer. Cancer 115 (4): 725-30, 2009.109Huo D, Senie RT, Daly M, et al.: Prediction of BRCA Mutations Using the BRCAPRO Model in Clinic-Based African American, Hispanic, and Other Minority Families in the United States. J Clin Oncol 27 (8): 1184-90, 2009.110Antoniou A, Pharoah PD, Narod S, et al.: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72 (5): 1117-30, 2003.111Chen S, Parmigiani G: Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25 (11): 1329-33, 2007.112Antoniou AC, Pharoah PD, Narod S, et al.: Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet 42 (7): 602-3, 2005.113Wang WW, Spurdle AB, Kolachana P, et al.: A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10 (9): 955-60, 2001.114Levy-Lahad E, Lahad A, Eisenberg S, et al.: A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci U S A 98 (6): 3232-6, 2001.115Narod SA: Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2 (2): 113-23, 2002.116Kramer JL, Velazquez IA, Chen BE, et al.: Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol 23 (34): 8629-35, 2005.117Antoniou AC, Spurdle AB, Sinilnikova OM, et al.: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 82 (4): 937-48, 2008.118Iodice S, Barile M, Rotmensz N, et al.: Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer 46 (12): 2275-84, 2010.119Antoniou AC, Rookus M, Andrieu N, et al.: Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev 18 (2): 601-10, 2009.120Milne RL, Osorio A, Ramón y Cajal T, et al.: Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 119 (1): 221-32, 2010.121Friedman E, Kotsopoulos J, Lubinski J, et al.: Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers. Breast Cancer Res 8 (2): R15, 2006.122Jernström H, Lubinski J, Lynch HT, et al.: Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 96 (14): 1094-8, 2004.123Terry P, Jain M, Miller AB, et al.: Dietary carotenoids and risk of breast cancer. Am J Clin Nutr 76 (4): 883-8, 2002.124Breast Cancer Family Registry., Kathleen Cuningham Consortium for Research into Familial Breast Cancer (Australasia)., Ontario Cancer Genetics Network (Canada).: Smoking and risk of breast cancer in carriers of mutations in BRCA1 or BRCA2 aged less than 50 years. Breast Cancer Res Treat 109 (1): 67-75, 2008.125Antoniou AC, Beesley J, McGuffog L, et al.: Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res 70 (23): 9742-54, 2010.126Ramus SJ, Kartsonaki C, Gayther SA, et al.: Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 103 (2): 105-16, 2011.127Milne RL, Antoniou AC: Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers. Ann Oncol 22 (Suppl 1): i11-7, 2011.128Litton JK, Ready K, Chen H, et al.: Earlier age of onset of BRCA mutation-related cancers in subsequent generations. Cancer 118 (2): 321-5, 2012.129Casey MJ, Synder C, Bewtra C, et al.: Intra-abdominal carcinomatosis after prophylactic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations. Gynecol Oncol 97 (2): 457-67, 2005.130Finch A, Beiner M, Lubinski J, et al.: Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA 296 (2): 185-92, 2006.131Evans DG, Susnerwala I, Dawson J, et al.: Risk of breast cancer in male BRCA2 carriers. J Med Genet 47 (10): 710-1, 2010.132Edwards SM, Kote-Jarai Z, Meitz J, et al.: Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72 (1): 1-12, 2003.133Giusti RM, Rutter JL, Duray PH, et al.: A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet 40 (10): 787-92, 2003.134van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, et al.: Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42 (9): 711-9, 2005.135Mitra A, Fisher C, Foster CS, et al.: Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer 98 (2): 502-7, 2008.136Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, et al.: Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst 99 (12): 929-35, 2007.137Agalliu I, Gern R, Leanza S, et al.: Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations. Clin Cancer Res 15 (3): 1112-20, 2009.138Narod SA, Neuhausen S, Vichodez G, et al.: Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer 99 (2): 371-4, 2008.139Edwards SM, Evans DG, Hope Q, et al.: Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer 103 (6): 918-24, 2010.140Gallagher DJ, Gaudet MM, Pal P, et al.: Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 16 (7): 2115-21, 2010.141Couch FJ, Johnson MR, Rabe KG, et al.: The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 16 (2): 342-6, 2007.142Hahn SA, Greenhalf B, Ellis I, et al.: BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 95 (3): 214-21, 2003.143Murphy KM, Brune KA, Griffin C, et al.: Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 62 (13): 3789-93, 2002.144Real FX, Malats N, Lesca G, et al.: Family history of cancer and germline BRCA2 mutations in sporadic exocrine pancreatic cancer. Gut 50 (5): 653-7, 2002.145Dagan E: Predominant Ashkenazi BRCA1/2 mutations in families with pancreatic cancer. Genet Test 12 (2): 267-71, 2008.146Goggins M, Schutte M, Lu J, et al.: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56 (23): 5360-4, 1996.147Lal G, Liu G, Schmocker B, et al.: Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res 60 (2): 409-16, 2000.148Ozçelik H, Schmocker B, Di Nicola N, et al.: Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 16 (1): 17-8, 1997.149Ferrone CR, Levine DA, Tang LH, et al.: BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol 27 (3): 433-8, 2009.150DevCan: Probability of Developing or Dying of Cancer Software. Version 6.5.0. Bethesda, Md: Statistical Research and Applications Branch, National Cancer Institute, 2010. Available online. Last accessed February 22, 2013.151Ford D, Easton DF, Bishop DT, et al.: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 (8899): 692-5, 1994.152Anton-Culver H, Cohen PF, Gildea ME, et al.: Characteristics of BRCA1 mutations in a population-based case series of breast and ovarian cancer. Eur J Cancer 36 (10): 1200-8, 2000.153Peelen T, de Leeuw W, van Lent K, et al.: Genetic analysis of a breast-ovarian cancer family, with 7 cases of colorectal cancer linked to BRCA1, fails to support a role for BRCA1 in colorectal tumorigenesis. Int J Cancer 88 (5): 778-82, 2000.154Berman DB, Costalas J, Schultz DC, et al.: A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals. Cancer Res 56 (15): 3409-14, 1996.155Aretini P, D'Andrea E, Pasini B, et al.: Different expressivity of BRCA1 and BRCA2: analysis of 179 Italian pedigrees with identified mutation. Breast Cancer Res Treat 81 (1): 71-9, 2003.156Kirchhoff T, Satagopan JM, Kauff ND, et al.: Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer. J Natl Cancer Inst 96 (1): 68-70, 2004.157Niell BL, Rennert G, Bonner JD, et al.: BRCA1 and BRCA2 founder mutations and the risk of colorectal cancer. J Natl Cancer Inst 96 (1): 15-21, 2004.158Chen-Shtoyerman R, Figer A, Fidder HH, et al.: The frequency of the predominant Jewish mutations in BRCA1 and BRCA2 in unselected Ashkenazi colorectal cancer patients. Br J Cancer 84 (4): 475-7, 2001.159Levine DA, Lin O, Barakat RR, et al.: Risk of endometrial carcinoma associated with BRCA mutation. Gynecol Oncol 80 (3): 395-8, 2001.160Goshen R, Chu W, Elit L, et al.: Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome? Gynecol Oncol 79 (3): 477-81, 2000.161Smith A, Moran A, Boyd MC, et al.: Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. J Med Genet 44 (1): 10-15, 2007.162Goldgar D, Venne V, Conner T, et al.: BRCA phenocopies or ascertainment bias? J Med Genet 44 (8): e86; author reply e88, 2007.163Eisinger F: Phenocopies: actual risk or self-fulfilling prophecy? J Med Genet 44 (8): e87; author reply e88, 2007.164Sasieni P: Phenocopies in families seen by cancer geneticists. J Med Genet 44 (6): e82, 2007.165Tilanus-Linthorst MM: No screening yet after a negative test for the family mutation. J Med Genet 44 (5): e79, 2007.166Katki HA, Gail MH, Greene MH: Breast-cancer risk in BRCA-mutation-negative women from BRCA-mutation-positive families. Lancet Oncol 8 (12): 1042-3, 2007.167Raskin L, Lejbkowicz F, Barnett-Griness O, et al.: BRCA1 breast cancer risk is modified by CYP19 polymorphisms in Ashkenazi Jews. Cancer Epidemiol Biomarkers Prev 18 (5): 1617-23, 2009.168Gronwald J, Cybulski C, Lubinski J, et al.: Phenocopies in breast cancer 1 (BRCA1) families: implications for genetic counselling. J Med Genet 44 (4): e76, 2007.169Rowan E, Poll A, Narod SA: A prospective study of breast cancer risk in relatives of BRCA1/BRCA2 mutation carriers. J Med Genet 44 (8): e89; author reply e88, 2007.170Domchek SM, Gaudet MM, Stopfer JE, et al.: Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2. Breast Cancer Res Treat 119 (2): 409-14, 2010.171Korde LA, Mueller CM, Loud JT, et al.: No evidence of excess breast cancer risk among mutation-negative women from BRCA mutation-positive families. Breast Cancer Res Treat 125 (1): 169-73, 2011.172Kurian AW, Gong GD, John EM, et al.: Breast cancer risk for noncarriers of family-specific BRCA1 and BRCA2 mutations: findings from the Breast Cancer Family Registry. J Clin Oncol 29 (34): 4505-9, 2011.173Harvey SL, Milne RL, McLachlan SA, et al.: Prospective study of breast cancer risk for mutation negative women from BRCA1 or BRCA2 mutation positive families. Breast Cancer Res Treat 130 (3): 1057-61, 2011.174Kauff ND, Mitra N, Robson ME, et al.: Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families. J Natl Cancer Inst 97 (18): 1382-4, 2005.175Lee JS, John EM, McGuire V, et al.: Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations. Cancer Epidemiol Biomarkers Prev 15 (2): 359-63, 2006.176Metcalfe KA, Finch A, Poll A, et al.: Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation. Br J Cancer 100 (2): 421-5, 2009.177Futreal PA, Liu Q, Shattuck-Eidens D, et al.: BRCA1 mutations in primary breast and ovarian carcinomas. Science 266 (5182): 120-2, 1994.178Lancaster JM, Wooster R, Mangion J, et al.: BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13 (2): 238-40, 1996.179Miki Y, Katagiri T, Kasumi F, et al.: Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet 13 (2): 245-7, 1996.180Teng DH, Bogden R, Mitchell J, et al.: Low incidence of BRCA2 mutations in breast carcinoma and other cancers. Nat Genet 13 (2): 241-4, 1996.181Berchuck A, Heron KA, Carney ME, et al.: Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer Res 4 (10): 2433-7, 1998.182Thompson ME, Jensen RA, Obermiller PS, et al.: Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 9 (4): 444-50, 1995.183Dobrovic A, Simpfendorfer D: Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res 57 (16): 3347-50, 1997.184Cleton-Jansen AM, Collins N, Lakhani SR, et al.: Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13. Br J Cancer 72 (5): 1241-4, 1995.185Hamann U, Herbold C, Costa S, et al.: Allelic imbalance on chromosome 13q: evidence for the involvement of BRCA2 and RB1 in sporadic breast cancer. Cancer Res 56 (9): 1988-90, 1996.186Birgisdottir V, Stefansson OA, Bodvarsdottir SK, et al.: Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res 8 (4): R38, 2006.187Turner NC, Reis-Filho JS, Russell AM, et al.: BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26 (14): 2126-32, 2007.188Rakha EA, El-Sheikh SE, Kandil MA, et al.: Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol 39 (6): 857-65, 2008.189Wong EM, Southey MC, Fox SB, et al.: Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer. Cancer Prev Res (Phila) 4 (1): 23-33, 2011.190Hilton JL, Geisler JP, Rathe JA, et al.: Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst 94 (18): 1396-406, 2002.191Quinn JE, James CR, Stewart GE, et al.: BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy. Clin Cancer Res 13 (24): 7413-20, 2007.192Geisler JP, Hatterman-Zogg MA, Rathe JA, et al.: Frequency of BRCA1 dysfunction in ovarian cancer. J Natl Cancer Inst 94 (1): 61-7, 2002.193Farmer H, McCabe N, Lord CJ, et al.: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434 (7035): 917-21, 2005.194Ford D, Easton DF, Stratton M, et al.: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62 (3): 676-89, 1998.195Koonin EV, Altschul SF, Bork P: BRCA1 protein products ... Functional motifs... Nat Genet 13 (3): 266-8, 1996.196Thompson D, Easton D; Breast Cancer Linkage Consortium.: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68 (2): 410-9, 2001.197Thompson D, Easton D; Breast Cancer Linkage Consortium.: Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev 11 (4): 329-36, 2002.198Scott CL, Jenkins MA, Southey MC, et al.: Average age-specific cumulative risk of breast cancer according to type and site of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast cancer families attending Australian family cancer clinics. Hum Genet 112 (5-6): 542-51, 2003.199Lubinski J, Phelan CM, Ghadirian P, et al.: Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer 3 (1): 1-10, 2004.200Satagopan JM, Boyd J, Kauff ND, et al.: Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res 8 (12): 3776-81, 2002.201Rennert G, Dishon S, Rennert HS, et al.: Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel. Eur J Cancer Prev 14 (4): 357-61, 2005.202Eisinger F, Jacquemier J, Charpin C, et al.: Mutations at BRCA1: the medullary breast carcinoma revisited. Cancer Res 58 (8): 1588-92, 1998.203Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet 349 (9064): 1505-10, 1997.204Armes JE, Egan AJ, Southey MC, et al.: The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study. Cancer 83 (11): 2335-45, 1998.205Foulkes WD, Stefansson IM, Chappuis PO, et al.: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95 (19): 1482-5, 2003.206Verhoog LC, Brekelmans CT, Seynaeve C, et al.: Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351 (9099): 316-21, 1998.207Manié E, Vincent-Salomon A, Lehmann-Che J, et al.: High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas but not in BRCA1 luminal breast tumors. Cancer Res 69 (2): 663-71, 2009.208Southey MC, Ramus SJ, Dowty JG, et al.: Morphological predictors of BRCA1 germline mutations in young women with breast cancer. Br J Cancer 104 (6): 903-9, 2011.209Mavaddat N, Barrowdale D, Andrulis IL, et al.: Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 21 (1): 134-47, 2012.210Lakhani SR, Van De Vijver MJ, Jacquemier J, et al.: The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20 (9): 2310-8, 2002.211Sorlie T, Tibshirani R, Parker J, et al.: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100 (14): 8418-23, 2003.212Lee E, McKean-Cowdin R, Ma H, et al.: Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women. J Clin Oncol 29 (33): 4373-80, 2011.213Anders C, Carey LA: Understanding and treating triple-negative breast cancer. Oncology (Williston Park) 22 (11): 1233-9; discussion 1239-40, 1243, 2008.214Atchley DP, Albarracin CT, Lopez A, et al.: Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 26 (26): 4282-8, 2008.215Tung N, Wang Y, Collins LC, et al.: Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features. Breast Cancer Res 12 (1): R12, 2010.216Lakhani SR, Khanna KK, Chenevix-Trench G: Are estrogen receptor-positive breast cancers in BRCA1 mutation carriers sporadic? Breast Cancer Res 12 (2): 104, 2010.217Foulkes WD, Metcalfe K, Sun P, et al.: Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin Cancer Res 10 (6): 2029-34, 2004.218Chang J, Hilsenbeck SG, Sng JH, et al.: Pathological features and BRCA1 mutation screening in premenopausal breast cancer patients. Clin Cancer Res 7 (6): 1739-42, 2001.219Lidereau R, Eisinger F, Champème MH, et al.: Major improvement in the efficacy of BRCA1 mutation screening using morphoclinical features of breast cancer. Cancer Res 60 (5): 1206-10, 2000.220Gonzalez-Angulo AM, Timms KM, Liu S, et al.: Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 17 (5): 1082-9, 2011.221Lee LJ, Alexander B, Schnitt SJ, et al.: Clinical outcome of triple negative breast cancer in BRCA1 mutation carriers and noncarriers. Cancer 117 (14): 3093-100, 2011.222Rakha EA, Elsheikh SE, Aleskandarany MA, et al.: Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15 (7): 2302-10, 2009.223Robertson L, Hanson H, Seal S, et al.: BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years. Br J Cancer 106 (6): 1234-8, 2012.224Hartman AR, Kaldate RR, Sailer LM, et al.: Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer. Cancer 118 (11): 2787-95, 2012.225Foulkes WD: BRCA1 functions as a breast stem cell regulator. J Med Genet 41 (1): 1-5, 2004.226Perou CM, Sørlie T, Eisen MB, et al.: Molecular portraits of human breast tumours. Nature 406 (6797): 747-52, 2000.227Sørlie T, Perou CM, Tibshirani R, et al.: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98 (19): 10869-74, 2001.228Hedenfalk I, Duggan D, Chen Y, et al.: Gene-expression profiles in hereditary breast cancer. N Engl J Med 344 (8): 539-48, 2001.229Wessels LF, van Welsem T, Hart AA, et al.: Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. Cancer Res 62 (23): 7110-7, 2002.230Palacios J, Honrado E, Osorio A, et al.: Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers. Clin Cancer Res 9 (10 Pt 1): 3606-14, 2003.231Nielsen TO, Hsu FD, Jensen K, et al.: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10 (16): 5367-74, 2004.232Palacios J, Honrado E, Osorio A, et al.: Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. Breast Cancer Res Treat 90 (1): 5-14, 2005.233Laakso M, Loman N, Borg A, et al.: Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors. Mod Pathol 18 (10): 1321-8, 2005.234Cheang MC, Voduc D, Bajdik C, et al.: Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14 (5): 1368-76, 2008.235Hwang ES, McLennan JL, Moore DH, et al.: Ductal carcinoma in situ in BRCA mutation carriers. J Clin Oncol 25 (6): 642-7, 2007.236Adem C, Reynolds C, Soderberg CL, et al.: Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. Cancer 97 (1): 1-11, 2003.237Claus EB, Petruzella S, Matloff E, et al.: Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ. JAMA 293 (8): 964-9, 2005.238Arun B, Vogel KJ, Lopez A, et al.: High prevalence of preinvasive lesions adjacent to BRCA1/2-associated breast cancers. Cancer Prev Res (Phila Pa) 2 (2): 122-7, 2009.239Garber JE: BRCA1/2-associated and sporadic breast cancers: fellow travelers or not? Cancer Prev Res (Phila Pa) 2 (2): 100-3, 2009.240Smith KL, Adank M, Kauff N, et al.: BRCA mutations in women with ductal carcinoma in situ. Clin Cancer Res 13 (14): 4306-10, 2007.241Hoogerbrugge N, Bult P, Bonenkamp JJ, et al.: Numerous high-risk epithelial lesions in familial breast cancer. Eur J Cancer 42 (15): 2492-8, 2006.242Kauff ND, Brogi E, Scheuer L, et al.: Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations. Cancer 97 (7): 1601-8, 2003.243Hall MJ, Reid JE, Wenstrup RJ: Prevalence of BRCA1 and BRCA2 mutations in women with breast carcinoma In Situ and referred for genetic testing. Cancer Prev Res (Phila) 3 (12): 1579-85, 2010.244Marcus JN, Watson P, Page DL, et al.: Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77 (4): 697-709, 1996.245Marcus JN, Watson P, Page DL, et al.: BRCA2 hereditary breast cancer pathophenotype. Breast Cancer Res Treat 44 (3): 275-7, 1997.246Agnarsson BA, Jonasson JG, Björnsdottir IB, et al.: Inherited BRCA2 mutation associated with high grade breast cancer. Breast Cancer Res Treat 47 (2): 121-7, 1998.247Lakhani SR, Jacquemier J, Sloane JP, et al.: Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90 (15): 1138-45, 1998.248Lakhani SR, Manek S, Penault-Llorca F, et al.: Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res 10 (7): 2473-81, 2004.249Evans DG, Young K, Bulman M, et al.: Probability of BRCA1/2 mutation varies with ovarian histology: results from screening 442 ovarian cancer families. Clin Genet 73 (4): 338-45, 2008.250Tonin PN, Maugard CM, Perret C, et al.: A review of histopathological subtypes of ovarian cancer in BRCA-related French Canadian cancer families. Fam Cancer 6 (4): 491-7, 2007.251Bolton KL, Chenevix-Trench G, Goh C, et al.: Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 307 (4): 382-90, 2012.252Liu J, Cristea MC, Frankel P, et al.: Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival. Cancer Genet 205 (1-2): 34-41, 2012 Jan-Feb.253Crum CP, Drapkin R, Kindelberger D, et al.: Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer. Clin Med Res 5 (1): 35-44, 2007.254Piek JM, Torrenga B, Hermsen B, et al.: Histopathological characteristics of BRCA1- and BRCA2-associated intraperitoneal cancer: a clinic-based study. Fam Cancer 2 (2): 73-8, 2003.255Vineyard MA, Daniels MS, Urbauer DL, et al.: Is low-grade serous ovarian cancer part of the tumor spectrum of hereditary breast and ovarian cancer? Gynecol Oncol 120 (2): 229-32, 2011.256Schorge JO, Muto MG, Lee SJ, et al.: BRCA1-related papillary serous carcinoma of the peritoneum has a unique molecular pathogenesis. Cancer Res 60 (5): 1361-4, 2000.257Jazaeri AA, Yee CJ, Sotiriou C, et al.: Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J Natl Cancer Inst 94 (13): 990-1000, 2002.258Gourley C, Michie CO, Roxburgh P, et al.: Increased incidence of visceral metastases in scottish patients with BRCA1/2-defective ovarian cancer: an extension of the ovarian BRCAness phenotype. J Clin Oncol 28 (15): 2505-11, 2010.259Piek JM, van Diest PJ, Zweemer RP, et al.: Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 195 (4): 451-6, 2001.260Carcangiu ML, Radice P, Manoukian S, et al.: Atypical epithelial proliferation in fallopian tubes in prophylactic salpingo-oophorectomy specimens from BRCA1 and BRCA2 germline mutation carriers. Int J Gynecol Pathol 23 (1): 35-40, 2004.261Medeiros F, Muto MG, Lee Y, et al.: The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 30 (2): 230-6, 2006.262American College of Medical Genetics.: Genetic susceptibility to breast and ovarian cancer: assessment, counseling and testing guidelines. New York: New York State Department of Health, American College of Medical Genetics Foundation, 1999. Also available online. Last accessed February 04, 2013.263ACOG committee opinion. Breast-ovarian cancer screening. Number 239, August 2000. American College of Obstetricians and Gynecologists. Committee on genetics. Int J Gynaecol Obstet 75 (3): 339-40, 2001.264Thomas DB, Gao DL, Self SG, et al.: Randomized trial of breast self-examination in Shanghai: methodology and preliminary results. J Natl Cancer Inst 89 (5): 355-65, 1997.265Scheuer L, Kauff N, Robson M, et al.: Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 20 (5): 1260-8, 2002.266Brekelmans CT, Seynaeve C, Bartels CC, et al.: Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol 19 (4): 924-30, 2001.267Burke W, Daly M, Garber J, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 277 (12): 997-1003, 1997.268Shapiro S: Periodic screening for breast cancer: the Health Insurance Plan project and its sequelae, 1963-1986. Baltimore, Md: Johns Hopkins University Press, 1988.269Kerlikowske K, Grady D, Barclay J, et al.: Effect of age, breast density, and family history on the sensitivity of first screening mammography. JAMA 276 (1): 33-8, 1996.270Kerlikowske K, Carney PA, Geller B, et al.: Performance of screening mammography among women with and without a first-degree relative with breast cancer. Ann Intern Med 133 (11): 855-63, 2000.271Kerlikowske K, Grady D, Barclay J, et al.: Positive predictive value of screening mammography by age and family history of breast cancer. JAMA 270 (20): 2444-50, 1993.272Tilanus-Linthorst M, Verhoog L, Obdeijn IM, et al.: A BRCA1/2 mutation, high breast density and prominent pushing margins of a tumor independently contribute to a frequent false-negative mammography. Int J Cancer 102 (1): 91-5, 2002.273Tilanus-Linthorst MM, Kriege M, Boetes C, et al.: Hereditary breast cancer growth rates and its impact on screening policy. Eur J Cancer 41 (11): 1610-7, 2005.274Mitchell G, Antoniou AC, Warren R, et al.: Mammographic density and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Res 66 (3): 1866-72, 2006.275Miller AB, To T, Baines CJ, et al.: Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 92 (18): 1490-9, 2000.276Shtern F: Digital mammography and related technologies: a perspective from the National Cancer Institute. Radiology 183 (3): 629-30, 1992.277Lewin JM, D'Orsi CJ, Hendrick RE, et al.: Clinical comparison of full-field digital mammography and screen-film mammography for detection of breast cancer. AJR Am J Roentgenol 179 (3): 671-7, 2002.278Pisano ED, Gatsonis C, Hendrick E, et al.: Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med 353 (17): 1773-83, 2005.279Sharan SK, Morimatsu M, Albrecht U, et al.: Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386 (6627): 804-10, 1997.280Gowen LC, Avrutskaya AV, Latour AM, et al.: BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281 (5379): 1009-12, 1998.281Abbott DW, Freeman ML, Holt JT: Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst 90 (13): 978-85, 1998.282Narod SA, Lubinski J, Ghadirian P, et al.: Screening mammography and risk of breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Lancet Oncol 7 (5): 402-6, 2006.283Goldfrank D, Chuai S, Bernstein JL, et al.: Effect of mammography on breast cancer risk in women with mutations in BRCA1 or BRCA2. Cancer Epidemiol Biomarkers Prev 15 (11): 2311-3, 2006.284Andrieu N, Easton DF, Chang-Claude J, et al.: Effect of chest X-rays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators' Group. J Clin Oncol 24 (21): 3361-6, 2006.285Pijpe A, Andrieu N, Easton DF, et al.: Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK). BMJ 345: e5660, 2012.286Berrington de Gonzalez A, Berg CD, Visvanathan K, et al.: Estimated risk of radiation-induced breast cancer from mammographic screening for young BRCA mutation carriers. J Natl Cancer Inst 101 (3): 205-9, 2009.287Lowry KP, Lee JM, Kong CY, et al.: Annual screening strategies in BRCA1 and BRCA2 gene mutation carriers: a comparative effectiveness analysis. Cancer 118 (8): 2021-30, 2012.288Kriege M, Brekelmans CT, Boetes C, et al.: Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 351 (5): 427-37, 2004.289Lehman CD, Blume JD, Weatherall P, et al.: Screening women at high risk for breast cancer with mammography and magnetic resonance imaging. Cancer 103 (9): 1898-905, 2005.290Leach MO, Boggis CR, Dixon AK, et al.: Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet 365 (9473): 1769-78, 2005 May 21-27.291Warner E, Plewes DB, Hill KA, et al.: Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA 292 (11): 1317-25, 2004.292Lehman CD, Isaacs C, Schnall MD, et al.: Cancer yield of mammography, MR, and US in high-risk women: prospective multi-institution breast cancer screening study. Radiology 244 (2): 381-8, 2007.293Sardanelli F, Podo F, D'Agnolo G, et al.: Multicenter comparative multimodality surveillance of women at genetic-familial high risk for breast cancer (HIBCRIT study): interim results. Radiology 242 (3): 698-715, 2007.294Kuhl C, Weigel S, Schrading S, et al.: Prospective multicenter cohort study to refine management recommendations for women at elevated familial risk of breast cancer: the EVA trial. J Clin Oncol 28 (9): 1450-7, 2010.295Shah P, Rosen M, Stopfer J, et al.: Prospective study of breast MRI in BRCA1 and BRCA2 mutation carriers: effect of mutation status on cancer incidence. Breast Cancer Res Treat 118 (3): 539-46, 2009.296Rijnsburger AJ, Obdeijn IM, Kaas R, et al.: BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: long-term follow-up of the Dutch MRISC Screening Study. J Clin Oncol 28 (36): 5265-73, 2010.297Weinstein SP, Localio AR, Conant EF, et al.: Multimodality screening of high-risk women: a prospective cohort study. J Clin Oncol 27 (36): 6124-8, 2009.298Sardanelli F, Podo F, Santoro F, et al.: Multicenter surveillance of women at high genetic breast cancer risk using mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (the high breast cancer risk italian 1 study): final results. Invest Radiol 46 (2): 94-105, 2011.299Lord SJ, Lei W, Craft P, et al.: A systematic review of the effectiveness of magnetic resonance imaging (MRI) as an addition to mammography and ultrasound in screening young women at high risk of breast cancer. Eur J Cancer 43 (13): 1905-17, 2007.300Obdeijn IM, Loo CE, Rijnsburger AJ, et al.: Assessment of false-negative cases of breast MR imaging in women with a familial or genetic predisposition. Breast Cancer Res Treat 119 (2): 399-407, 2010.301Saslow D, Boetes C, Burke W, et al.: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 57 (2): 75-89, 2007 Mar-Apr.302O'Driscoll D, Warren R, MacKay J, et al.: Screening with breast ultrasound in a population at moderate risk due to family history. J Med Screen 8 (2): 106-9, 2001.303Berg WA, Blume JD, Cormack JB, et al.: Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA 299 (18): 2151-63, 2008.304Ariyan S: Prophylactic mastectomy for precancerous and high-risk lesions of the breast. Can J Surg 28 (3): 262-4, 266, 1985.305Hartmann LC, Schaid DJ, Woods JE, et al.: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340 (2): 77-84, 1999.306Hartmann LC, Sellers TA, Schaid DJ, et al.: Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 93 (21): 1633-7, 2001.307Meijers-Heijboer H, van Geel B, van Putten WL, et al.: Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 345 (3): 159-64, 2001.308Rebbeck TR, Friebel T, Lynch HT, et al.: Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 22 (6): 1055-62, 2004.309van Sprundel TC, Schmidt MK, Rookus MA, et al.: Risk reduction of contralateral breast cancer and survival after contralateral prophylactic mastectomy in BRCA1 or BRCA2 mutation carriers. Br J Cancer 93 (3): 287-92, 2005.310Evans DG, Baildam AD, Anderson E, et al.: Risk reducing mastectomy: outcomes in 10 European centres. J Med Genet 46 (4): 254-8, 2009.311Hoogerbrugge N, Bult P, de Widt-Levert LM, et al.: High prevalence of premalignant lesions in prophylactically removed breasts from women at hereditary risk for breast cancer. J Clin Oncol 21 (1): 41-5, 2003.312Kroiss R, Winkler V, Kalteis K, et al.: Prevalence of pre-malignant and malignant lesions in prophylactic mastectomy specimens of BRCA1 mutation carriers: comparison with a control group. J Cancer Res Clin Oncol 134 (10): 1113-21, 2008.313Scott CI, Iorgulescu DG, Thorne HJ, et al.: Clinical, pathological and genetic features of women at high familial risk of breast cancer undergoing prophylactic mastectomy. Clin Genet 64 (2): 111-21, 2003.314Isern AE, Loman N, Malina J, et al.: Histopathological findings and follow-up after prophylactic mastectomy and immediate breast reconstruction in 100 women from families with hereditary breast cancer. Eur J Surg Oncol 34 (10): 1148-54, 2008.315Lerman C, Hughes C, Croyle RT, et al.: Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing. Prev Med 31 (1): 75-80, 2000.316Stefanek ME, Helzlsouer KJ, Wilcox PM, et al.: Predictors of and satisfaction with bilateral prophylactic mastectomy. Prev Med 24 (4): 412-9, 1995.317Meijers-Heijboer EJ, Verhoog LC, Brekelmans CT, et al.: Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355 (9220): 2015-20, 2000.318Schrag D, Kuntz KM, Garber JE, et al.: Decision analysis--effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med 336 (20): 1465-71, 1997.319Unic I, Stalmeier PF, Verhoef LC, et al.: Assessment of the time-tradeoff values for prophylactic mastectomy of women with a suspected genetic predisposition to breast cancer. Med Decis Making 18 (3): 268-77, 1998 Jul-Sep.320Grann VR, Panageas KS, Whang W, et al.: Decision analysis of prophylactic mastectomy and oophorectomy in BRCA1-positive or BRCA2-positive patients. J Clin Oncol 16 (3): 979-85, 1998.321Kurian AW, Sigal BM, Plevritis SK: Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers. J Clin Oncol 28 (2): 222-31, 2010.322Kurian AW, Munoz DF, Rust P, et al.: Online tool to guide decisions for BRCA1/2 mutation carriers. J Clin Oncol 30 (5): 497-506, 2012.323Giuliano AE, Boolbol S, Degnim A, et al.: Society of Surgical Oncology: position statement on prophylactic mastectomy. Approved by the Society of Surgical Oncology Executive Council, March 2007. Ann Surg Oncol 14 (9): 2425-7, 2007.324Olson JE, Sellers TA, Iturria SJ, et al.: Bilateral oophorectomy and breast cancer risk reduction among women with a family history. Cancer Detect Prev 28 (5): 357-60, 2004.325Struewing JP, Watson P, Easton DF, et al.: Prophylactic oophorectomy in inherited breast/ovarian cancer families. J Natl Cancer Inst Monogr (17): 33-5, 1995.326Rebbeck TR, Levin AM, Eisen A, et al.: Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91 (17): 1475-9, 1999.327Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.328Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002.329Kauff ND, Domchek SM, Friebel TM, et al.: Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 26 (8): 1331-7, 2008.330Rebbeck TR, Kauff ND, Domchek SM: Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst 101 (2): 80-7, 2009.331Domchek SM, Friebel TM, Singer CF, et al.: Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 304 (9): 967-75, 2010.332Fisher B, Costantino JP, Wickerham DL, et al.: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90 (18): 1371-88, 1998.333Veronesi U, Maisonneuve P, Costa A, et al.: Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 352 (9122): 93-7, 1998.334Powles T, Eeles R, Ashley S, et al.: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352 (9122): 98-101, 1998.335King MC, Wieand S, Hale K, et al.: Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 286 (18): 2251-6, 2001.336Narod SA, Brunet JS, Ghadirian P, et al.: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet 356 (9245): 1876-81, 2000.337Pierce LJ, Levin AM, Rebbeck TR, et al.: Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol 24 (16): 2437-43, 2006.338Gronwald J, Tung N, Foulkes WD, et al.: Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer 118 (9): 2281-4, 2006.339Vogel VG, Costantino JP, Wickerham DL, et al.: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295 (23): 2727-41, 2006.340Land SR, Wickerham DL, Costantino JP, et al.: Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295 (23): 2742-51, 2006.341Vicus D, Rosen B, Lubinski J, et al.: Tamoxifen and the risk of ovarian cancer in BRCA1 mutation carriers. Gynecol Oncol 115 (1): 135-7, 2009.342Colditz GA, Rosner BA, Speizer FE: Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group. J Natl Cancer Inst 88 (6): 365-71, 1996.343Narod S, Lynch H, Conway T, et al.: Increasing incidence of breast cancer in family with BRCA1 mutation. Lancet 341 (8852): 1101-2, 1993.344Narod SA, Goldgar D, Cannon-Albright L, et al.: Risk modifiers in carriers of BRCA1 mutations. Int J Cancer 64 (6): 394-8, 1995.345McCredie M, Paul C, Skegg DC, et al.: Family history and risk of breast cancer in New Zealand. Int J Cancer 73 (4): 503-7, 1997.346Jernström H, Lerman C, Ghadirian P, et al.: Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 354 (9193): 1846-50, 1999.347Cullinane CA, Lubinski J, Neuhausen SL, et al.: Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers. Int J Cancer 117 (6): 988-91, 2005.348Antoniou AC, Shenton A, Maher ER, et al.: Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 8 (6): R72, 2006.349Andrieu N, Goldgar DE, Easton DF, et al.: Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). J Natl Cancer Inst 98 (8): 535-44, 2006.350Collaborative Group on Hormonal Factors in Breast Cancer.: Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360 (9328): 187-95, 2002.351Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 347 (9017): 1713-27, 1996.352Ursin G, Henderson BE, Haile RW, et al.: Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57 (17): 3678-81, 1997.353Jernström H, Loman N, Johannsson OT, et al.: Impact of teenage oral contraceptive use in a population-based series of early-onset breast cancer cases who have undergone BRCA mutation testing. Eur J Cancer 41 (15): 2312-20, 2005.354Brohet RM, Goldgar DE, Easton DF, et al.: Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol 25 (25): 3831-6, 2007.355Haile RW, Thomas DC, McGuire V, et al.: BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev 15 (10): 1863-70, 2006.356Narod SA, Dubé MP, Klijn J, et al.: Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 94 (23): 1773-9, 2002.357Narod SA, Risch H, Moslehi R, et al.: Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 339 (7): 424-8, 1998.358Chen CL, Weiss NS, Newcomb P, et al.: Hormone replacement therapy in relation to breast cancer. JAMA 287 (6): 734-41, 2002.359Writing Group for the Women's Health Initiative Investigators.: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288 (3): 321-33, 2002.360Chlebowski RT, Hendrix SL, Langer RD, et al.: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289 (24): 3243-53, 2003.361Chlebowski RT, Kuller LH, Prentice RL, et al.: Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med 360 (6): 573-87, 2009.362Schuurman AG, van den Brandt PA, Goldbohm RA: Exogenous hormone use and the risk of postmenopausal breast cancer: results from The Netherlands Cohort Study. Cancer Causes Control 6 (5): 416-24, 1995.363Steinberg KK, Thacker SB, Smith SJ, et al.: A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 265 (15): 1985-90, 1991.364Colditz GA, Egan KM, Stampfer MJ: Hormone replacement therapy and risk of breast cancer: results from epidemiologic studies. Am J Obstet Gynecol 168 (5): 1473-80, 1993.365Sellers TA, Mink PJ, Cerhan JR, et al.: The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 127 (11): 973-80, 1997.366Stanford JL, Weiss NS, Voigt LF, et al.: Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 274 (2): 137-42, 1995.367Gorsky RD, Koplan JP, Peterson HB, et al.: Relative risks and benefits of long-term estrogen replacement therapy: a decision analysis. Obstet Gynecol 83 (2): 161-6, 1994.368Rebbeck TR, Friebel T, Wagner T, et al.: Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 23 (31): 7804-10, 2005.369Eisen A, Lubinski J, Gronwald J, et al.: Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 100 (19): 1361-7, 2008.370Chlebowski RT, Prentice RL: Menopausal hormone therapy in BRCA1 mutation carriers: uncertainty and caution. J Natl Cancer Inst 100 (19): 1341-3, 2008.371Buys SS, Partridge E, Black A, et al.: Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA 305 (22): 2295-303, 2011.372Hermsen BB, Olivier RI, Verheijen RH, et al.: No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study. Br J Cancer 96 (9): 1335-42, 2007.373Stirling D, Evans DG, Pichert G, et al.: Screening for familial ovarian cancer: failure of current protocols to detect ovarian cancer at an early stage according to the international Federation of gynecology and obstetrics system. J Clin Oncol 23 (24): 5588-96, 2005.374Olivier RI, Lubsen-Brandsma MA, Verhoef S, et al.: CA125 and transvaginal ultrasound monitoring in high-risk women cannot prevent the diagnosis of advanced ovarian cancer. Gynecol Oncol 100 (1): 20-6, 2006.375Meeuwissen PA, Seynaeve C, Brekelmans CT, et al.: Outcome of surveillance and prophylactic salpingo-oophorectomy in asymptomatic women at high risk for ovarian cancer. Gynecol Oncol 97 (2): 476-82, 2005.376Dørum A, Kristensen GB, Abeler VM, et al.: Early detection of familial ovarian cancer. Eur J Cancer 32A (10): 1645-51, 1996.377Tailor A, Bourne TH, Campbell S, et al.: Results from an ultrasound-based familial ovarian cancer screening clinic: a 10-year observational study. Ultrasound Obstet Gynecol 21 (4): 378-85, 2003.378Karlan BY, Raffel LJ, Crvenkovic G, et al.: A multidisciplinary approach to the early detection of ovarian carcinoma: rationale, protocol design, and early results. Am J Obstet Gynecol 169 (3): 494-501, 1993.379Muto MG, Cramer DW, Brown DL, et al.: Screening for ovarian cancer: the preliminary experience of a familial ovarian cancer center. Gynecol Oncol 51 (1): 12-20, 1993.380Liede A, Karlan BY, Baldwin RL, et al.: Cancer incidence in a population of Jewish women at risk of ovarian cancer. J Clin Oncol 20 (6): 1570-7, 2002.381Laframboise S, Nedelcu R, Murphy J, et al.: Use of CA-125 and ultrasound in high-risk women. Int J Gynecol Cancer 12 (1): 86-91, 2002 Jan-Feb.382Woodward ER, Sleightholme HV, Considine AM, et al.: Annual surveillance by CA125 and transvaginal ultrasound for ovarian cancer in both high-risk and population risk women is ineffective. BJOG 114 (12): 1500-9, 2007.383van der Velde NM, Mourits MJ, Arts HJ, et al.: Time to stop ovarian cancer screening in BRCA1/2 mutation carriers? Int J Cancer 124 (4): 919-23, 2009.384Evans DG, Gaarenstroom KN, Stirling D, et al.: Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers. J Med Genet 46 (9): 593-7, 2009.385NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA 273 (6): 491-7, 1995.386Pepe MS, Etzioni R, Feng Z, et al.: Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 93 (14): 1054-61, 2001.387Grosse SD, Khoury MJ: What is the clinical utility of genetic testing? Genet Med 8 (7): 448-50, 2006.388Finch A, Shaw P, Rosen B, et al.: Clinical and pathologic findings of prophylactic salpingo-oophorectomies in 159 BRCA1 and BRCA2 carriers. Gynecol Oncol 100 (1): 58-64, 2006.389Andersen MR, Goff BA, Lowe KA, et al.: Combining a symptoms index with CA 125 to improve detection of ovarian cancer. Cancer 113 (3): 484-9, 2008.390Skates SJ, Xu FJ, Yu YH, et al.: Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor markers. Cancer 76 (10 Suppl): 2004-10, 1995.391Skates SJ, Menon U, MacDonald N, et al.: Calculation of the risk of ovarian cancer from serial CA-125 values for preclinical detection in postmenopausal women. J Clin Oncol 21 (10 Suppl): 206s-210s, 2003.392Menon U, Skates SJ, Lewis S, et al.: Prospective study using the risk of ovarian cancer algorithm to screen for ovarian cancer. J Clin Oncol 23 (31): 7919-26, 2005.393Greene MH, Piedmonte M, Alberts D, et al.: A prospective study of risk-reducing salpingo-oophorectomy and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer: design and baseline characteristics: a Gynecologic Oncology Group study. Cancer Epidemiol Biomarkers Prev 17 (3): 594-604, 2008.394Gagnon A, Ye B: Discovery and application of protein biomarkers for ovarian cancer. Curr Opin Obstet Gynecol 20 (1): 9-13, 2008.395Hennessy BT, Murph M, Nanjundan M, et al.: Ovarian cancer: linking genomics to new target discovery and molecular markers--the way ahead. Adv Exp Med Biol 617: 23-40, 2008.396Badgwell D, Bast RC Jr: Early detection of ovarian cancer. Dis Markers 23 (5-6): 397-410, 2007.397Petricoin EF, Ardekani AM, Hitt BA, et al.: Use of proteomic patterns in serum to identify ovarian cancer. Lancet 359 (9306): 572-7, 2002.398Zhang Z, Bast RC Jr, Yu Y, et al.: Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res 64 (16): 5882-90, 2004.399Koehn H, Oehler MK: Proteins' promise--progress and challenges in ovarian cancer proteomics. Menopause Int 13 (4): 148-53, 2007.400Visintin I, Feng Z, Longton G, et al.: Diagnostic markers for early detection of ovarian cancer. Clin Cancer Res 14 (4): 1065-72, 2008.401Simon R: Roadmap for developing and validating therapeutically relevant genomic classifiers. J Clin Oncol 23 (29): 7332-41, 2005.402Rutter JL, Wacholder S, Chetrit A, et al.: Gynecologic surgeries and risk of ovarian cancer in women with BRCA1 and BRCA2 Ashkenazi founder mutations: an Israeli population-based case-control study. J Natl Cancer Inst 95 (14): 1072-8, 2003.403Domchek SM, Friebel TM, Neuhausen SL, et al.: Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Lancet Oncol 7 (3): 223-9, 2006.404Leeper K, Garcia R, Swisher E, et al.: Pathologic findings in prophylactic oophorectomy specimens in high-risk women. Gynecol Oncol 87 (1): 52-6, 2002.405Olivier RI, van Beurden M, Lubsen MA, et al.: Clinical outcome of prophylactic oophorectomy in BRCA1/BRCA2 mutation carriers and events during follow-up. Br J Cancer 90 (8): 1492-7, 2004.406Colgan TJ, Murphy J, Cole DE, et al.: Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am J Surg Pathol 25 (10): 1283-9, 2001.407Powell CB, Kenley E, Chen LM, et al.: Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: role of serial sectioning in the detection of occult malignancy. J Clin Oncol 23 (1): 127-32, 2005.408Callahan MJ, Crum CP, Medeiros F, et al.: Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol 25 (25): 3985-90, 2007.409Domchek SM, Friebel TM, Garber JE, et al.: Occult ovarian cancers identified at risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA1/2 mutation carriers. Breast Cancer Res Treat 124 (1): 195-203, 2010.410Powell CB, Chen LM, McLennan J, et al.: Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: experience with a consecutive series of 111 patients using a standardized surgical-pathological protocol. Int J Gynecol Cancer 21 (5): 846-51, 2011.411Paley PJ, Swisher EM, Garcia RL, et al.: Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol 80 (2): 176-80, 2001.412Rose PG, Shrigley R, Wiesner GL: Germline BRCA2 mutation in a patient with fallopian tube carcinoma: a case report. Gynecol Oncol 77 (2): 319-20, 2000.413Zweemer RP, van Diest PJ, Verheijen RH, et al.: Molecular evidence linking primary cancer of the fallopian tube to BRCA1 germline mutations. Gynecol Oncol 76 (1): 45-50, 2000.414Kindelberger DW, Lee Y, Miron A, et al.: Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 31 (2): 161-9, 2007.415Rabban JT, Krasik E, Chen LM, et al.: Multistep level sections to detect occult fallopian tube carcinoma in risk-reducing salpingo-oophorectomies from women with BRCA mutations: implications for defining an optimal specimen dissection protocol. Am J Surg Pathol 33 (12): 1878-85, 2009.416Society of Gynecologic Oncologists Clinical Practice Committee Statement on Prophylactic Salpingo-oophorectomy. Gynecol Oncol 98 (2): 179-81, 2005.417Chen KT, Schooley JL, Flam MS: Peritoneal carcinomatosis after prophylactic oophorectomy in familial ovarian cancer syndrome. Obstet Gynecol 66 (3 Suppl): 93S-94S, 1985.418Lynch HT, Bewtra C, Lynch JF: Familial ovarian carcinoma. Clinical nuances. Am J Med 81 (6): 1073-6, 1986.419Lynch HT, Watson P, Bewtra C, et al.: Hereditary ovarian cancer. Heterogeneity in age at diagnosis. Cancer 67 (5): 1460-6, 1991.420Tobacman JK, Greene MH, Tucker MA, et al.: Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet 2 (8302): 795-7, 1982.421Truong LD, Maccato ML, Awalt H, et al.: Serous surface carcinoma of the peritoneum: a clinicopathologic study of 22 cases. Hum Pathol 21 (1): 99-110, 1990.422Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 71 (9): 2751-5, 1993.423Chen S, Iversen ES, Friebel T, et al.: Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol 24 (6): 863-71, 2006.424Lavie O, Hornreich G, Ben-Arie A, et al.: BRCA germline mutations in Jewish women with uterine serous papillary carcinoma. Gynecol Oncol 92 (2): 521-4, 2004.425Karlan BY: Defining cancer risks for BRCA germline mutation carriers: implications for surgical prophylaxis. Gynecol Oncol 92 (2): 519-20, 2004.426Biron-Shental T, Drucker L, Altaras M, et al.: High incidence of BRCA1-2 germline mutations, previous breast cancer and familial cancer history in Jewish patients with uterine serous papillary carcinoma. Eur J Surg Oncol 32 (10): 1097-100, 2006.427Beiner ME, Finch A, Rosen B, et al.: The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study. Gynecol Oncol 104 (1): 7-10, 2007.428Lu KH, Kauff ND: Does a BRCA mutation plus tamoxifen equal hysterectomy? Gynecol Oncol 104 (1): 3-4, 2007.429Madalinska JB, Hollenstein J, Bleiker E, et al.: Quality-of-life effects of prophylactic salpingo-oophorectomy versus gynecologic screening among women at increased risk of hereditary ovarian cancer. J Clin Oncol 23 (28): 6890-8, 2005.430Rocca WA, Grossardt BR, de Andrade M, et al.: Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 7 (10): 821-8, 2006.431Rocca WA, Bower JH, Maraganore DM, et al.: Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology 70 (3): 200-9, 2008.432Shuster LT, Rhodes DJ, Gostout BS, et al.: Premature menopause or early menopause: long-term health consequences. Maturitas 65 (2): 161-6, 2010.433Parker WH, Broder MS, Chang E, et al.: Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study. Obstet Gynecol 113 (5): 1027-37, 2009.434Rivera CM, Grossardt BR, Rhodes DJ, et al.: Increased cardiovascular mortality after early bilateral oophorectomy. Menopause 16 (1): 15-23, 2009 Jan-Feb.435Michelsen TM, Pripp AH, Tonstad S, et al.: Metabolic syndrome after risk-reducing salpingo-oophorectomy in women at high risk for hereditary breast ovarian cancer: a controlled observational study. Eur J Cancer 45 (1): 82-9, 2009.436Greene MH, Mai PL, Schwartz PE: Does bilateral salpingectomy with ovarian retention warrant consideration as a temporary bridge to risk-reducing bilateral oophorectomy in BRCA1/2 mutation carriers? Am J Obstet Gynecol 204 (1): 19.e1-6, 2011.437Dietl J, Wischhusen J, Häusler SF: The post-reproductive Fallopian tube: better removed? Hum Reprod 26 (11): 2918-24, 2011.438Leblanc E, Narducci F, Farre I, et al.: Radical fimbriectomy: a reasonable temporary risk-reducing surgery for selected women with a germ line mutation of BRCA 1 or 2 genes? Rationale and preliminary development. Gynecol Oncol 121 (3): 472-6, 2011.439Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Doll R, et al.: Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 371 (9609): 303-14, 2008.440Narod SA, Sun P, Ghadirian P, et al.: Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet 357 (9267): 1467-70, 2001.441Whittemore AS, Balise RR, Pharoah PD, et al.: Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer 91 (11): 1911-5, 2004.442McGuire V, Felberg A, Mills M, et al.: Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations. Am J Epidemiol 160 (7): 613-8, 2004.443McLaughlin JR, Risch HA, Lubinski J, et al.: Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet Oncol 8 (1): 26-34, 2007.444Modan B, Hartge P, Hirsh-Yechezkel G, et al.: Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 345 (4): 235-40, 2001.445Risch HA: Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 90 (23): 1774-86, 1998.446Hankinson SE, Colditz GA, Hunter DJ, et al.: A prospective study of reproductive factors and risk of epithelial ovarian cancer. Cancer 76 (2): 284-90, 1995.447Gronwald J, Byrski T, Huzarski T, et al.: Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland. Breast Cancer Res Treat 95 (2): 105-9, 2006.448Whittemore AS, Harris R, Itnyre J: Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. Am J Epidemiol 136 (10): 1212-20, 1992.449Miracle-McMahill HL, Calle EE, Kosinski AS, et al.: Tubal ligation and fatal ovarian cancer in a large prospective cohort study. Am J Epidemiol 145 (4): 349-57, 1997.450Liede A, Malik IA, Aziz Z, et al.: Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan. Am J Hum Genet 71 (3): 595-606, 2002.451Mohamad HB, Apffelstaedt JP: Counseling for male BRCA mutation carriers: a review. Breast 17 (5): 441-50, 2008.452Schröder FH, Hugosson J, Roobol MJ, et al.: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 360 (13): 1320-8, 2009.453Andriole GL, Grubb RL 3rd, Buys SS, et al.: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 360 (13): 1310-9, 2009.454Fiorentino M, Judson G, Penney K, et al.: Immunohistochemical expression of BRCA1 and lethal prostate cancer. Cancer Res 70 (8): 3136-9, 2010.455Horsburgh S, Matthew A, Bristow R, et al.: Male BRCA1 and BRCA2 mutation carriers: a pilot study investigating medical characteristics of patients participating in a prostate cancer prevention clinic. Prostate 65 (2): 124-9, 2005.456Hubert A, Peretz T, Manor O, et al.: The Jewish Ashkenazi founder mutations in the BRCA1/BRCA2 genes are not found at an increased frequency in Ashkenazi patients with prostate cancer. Am J Hum Genet 65 (3): 921-4, 1999.457Mitra AV, Bancroft EK, Barbachano Y, et al.: Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. BJU Int 107 (1): 28-39, 2011.458National Comprehensive Cancer Network.: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2012. Rockledge, PA : National Comprehensive Cancer Network, 2012. Available online with free subscription. Last accessed February 22, 2013.459Foulkes WD, Metcalfe K, Hanna W, et al.: Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinoma. Cancer 98 (8): 1569-77, 2003.460Jóhannsson OT, Ranstam J, Borg A, et al.: Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol 16 (2): 397-404, 1998.461Stoppa-Lyonnet D, Ansquer Y, Dreyfus H, et al.: Familial invasive breast cancers: worse outcome related to BRCA1 mutations. J Clin Oncol 18 (24): 4053-9, 2000.462Haffty BG, Harrold E, Khan AJ, et al.: Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet 359 (9316): 1471-7, 2002.463Robson M, Levin D, Federici M, et al.: Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations. J Natl Cancer Inst 91 (24): 2112-7, 1999.464Graeser MK, Engel C, Rhiem K, et al.: Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27 (35): 5887-92, 2009.465Robson ME, Chappuis PO, Satagopan J, et al.: A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res 6 (1): R8-R17, 2004.466Rennert G, Bisland-Naggan S, Barnett-Griness O, et al.: Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 357 (2): 115-23, 2007.467Kriege M, Seynaeve C, Meijers-Heijboer H, et al.: Sensitivity to first-line chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27 (23): 3764-71, 2009.468Goodwin PJ, Phillips KA, West DW, et al.: Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study. J Clin Oncol 30 (1): 19-26, 2012.469Verhoog LC, Berns EM, Brekelmans CT, et al.: Prognostic significance of germline BRCA2 mutations in hereditary breast cancer patients. J Clin Oncol 18 (21 Suppl): 119S-24S, 2000.470Brekelmans CT, Tilanus-Linthorst MM, Seynaeve C, et al.: Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer 43 (5): 867-76, 2007.471Budroni M, Cesaraccio R, Coviello V, et al.: Role of BRCA2 mutation status on overall survival among breast cancer patients from Sardinia. BMC Cancer 9: 62, 2009.472Moynahan ME, Cui TY, Jasin M: Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 61 (12): 4842-50, 2001.473Husain A, He G, Venkatraman ES, et al.: BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res 58 (6): 1120-3, 1998.474Mullan PB, Quinn JE, Gilmore PM, et al.: BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents. Oncogene 20 (43): 6123-31, 2001.475Quinn JE, Kennedy RD, Mullan PB, et al.: BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res 63 (19): 6221-8, 2003.476Lafarge S, Sylvain V, Ferrara M, et al.: Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway. Oncogene 20 (45): 6597-606, 2001.477Tutt A, Ashworth A: Can genetic testing guide treatment in breast cancer? Eur J Cancer 44 (18): 2774-80, 2008.478Byrski T, Huzarski T, Dent R, et al.: Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 115 (2): 359-63, 2009.479Chappuis PO, Goffin J, Wong N, et al.: A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 39 (8): 608-10, 2002.480Byrski T, Gronwald J, Huzarski T, et al.: Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 28 (3): 375-9, 2010.481Fourquet A, Stoppa-Lyonnet D, Kirova YM, et al.: Familial breast cancer: clinical response to induction chemotherapy or radiotherapy related to BRCA1/2 mutations status. Am J Clin Oncol 32 (2): 127-31, 2009.482Arun B, Bayraktar S, Liu DD, et al.: Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol 29 (28): 3739-46, 2011.483Byrski T, Gronwald J, Huzarski T, et al.: Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat 108 (2): 289-96, 2008.484Silver DP, Richardson AL, Eklund AC, et al.: Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 28 (7): 1145-53, 2010.485Bryant HE, Schultz N, Thomas HD, et al.: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434 (7035): 913-7, 2005.486Fong PC, Boss DS, Yap TA, et al.: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361 (2): 123-34, 2009.487Tutt A, Robson M, Garber JE, et al.: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376 (9737): 235-44, 2010.488Audeh MW, Carmichael J, Penson RT, et al.: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376 (9737): 245-51, 2010.489Rottenberg S, Jaspers JE, Kersbergen A, et al.: High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A 105 (44): 17079-84, 2008.490Evers B, Drost R, Schut E, et al.: Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin Cancer Res 14 (12): 3916-25, 2008.491Leong T, Whitty J, Keilar M, et al.: Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients. Int J Radiat Oncol Biol Phys 48 (4): 959-65, 2000.492Pierce LJ, Strawderman M, Narod SA, et al.: Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 18 (19): 3360-9, 2000.493Shanley S, McReynolds K, Ardern-Jones A, et al.: Late toxicity is not increased in BRCA1/BRCA2 mutation carriers undergoing breast radiotherapy in the United Kingdom. Clin Cancer Res 12 (23): 7025-32, 2006.494Pierce LJ, Phillips KA, Griffith KA, et al.: Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy. Breast Cancer Res Treat 121 (2): 389-98, 2010.495Kirova YM, Savignoni A, Sigal-Zafrani B, et al.: Is the breast-conserving treatment with radiotherapy appropriate in BRCA1/2 mutation carriers? Long-term results and review of the literature. Breast Cancer Res Treat 120 (1): 119-26, 2010.496Metcalfe K, Lynch HT, Ghadirian P, et al.: Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 127 (1): 287-96, 2011.497Reding KW, Bernstein JL, Langholz BM, et al.: Adjuvant systemic therapy for breast cancer in BRCA1/BRCA2 mutation carriers in a population-based study of risk of contralateral breast cancer. Breast Cancer Res Treat 123 (2): 491-8, 2010.498Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56 (1): 265-71, 1995.499Robson M, Gilewski T, Haas B, et al.: BRCA-associated breast cancer in young women. J Clin Oncol 16 (5): 1642-9, 1998.500Robson M, Svahn T, McCormick B, et al.: Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic-based series. Cancer 103 (1): 44-51, 2005.501Verhoog LC, Brekelmans CT, Seynaeve C, et al.: Contralateral breast cancer risk is influenced by the age at onset in BRCA1-associated breast cancer. Br J Cancer 83 (3): 384-6, 2000.502Verhoog LC, Brekelmans CT, Seynaeve C, et al.: Survival in hereditary breast cancer associated with germline mutations of BRCA2. J Clin Oncol 17 (11): 3396-402, 1999.503van der Kolk DM, de Bock GH, Leegte BK, et al.: Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age. Breast Cancer Res Treat 124 (3): 643-51, 2010.504Kirova YM, Stoppa-Lyonnet D, Savignoni A, et al.: Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy. Eur J Cancer 41 (15): 2304-11, 2005.505Metcalfe K, Lynch HT, Ghadirian P, et al.: Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22 (12): 2328-35, 2004.506Weitzel JN, Robson M, Pasini B, et al.: A comparison of bilateral breast cancers in BRCA carriers. Cancer Epidemiol Biomarkers Prev 14 (6): 1534-8, 2005.507Malone KE, Begg CB, Haile RW, et al.: Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol 28 (14): 2404-10, 2010.508Rubin SC, Benjamin I, Behbakht K, et al.: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335 (19): 1413-6, 1996.509Ben David Y, Chetrit A, Hirsh-Yechezkel G, et al.: Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20 (2): 463-6, 2002.510Cass I, Baldwin RL, Varkey T, et al.: Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 97 (9): 2187-95, 2003.511Aida H, Takakuwa K, Nagata H, et al.: Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res 4 (1): 235-40, 1998.512Boyd J, Sonoda Y, Federici MG, et al.: Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 283 (17): 2260-5, 2000.513Tan DS, Rothermundt C, Thomas K, et al.: "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 26 (34): 5530-6, 2008.514Chetrit A, Hirsh-Yechezkel G, Ben-David Y, et al.: Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol 26 (1): 20-5, 2008.515Lacour RA, Westin SN, Meyer LA, et al.: Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations. Gynecol Oncol 121 (2): 358-63, 2011.516Vencken PM, Kriege M, Hoogwerf D, et al.: Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 22 (6): 1346-52, 2011.517Pal T, Permuth-Wey J, Kapoor R, et al.: Improved survival in BRCA2 carriers with ovarian cancer. Fam Cancer 6 (1): 113-9, 2007.518Yang D, Khan S, Sun Y, et al.: Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 306 (14): 1557-65, 2011.519Zweemer RP, Verheijen RH, Coebergh JW, et al.: Survival analysis in familial ovarian cancer, a case control study. Eur J Obstet Gynecol Reprod Biol 98 (2): 219-23, 2001.520Pharoah PD, Easton DF, Stockton DL, et al.: Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. Cancer Res 59 (4): 868-71, 1999.521Buller RE, Shahin MS, Geisler JP, et al.: Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin Cancer Res 8 (5): 1196-202, 2002.522Fong PC, Yap TA, Boss DS, et al.: Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 28 (15): 2512-9, 2010.523Hennessy BT, Timms KM, Carey MS, et al.: Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol 28 (22): 3570-6, 2010.524Kaye SB, Lubinski J, Matulonis U, et al.: Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30 (4): 372-9, 2012.525Adams SF, Marsh EB, Elmasri W, et al.: A high response rate to liposomal doxorubicin is seen among women with BRCA mutations treated for recurrent epithelial ovarian cancer. Gynecol Oncol 123 (3): 486-91, 2011.526Gelmon KA, Tischkowitz M, Mackay H, et al.: Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12 (9): 852-61, 2011.527Ledermann J, Harter P, Gourley C, et al.: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366 (15): 1382-92, 2012.528Vasen HF: Clinical description of the Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)]. Fam Cancer 4 (3): 219-25, 2005.529Jascur T, Boland CR: Structure and function of the components of the human DNA mismatch repair system. Int J Cancer 119 (9): 2030-5, 2006.530Papadopoulos N, Nicolaides NC, Wei YF, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 263 (5153): 1625-9, 1994.531Peltomäki P, Vasen HF: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113 (4): 1146-58, 1997.532Akiyama Y, Sato H, Yamada T, et al.: Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res 57 (18): 3920-3, 1997.533Miyaki M, Konishi M, Tanaka K, et al.: Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17 (3): 271-2, 1997.534Huang J, Kuismanen SA, Liu T, et al.: MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer. Cancer Res 61 (4): 1619-23, 2001.535Nicolaides NC, Papadopoulos N, Liu B, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371 (6492): 75-80, 1994.536Hendriks YM, Jagmohan-Changur S, van der Klift HM, et al.: Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 130 (2): 312-22, 2006.537Worthley DL, Walsh MD, Barker M, et al.: Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 128 (5): 1431-6, 2005.538Watson P, Lynch HT: Cancer risk in mismatch repair gene mutation carriers. Fam Cancer 1 (1): 57-60, 2001.539Vasen HF, Wijnen JT, Menko FH, et al.: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110 (4): 1020-7, 1996.540Aarnio M, Mecklin JP, Aaltonen LA, et al.: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64 (6): 430-3, 1995.541Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71 (3): 677-85, 1993.542Brown GJ, St John DJ, Macrae FA, et al.: Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer: implications for gynecologic surveillance. Gynecol Oncol 80 (3): 346-9, 2001.543Aarnio M, Sankila R, Pukkala E, et al.: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81 (2): 214-8, 1999.544Grindedal EM, Renkonen-Sinisalo L, Vasen H, et al.: Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds. J Med Genet 47 (2): 99-102, 2010.545Pal T, Permuth-Wey J, Sellers TA: A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer. Cancer 113 (4): 733-42, 2008.546Jensen UB, Sunde L, Timshel S, et al.: Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 120 (3): 777-82, 2010.547Shanley S, Fung C, Milliken J, et al.: Breast cancer immunohistochemistry can be useful in triage of some HNPCC families. Fam Cancer 8 (3): 251-5, 2009.548Walsh MD, Buchanan DD, Cummings MC, et al.: Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry. Clin Cancer Res 16 (7): 2214-24, 2010.549Buerki N, Gautier L, Kovac M, et al.: Evidence for breast cancer as an integral part of Lynch syndrome. Genes Chromosomes Cancer 51 (1): 83-91, 2012.550Win AK, Young JP, Lindor NM, et al.: Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol 30 (9): 958-64, 2012.551Win AK, Lindor NM, Young JP, et al.: Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst 104 (18): 1363-72, 2012.552Garber JE, Goldstein AM, Kantor AF, et al.: Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 51 (22): 6094-7, 1991.553Bottomley RH, Condit PT: Cancer families. Cancer Bull 20: 22-24, 1968.554Malkin D: The Li-Fraumeni syndrome. Cancer: Principles and Practice of Oncology Updates 7(7): 1-14, 1993.555Olivier M, Goldgar DE, Sodha N, et al.: Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63 (20): 6643-50, 2003.556Gonzalez KD, Noltner KA, Buzin CH, et al.: Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 27 (8): 1250-6, 2009.557Ginsburg OM, Akbari MR, Aziz Z, et al.: The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30. Fam Cancer 8 (4): 563-7, 2009.558Mouchawar J, Korch C, Byers T, et al.: Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res 70 (12): 4795-800, 2010.559Harris CC, Hollstein M: Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329 (18): 1318-27, 1993.560Sidransky D, Tokino T, Helzlsouer K, et al.: Inherited p53 gene mutations in breast cancer. Cancer Res 52 (10): 2984-6, 1992.561Wilson JR, Bateman AC, Hanson H, et al.: A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet 47 (11): 771-4, 2010.562Melhem-Bertrandt A, Bojadzieva J, Ready KJ, et al.: Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer 118 (4): 908-13, 2012.563Masciari S, Dillon DA, Rath M, et al.: Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat 133 (3): 1125-30, 2012.564Villani A, Tabori U, Schiffman J, et al.: Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 12 (6): 559-67, 2011.565Masciari S, Van den Abbeele AD, Diller LR, et al.: F18-fluorodeoxyglucose-positron emission tomography/computed tomography screening in Li-Fraumeni syndrome. JAMA 299 (11): 1315-9, 2008.566Tsou HC, Teng DH, Ping XL, et al.: The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet 61 (5): 1036-43, 1997.567Pilarski R, Eng C: Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 41 (5): 323-6, 2004.568Olopade OI, Weber BL: Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: part I. Cancer: Principles and Practice of Oncology Updates 12(10): 1-12, 1998.569Nelen MR, Padberg GW, Peeters EA, et al.: Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet 13 (1): 114-6, 1996.570Lachlan KL, Lucassen AM, Bunyan D, et al.: Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet 44 (9): 579-85, 2007.571Lynch ED, Ostermeyer EA, Lee MK, et al.: Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis. Am J Hum Genet 61 (6): 1254-60, 1997.572Myers MP, Tonks NK: PTEN: sometimes taking it off can be better than putting it on. Am J Hum Genet 61 (6): 1234-8, 1997.573Peutz JL: On a very remarkable case of familial polyposis of the mucous membrane of the intestinal tract and nasopharynx accompanied by peculiar pigmentations of the skin and mucous membrane. Ned Tijdschr Geneeskd 10: 134-146, 1921.574Jeghers H, McKusick VA, Katz KH: Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits: a syndrome of diagnostic significance. N Engl J Med 241(25): 993-1005, 1949.575Spigelman AD, Murday V, Phillips RK: Cancer and the Peutz-Jeghers syndrome. Gut 30 (11): 1588-90, 1989.576Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 26 (6): 513-9, 2005.577Hemminki A, Markie D, Tomlinson I, et al.: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (6663): 184-7, 1998.578Jenne DE, Reimann H, Nezu J, et al.: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18 (1): 38-43, 1998.579Boudeau J, Kieloch A, Alessi DR, et al.: Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers Syndrome patients. Hum Mutat 21 (2): 172, 2003.580Lim W, Hearle N, Shah B, et al.: Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer 89 (2): 308-13, 2003.581van Lier MG, Wagner A, Mathus-Vliegen EM, et al.: High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 105 (6): 1258-64; author reply 1265, 2010.582Westerman AM, Entius MM, de Baar E, et al.: Peutz-Jeghers syndrome: 78-year follow-up of the original family. Lancet 353 (9160): 1211-5, 1999.583Giardiello FM, Brensinger JD, Tersmette AC, et al.: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119 (6): 1447-53, 2000.584Hearle N, Schumacher V, Menko FH, et al.: Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12 (10): 3209-15, 2006.585Mehenni H, Resta N, Park JG, et al.: Cancer risks in LKB1 germline mutation carriers. Gut 55 (7): 984-90, 2006.586Lim W, Olschwang S, Keller JJ, et al.: Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 126 (7): 1788-94, 2004.
Low- and Moderate-Penetrance Genes Associated With Breast and/or Ovarian Cancer
Mutations in BRCA1, BRCA2, and the genes involved in other rare syndromes discussed in the High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes section of this summary account for less than 25% of the familial risk of breast cancer. Despite intensive genetic linkage studies, there do not appear to be other BRCA1/BRCA2-like high-penetrance genes that account for a significant fraction of the remaining multiple-case familial clusters. These observations suggest that the remaining breast cancer susceptibility is polygenic in nature, meaning that a relatively large number of low-penetrance genes are involved. On its own, each low-penetrance locus would be expected to have a relatively small effect on breast cancer risk and would not produce dramatic familial aggregation or influence patient management. However in combination with other genetic loci and/or environmental factors, particularly given how common these can be, variants of this kind might significantly alter breast cancer risk. These types of genetic variations are sometimes referred to as “polymorphisms,” meaning that the gene or locus occurs in several “forms” within the population (and more formally defined as polymorphic when a specific variation in a given locus occurs in more than 1% of the population). Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed “disease-associated polymorphisms” or “functionally relevant polymorphisms.” This polygenic model of susceptibility is consistent with the observed patterns of familial aggregation of breast cancer. Although the clinical significance and causality of associations with breast cancer are often difficult to evaluate and establish, genetic polymorphisms may account for why some individuals are more sensitive than others to environmental carcinogens.
Polymorphisms underlying polygenic susceptibility to breast cancer are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to “high-penetrance” variants or alleles that are typically associated with more severe phenotypes, for example those BRCA1/BRCA2 mutations leading to an autosomal dominant inheritance patterns in a family. The definition of a “moderate” risk of cancer is arbitrary, but it is usually considered to be in the range of a relative risk (RR) of 1.5 to 2.0. Because these types of sequence variants (also called low-penetrance genes, alleles, mutations, and polymorphisms) are relatively common in the general population, their contribution to cancer risk overall is estimated to be much greater than the attributable risk in the population from mutations in BRCA1 and BRCA2. For example, it is estimated by segregation analysis that half of all breast cancer occurs in 12% of the population that is deemed most susceptible. There are no known low-penetrance variants in BRCA1/BRCA2. The N372H variation in BRCA2, initially thought to be a low-penetrance allele, was not verified in a large combined analysis.
Two strategies have been taken to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design. The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and, despite some confirmed associations (described below), has been relatively disappointing  The candidate gene approach has largely been replaced by the genome-wide association studies (GWAS) in which a very large number of single nucleotide polymorphisms (SNPs) (potentially 1 million or more) are chosen within the genome and tested, mostly without regard to their possible biological function, but instead to capture all genetic variation throughout the genome more uniformly.
Breast Cancer Susceptibility Genes Identified Through Candidate Gene Approaches
There is a very large literature of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. This section is not a comprehensive review of all reported associations. This section describes associations that are believed by the editors to be clinically valid, in that they have been described in several different studies or are supported by robust meta-analyses. The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response.
CHEK2 (OMIM) is a gene involved in the DNA damage repair response pathway. Based on numerous studies, a polymorphism, 1100delC, appears to be a rare, moderate-penetrance cancer susceptibility allele. One study identified the mutation in 1.2% of the European controls, 4.2% of the European BRCA1/BRCA2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases. In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the CHEK2 1100delC mutation. In additional European and U.S. (where the mutation appears to be slightly less common) studies, including a large prospective study, the frequency of CHEK2 mutations detected in familial breast or ovarian cancer cases has ranged from 0%  to 11%; overall, these studies have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer. A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among mutation carriers.
Two studies have suggested that the risk associated with a CHEK2 1100delC mutation was stronger in the families of probands ascertained because of bilateral breast cancer. Furthermore, a meta-analysis of 1100delC mutation carriers estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer. Similarly, a Polish study reported that CHEK2 truncating mutations confer breast cancer risks based on a family history of breast cancer as follows: no family history: 20%; one second-degree relative: 28%; one first-degree relative: 34%; and both first- and second-degree relatives: 44%. Moreover, a Dutch study suggested that female homozygotes for the CHEK2 1100delC mutation have a greater-than-twofold increased breast cancer risk compared to heterozygotes. Although there have been conflicting reports regarding cancers other than breast cancer associated with CHEK2 mutations, this may be dependent on mutation type (i.e., missense vs. truncating) or population studied and is not currently of clinical utility. The contribution of CHEK2 mutations to breast cancer may depend on the population studied, with a potentially higher mutation prevalence in Poland. CHEK2 mutation carriers in Poland may be more susceptible to ER-positive breast cancer.
Currently, the clinical applicability of CHEK mutations remains uncertain because of low mutation prevalence and lack of guidelines for clinical management.
Ataxia telangiectasia (AT) (OMIM) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of ATM mutations (OMIM). More than 300 mutations in the gene have been identified to date, most of which are truncating mutations. ATM proteins have been shown to play a role in cell cycle control. In vitro, AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.
Initial studies searching for an excess of ATM mutations among breast cancer patients provided conflicting results, perhaps due to study design and mutation testing strategies. However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated RR of approximately 2.0. Despite this convincing epidemiologic association, the clinical application of testing for ATM mutations is unclear due to the wide mutational spectrum and the logistics of testing. Because the presence of a mutation could pose a risk in screening-related radiation exposure, further investigation is needed.
BRIP1 (also known as BACH1) encodes a helicase that interacts with the BRCT domain of BRCA1. This gene also has a role in BRCA1-dependent DNA repair and cell cycle checkpoint function. Biallelic mutations in BRIP1 are a cause of Fanconi anemia, much like such mutations in BRCA2. Inactivating mutations of BRIP1 are associated with an increased risk of breast cancer. In one study, more than 3,000 individuals from BRCA1/BRCA2 mutation negative families were examined for BRIP1 mutations. Mutations were identified in 9 of 1,212 individuals with breast cancer but in only 2 of 2,081 controls (P = .003). The RR of breast cancer was estimated to be 2.0 (95% confidence interval [CI], 1.2–3.2; P = .012). Of note, in families with BRIP1 mutations and multiple cases of breast cancer, there was incomplete segregation of the mutation with breast cancer, consistent with a low penetrance allele and similar to that seen with CHEK2.
PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double-stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic mutations in PALB2 have also been shown to cause Fanconi anemia. PALB2 mutations have been screened for in multiple small studies of familial and early-onset breast cancer in multiple populations. Mutation prevalence has ranged from 0.4% to 3.4%. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 mutations in families with hereditary breast cancer. Among 559 cases with contralateral breast cancer and 565 matched controls with unilateral breast cancer, pathogenic (truncating) PALB2 mutations were identified in 0.9% of cases and in none of the controls (RR, 5.3; 95% CI, 1.8–13.2). A Finnish PALB2 founder mutation (c.1592delT) has been reported to confer a 40% risk of breast cancer to age 70 years  and is associated with a high incidence (54%) of triple-negative disease and lower survival. Mutations have been observed in early-onset and familial breast cancer in many populations.
Male breast cancer has been observed in PALB2 mutation–positive breast cancer families. In a study of 115 male breast cancer cases in which 18 men had BRCA2 mutations, an additional two men had either a pathogenic or predicted pathogenic PALB2 mutation (accounting for about 10% of germline mutations in the study and 1%–2% of the total sample). Following the identification of PALB2 mutations in pancreatic tumors and the detection of germline mutations in 3% of 96 familial pancreatic patients, numerous studies have pointed to a role for PALB2 in pancreatic cancer. A sixfold increase in pancreatic cancer was observed in the relatives of 33 BRCA1/2-negative, PALB2 mutation–positive breast cancer probands. PALB2 mutations were detected in 3.7% of 81 familial pancreatic cancer families  and in 2.1% of 94 BRCA1/2 mutation–negative breast cancer patients who had either a personal or family history of pancreatic cancer. Two relatively small studies, one of 77 BRCA1/2 mutation–negative probands with a personal or family history of pancreatic cancer, one-half of whom were of Ashkenazi Jewish descent, and another study of 29 Italian pancreatic cancer patients with a personal or family history of breast or ovarian cancer, failed to detect any PALB2 mutations.
The observed prevalence of PALB2 mutations in familial breast cancer varied depending on ascertainment relative to personal and family history of pancreatic and ovarian cancers, but in all studies, the observed mutation rate was less than 4%. The RR of breast cancer appears moderate, and the risk of other cancers (e.g., pancreatic) is poorly defined; therefore, the clinical utility of testing is not clear. There is insufficient evidence to support routine screening of PALB2 when tests of the more common genes, namely BRCA1/2, are negative.
CASP8 and TGFB1
The Breast Cancer Association Consortium (BCAC) investigated single nucleotide polymorphisms identified in previous studies as possibly associated with excess breast cancer risk in 15,000 to 20,000 cases and 15,000 to 20,000 controls. Two SNPs, CASP8 D302H and TGFB1 L10P, were associated with invasive breast cancer with RRs of 0.88 (95% CI, 0.84–0.92) and 1.08 (95% CI, 1.04–1.11), respectively.
RAD51 and the family of RAD51-related genes, also known as RAD51 paralogs, are thought to encode proteins that are involved in DNA damage repair through homologous recombination and interaction with numerous other DNA repair proteins, including BRCA1 and BRCA2. RAD51 protein plays a central role in single-strand annealing in the DNA damage response. RAD51 recruitment to break sites and recombinational DNA repair depend on the RAD51 paralogs, although their precise cellular functions are poorly characterized. Mutations in these genes are thought to result in loss of RAD51 focus formation in response to DNA damage.
One of five RAD51-related genes, RAD51C has been reported to be linked to both Fanconi anemia–like disorders and familial breast and ovarian cancers. The literature, however, has produced contradictory findings. In a study of 480 German families characterized by breast and ovarian cancers who were negative for BRCA1 and BRCA2 mutations, six monoallelic mutations in RAD51C were found (frequency of 1.3%). No mutations were found in breast cancer–only families or in healthy controls. Another study screened 286 BRCA1/2-negative patients with breast cancer and/or ovarian cancer and found one likely deleterious mutation in RAD51C-G153D. RAD51C mutations have also been reported in Australian, Finnish, and Spanish non-BRCA1/2 ovarian cancer–only and breast/ovarian cancer families, and in unselected ovarian cancer cases. Three additional studies were unable to confirm an association between the RAD51C gene and hereditary breast cancer or ovarian cancer.
In addition to RAD51C mutation carriers, there are other RAD51 paralogs, including RAD51D and RAD51L1, that may be associated with breast and/or ovarian cancer risk, although the clinical significance of these findings is unknown.
In addition to germline mutations, different polymorphisms of RAD51 have been hypothesized to have reduced capacity to repair DNA defects, resulting in increased susceptibility to familial breast cancer. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) pooled data from 8,512 BRCA1 and BRCA2 mutation carriers and found evidence of an increased risk of breast cancer among women who were BRCA2 carriers and who were homozygous for CC at the RAD51 135G→C SNP (hazard ratio, 1.17; 95% CI, 0.91–1.51).
Several meta-analyses have investigated the association between the RAD51 135G→C polymorphism and breast cancer risk. There is significant overlap in the studies reported in these meta-analyses, significant variability in the characteristics of the populations included, and significant methodologic limitations to their findings.  A meta-analysis of nine epidemiologic studies involving 13,241 cases and 13,203 controls of unknown BRCA1/2 status found that women carrying the CC genotype had an increased risk of breast cancer compared to women with the GG or GC genotype (OR [odds ratio], 1.35; 95% CI, 1.04–1.74). A meta-analysis of 14 case-control studies involving 12,183 cases and 10,183 controls confirmed an increased risk only for women who were known BRCA2 carriers (OR, 4.92; 95% CI, 1.10–21.83). Another meta-analysis of 12 studies included only studies of known BRCA-negative cases and found no association between RAD51 135G→C and breast cancer.
In summary, among this conflicting data there is substantial evidence for a weak association between germline mutations in RAD51C and breast cancer and ovarian cancer. There is also evidence of an association between polymorphisms in RAD51 135G→C among women with homozygous CC genotypes and breast cancer, particularly among BRCA2 carriers. These associations are plausible given the known role of RAD51 in the maintenance of genomic stability.
Mutations in the BRCA1-interacting gene Abraxas were found in three Finnish breast cancer families and no controls. The significance of this finding outside of this population is not yet known.
In contrast to assessing candidate genes and/or alleles, genome wide association studies involve comparing a very large set of genetic variants spread throughout the genome. The current paradigm uses sets of up to 5 million SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap and the 1000 Genomes Project. By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained. The strong correlation between many SNPs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to “scan” the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNPs. While this between-SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is causal.
Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including breast cancer. The first study involved an initial scan in familial breast cancer cases followed by replication in two large sample sets of sporadic breast cancer, the final being a collection of over 20,000 cases and 20,000 controls from the BCAC, an international group of investigators. Five distinct genomic regions were identified that were within or near the FGFR2, TNRC9, MAP3K1, and LSP1 genes or at the chromosome 8q region. The 8q region and others may harbor multiple independent loci associated with risk, but these regions are included only once in Table 8. Subsequent genome-wide studies have replicated these loci and identified additional ones, as summarized in Table 8. Numerous SNPs identified through large studies of sporadic breast cancer appear to be associated more strongly with estrogen receptor–positive disease; however, some are associated primarily or exclusively with other subtypes, including triple-negative disease. An online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs) is available.Table 8. High-probability Breast Cancer Susceptibility Loci Identified Through Genome-Wide Association StudiesPutative Gene(s)Chromosome SNPStudy CitationaOdds Ratio (OR) (95% Confidence Interval [CI])bComments ER- = estrogen receptor–negative; ER+ = estrogen receptor–positive; PR- = progesterone receptor–negative; PR+ = progesterone receptor–positive; SNP = single nucleotide polymorphism; triple-negative = ER-/PR-/HER2/neu-. aInitial study that demonstrated genome-wide significance for each locus.bAll associations observed in the general population, unless otherwise indicated; when relevant, if association was also observed in BRCA1 or BRCA2 mutation carriers, it is indicated.cOR for best tagSNP was used  as a surrogate for published SNP.Intergenic /NOTCH2 1p11.2rs112494331.08 (1.02–1.15) Stronger in ER+, low-grade ; also in BRCA2  ERBB22q34rs133935771.53 (1.37–1.70) Identified in Korean subjects  Intergenic 2q35rs133870421.21 (1.14–1.29) Stronger in bilateral and lobular ; also in BRCA1 and BRCA2 SLC4A7, NEK103p24rs49737681.16 (1.10–1.24) Also in BRCA2  MRPS30 5p12rs109416791.11c (1.04–1.19) Strongest in PR+, low-grade ; also in BRCA2 TERT-/CLPTM15p15rs100696901.25 (1.16–1.34) Strongest in triple-negative MAP3K1 5q11.2 rs8893121.22 (1.14–1.30) Stronger in ER+ ; also in BRCA2 RNF1466q22rs21803411.24 (1.13–1.36)  Stronger in Ashkenazi Jews  ESR1 6q25.1rs20462101.15c (1.08–1.22) Also in BRCA1  TAB26q25.1rs94853720.90 (0.87–0.92) Identified in Chinese subjects  Intergenic7q32.3rs20486721.11 (1.05–1.17) Identified in East Asian subjects Intergenic/MYC 8q24.21rs132816151.14 (1.07–1.21) Stronger in ER+  CDKN2A, CDKN2B 9p21rs10119701.09 (1.04–1.14) Stronger in ER+ ; also in BRCA2 Intergenic9q31.2rs8656860.89 (0.85–0.92) Also in BRCA2 ANKRD16, FBXO18 10p15.1 rs23802050.94 (0.91–0.98) ZNF365 10q21.2 rs109951900.86 (0.82–0.91) Stronger in ER+ in general population ; also in BRCA2 ZMIZ110q22.3rs7040101.07 (1.03–1.11) FGFR2 10q26.13rs29815821.43 (1.35–1.53) Strongest for ER+, low-grade ; also in BRCA2  LSP111p15.5 rs38171981.12 (1.05–1.19) Also in BRCA2 Intergenic11q13rs6143671.15 (1.10–1.20) Restricted to ER+ tumors; strongest for ER+/PR+BARX211q24.3rs7107217 1.08 (1.05–1.11) Identified in Chinese subjects PTHLH12p11rs107713990.85 (0.83–0.88) Also in BRCA1 Intergenic12q24rs12920110.92 (0.91–0.94) Restricted to ER+ ; also in BRCA2 RAD51B 14q24.1rs9997370.89 (0.83–0.95) Associated with all subtypes, including triple-negative ; also in BRCA2 TOX3 16q12.1 rs38036621.30 (1.22–1.39) Stronger in ER+ ; also in BRCA1 and BRCA2  COX1117q23.2rs65049500.92c (0.86–0.99) BABAM1 19p13.1rs81701.26 (1.17–1.35) Restricted to triple-negative in general population ; also in BRCA1 NRIP121q21rs28230930.94 (0.92–0.96) Restricted to ER+ Table 9. High-probability Ovarian Cancer Susceptibility Loci Identified Through Genome-Wide Association StudiesPutative Gene(s)ChromosomeSNPStudy CitationOdds Ratio (95% Confidence Interval)CommentSNP = single nucleotide polymorphism.HOXD12q31.1rs20725901.16 (1.12–1.21)Stronger in serous cancersTIPARP3q25.31rs26653901.19 (1.11–1.27)Intergenic/MYC, THEM758q24.21rs100882180.84 (0.80–0.89)BNC29p22.2rs38141130.82 (0.79–0.86)Stronger in serous cancers; also in BRCA1 and BRCA2 SKAP117q21.32rs93035421.11 (1.06–1.16)BABAM1 19p13.11rs81701.18 (1.12–1.25)Serous cancers onlyANKLE119p13.11rs23639561.16 (1.11–1.21)
Although the statistical evidence for an association between genetic variation at these loci and breast and ovarian cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk (typically, OR <1.5), with more risk variants likely to be identified. No interaction between the SNPs and epidemiologic risk factors for breast cancer have been identified. At this time, because their individual and collective influences on cancer risk have not been evaluated prospectively, they are not considered clinically relevant. Furthermore, theoretical models have suggested that common moderate-risk SNPs have limited potential to improve models for individualized risk assessment. These models used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC) as a measure of discriminatory accuracy. A more recent study used ROC curve analysis to examine the utility of SNPs in a clinical dataset of greater than 5,500 breast cancer cases and nearly 6,000 controls, using a model with traditional risk factors compared to a model using both standard risk factors and ten previously identified SNPs. The addition of genetic information modestly changed the AUC from 58% to 61.8%, a result that was not felt to be clinically significant. Despite this, 32.5% of patients were in a higher quintile of breast cancer risk when genetic information was included, and 20.4% were in a lower quintile of risk. It remains unclear whether such information has clinical utility.
More limited data are available regarding ovarian cancer risk. Three GWAS involving staged analysis of over 10,000 cases and 13,000 controls have been carried out for ovarian cancer. The seven loci that reached genome-wide significance are shown in Table 9. As in other GWAS, the ORs are modest, generally about 1.2 or weaker, but implicate a number of genes with plausible biological ties to ovarian cancer, such as BABAM1, whose protein complexes with and may regulate BRCA1, and TIRAPR, which codes for a poly (ADP-ribose) polymerase (PARP), molecules that may be important in BRCA1/BRCA2-deficient cells.
In addition to genome-wide studies interrogating common genetic variants, sequencing-based studies involving whole-genome or whole-exome sequencing  are also identifying genes associated with breast cancer, such as XRCC2, a rare, moderate-penetrance, breast cancer susceptibility gene.1Easton DF: How many more breast cancer predisposition genes are there? Breast Cancer Res 1 (1): 14-7, 1999.2Smith P, McGuffog L, Easton DF, et al.: A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45 (7): 646-55, 2006.3Pharoah PD, Antoniou A, Bobrow M, et al.: Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31 (1): 33-6, 2002.4Antoniou AC, Pharoah PP, Smith P, et al.: The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 91 (8): 1580-90, 2004.5Chen YC, Hunter DJ: Molecular epidemiology of cancer. CA Cancer J Clin 55 (1): 45-54; quiz 57, 2005 Jan-Feb.6Breast Cancer Association Consortium: Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J Natl Cancer Inst 98 (19): 1382-96, 2006.7Dunning AM, Healey CS, Pharoah PD, et al.: A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8 (10): 843-54, 1999.8Meijers-Heijboer H, van den Ouweland A, Klijn J, et al.: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31 (1): 55-9, 2002.9Kuschel B, Auranen A, Gregory CS, et al.: Common polymorphisms in checkpoint kinase 2 are not associated with breast cancer risk. Cancer Epidemiol Biomarkers Prev 12 (8): 809-12, 2003.10Sodha N, Bullock S, Taylor R, et al.: CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours. Br J Cancer 87 (12): 1445-8, 2002.11Ingvarsson S, Sigbjornsdottir BI, Huiping C, et al.: Mutation analysis of the CHK2 gene in breast carcinoma and other cancers. Breast Cancer Res 4 (3): R4, 2002.12Vahteristo P, Bartkova J, Eerola H, et al.: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71 (2): 432-8, 2002.13Meijers-Heijboer H, Wijnen J, Vasen H, et al.: The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 72 (5): 1308-14, 2003.14Schmidt MK, Tollenaar RA, de Kemp SR, et al.: Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. J Clin Oncol 25 (1): 64-9, 2007.15Weischer M, Bojesen SE, Tybjaerg-Hansen A, et al.: Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol 25 (1): 57-63, 2007.16Iniesta MD, Gorin MA, Chien LC, et al.: Absence of CHEK2*1100delC mutation in families with hereditary breast cancer in North America. Cancer Genet Cytogenet 202 (2): 136-40, 2010.17Offit K, Pierce H, Kirchhoff T, et al.: Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 4 (1): 1, 2003.18Oldenburg RA, Kroeze-Jansema K, Kraan J, et al.: The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res 63 (23): 8153-7, 2003.19Neuhausen S, Dunning A, Steele L, et al.: Role of CHEK2*1100delC in unselected series of non-BRCA1/2 male breast cancers. Int J Cancer 108 (3): 477-8, 2004.20Ohayon T, Gal I, Baruch RG, et al.: CHEK2*1100delC and male breast cancer risk in Israel. Int J Cancer 108 (3): 479-80, 2004.21CHEK2 Breast Cancer Case-Control Consortium.: CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 74 (6): 1175-82, 2004.22Johnson N, Fletcher O, Naceur-Lombardelli C, et al.: Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study. Lancet 366 (9496): 1554-7, 2005 Oct 29-Nov 4.23Fletcher O, Johnson N, Dos Santos Silva I, et al.: Family history, genetic testing, and clinical risk prediction: pooled analysis of CHEK2 1100delC in 1,828 bilateral breast cancers and 7,030 controls. Cancer Epidemiol Biomarkers Prev 18 (1): 230-4, 2009.24Weischer M, Bojesen SE, Ellervik C, et al.: CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 26 (4): 542-8, 2008.25Cybulski C, Wokołorczyk D, Jakubowska A, et al.: Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol 29 (28): 3747-52, 2011.26Adank MA, Jonker MA, Kluijt I, et al.: CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women. J Med Genet 48 (12): 860-3, 2011.27Gronwald J, Cybulski C, Piesiak W, et al.: Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband. Br J Cancer 100 (9): 1508-12, 2009.28Wasielewski M, den Bakker MA, van den Ouweland A, et al.: CHEK2 1100delC and male breast cancer in the Netherlands. Breast Cancer Res Treat 116 (2): 397-400, 2009.29Osorio A, Rodríguez-López R, Díez O, et al.: The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer 108 (1): 54-6, 2004.30Syrjäkoski K, Kuukasjärvi T, Auvinen A, et al.: CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer 108 (3): 475-6, 2004.31Tsou HC, Teng DH, Ping XL, et al.: The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet 61 (5): 1036-43, 1997.32Olopade OI, Weber BL: Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: part I. Cancer: Principles and Practice of Oncology Updates 12(10): 1-12, 1998.33Cybulski C, Górski B, Huzarski T, et al.: CHEK2-positive breast cancers in young Polish women. Clin Cancer Res 12 (16): 4832-5, 2006.34Cybulski C, Huzarski T, Byrski T, et al.: Estrogen receptor status in CHEK2-positive breast cancers: implications for chemoprevention. Clin Genet 75 (1): 72-8, 2009.35Offit K, Garber JE: Time to check CHEK2 in families with breast cancer? J Clin Oncol 26 (4): 519-20, 2008.36Savitsky K, Bar-Shira A, Gilad S, et al.: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268 (5218): 1749-53, 1995.37Telatar M, Teraoka S, Wang Z, et al.: Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet 62 (1): 86-97, 1998.38Uhrhammer N, Bay JO, Bignon YJ: Seventh International Workshop on Ataxia-Telangiectasia. Cancer Res 58 (15): 3480-5, 1998.39Ahmed M, Rahman N: ATM and breast cancer susceptibility. Oncogene 25 (43): 5906-11, 2006.40Khanna KK, Chenevix-Trench G: ATM and genome maintenance: defining its role in breast cancer susceptibility. J Mammary Gland Biol Neoplasia 9 (3): 247-62, 2004.41Gilad S, Chessa L, Khosravi R, et al.: Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 62 (3): 551-61, 1998.42FitzGerald MG, Bean JM, Hegde SR, et al.: Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 15 (3): 307-10, 1997.43Chen J, Birkholtz GG, Lindblom P, et al.: The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res 58 (7): 1376-9, 1998.44Bay JO, Grancho M, Pernin D, et al.: No evidence for constitutional ATM mutation in breast/gastric cancer families. Int J Oncol 12 (6): 1385-90, 1998.45Laake K, Vu P, Andersen TI, et al.: Screening breast cancer patients for Norwegian ATM mutations. Br J Cancer 83 (12): 1650-3, 2000.46Dörk T, Bendix R, Bremer M, et al.: Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61 (20): 7608-15, 2001.47Teraoka SN, Malone KE, Doody DR, et al.: Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 92 (3): 479-87, 2001.48Chenevix-Trench G, Spurdle AB, Gatei M, et al.: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 94 (3): 205-15, 2002.49Thorstenson YR, Roxas A, Kroiss R, et al.: Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63 (12): 3325-33, 2003.50Cavaciuti E, Laugé A, Janin N, et al.: Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families. Genes Chromosomes Cancer 42 (1): 1-9, 2005.51Olsen JH, Hahnemann JM, Børresen-Dale AL, et al.: Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia. Br J Cancer 93 (2): 260-5, 2005.52Renwick A, Thompson D, Seal S, et al.: ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38 (8): 873-5, 2006.53Thompson D, Duedal S, Kirner J, et al.: Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97 (11): 813-22, 2005.54Levitus M, Waisfisz Q, Godthelp BC, et al.: The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet 37 (9): 934-5, 2005.55Levran O, Attwooll C, Henry RT, et al.: The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet 37 (9): 931-3, 2005.56Litman R, Peng M, Jin Z, et al.: BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8 (3): 255-65, 2005.57Seal S, Thompson D, Renwick A, et al.: Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38 (11): 1239-41, 2006.58Reid S, Schindler D, Hanenberg H, et al.: Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39 (2): 162-4, 2007.59Ding YC, Steele L, Kuan CJ, et al.: Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. Breast Cancer Res Treat 126 (3): 771-8, 2011.60Rahman N, Seal S, Thompson D, et al.: PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39 (2): 165-7, 2007.61Erkko H, Dowty JG, Nikkilä J, et al.: Penetrance analysis of the PALB2 c.1592delT founder mutation. Clin Cancer Res 14 (14): 4667-71, 2008.62Heikkinen T, Kärkkäinen H, Aaltonen K, et al.: The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clin Cancer Res 15 (9): 3214-22, 2009.63Ding YC, Steele L, Chu LH, et al.: Germline mutations in PALB2 in African-American breast cancer cases. Breast Cancer Res Treat 126 (1): 227-30, 2011.64Foulkes WD, Ghadirian P, Akbari MR, et al.: Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res 9 (6): R83, 2007.65Casadei S, Norquist BM, Walsh T, et al.: Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res 71 (6): 2222-9, 2011.66Southey MC, Teo ZL, Dowty JG, et al.: A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Res 12 (6): R109, 2010.67Hellebrand H, Sutter C, Honisch E, et al.: Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. Hum Mutat 32 (6): E2176-88, 2011.68Bogdanova N, Sokolenko AP, Iyevleva AG, et al.: PALB2 mutations in German and Russian patients with bilateral breast cancer. Breast Cancer Res Treat 126 (2): 545-50, 2011.69Wong MW, Nordfors C, Mossman D, et al.: BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. Breast Cancer Res Treat 127 (3): 853-9, 2011.70Zheng Y, Zhang J, Niu Q, et al.: Novel germline PALB2 truncating mutations in African American breast cancer patients. Cancer 118 (5): 1362-70, 2012.71Tischkowitz M, Capanu M, Sabbaghian N, et al.: Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum Mutat 33 (4): 674-80, 2012.72Jones S, Hruban RH, Kamiyama M, et al.: Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324 (5924): 217, 2009.73Slater EP, Langer P, Niemczyk E, et al.: PALB2 mutations in European familial pancreatic cancer families. Clin Genet 78 (5): 490-4, 2010.74Hofstatter EW, Domchek SM, Miron A, et al.: PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer 10 (2): 225-31, 2011.75Stadler ZK, Salo-Mullen E, Sabbaghian N, et al.: Germline PALB2 mutation analysis in breast-pancreas cancer families. J Med Genet 48 (8): 523-5, 2011.76Ghiorzo P, Pensotti V, Fornarini G, et al.: Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy. Fam Cancer 11 (1): 41-7, 2012.77Cox Angela, Dunning Alison, Garcia-Closas Montserrat, et al.: Nature genetics. Nat Genet 39 (5): 352-8, 2007.78Suwaki N, Klare K, Tarsounas M: RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. Semin Cell Dev Biol 22 (8): 898-905, 2011.79Vaz F, Hanenberg H, Schuster B, et al.: Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42 (5): 406-9, 2010.80Meindl A, Hellebrand H, Wiek C, et al.: Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42 (5): 410-4, 2010.81Clague J, Wilhoite G, Adamson A, et al.: RAD51C germline mutations in breast and ovarian cancer cases from high-risk families. PLoS One 6 (9): e25632, 2011.82Thompson ER, Boyle SE, Johnson J, et al.: Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Hum Mutat 33 (1): 95-9, 2012.83Pelttari LM, Heikkinen T, Thompson D, et al.: RAD51C is a susceptibility gene for ovarian cancer. Hum Mol Genet 20 (16): 3278-88, 2011.84Vuorela M, Pylkäs K, Hartikainen JM, et al.: Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility. Breast Cancer Res Treat 130 (3): 1003-10, 2011.85Romero A, Pérez-Segura P, Tosar A, et al.: A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families. Breast Cancer Res Treat 129 (3): 939-46, 2011.86Zheng Y, Zhang J, Hope K, et al.: Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer. Breast Cancer Res Treat 124 (3): 857-61, 2010.87Akbari MR, Tonin P, Foulkes WD, et al.: RAD51C germline mutations in breast and ovarian cancer patients. Breast Cancer Res 12 (4): 404, 2010.88Loveday C, Turnbull C, Ramsay E, et al.: Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43 (9): 879-82, 2011.89Thomas G, Jacobs KB, Kraft P, et al.: A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41 (5): 579-84, 2009.90Figueroa JD, Garcia-Closas M, Humphreys M, et al.: Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20 (23): 4693-706, 2011.91Osher DJ, De Leeneer K, Michils G, et al.: Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families. Br J Cancer 106 (8): 1460-3, 2012.92Antoniou AC, Sinilnikova OM, Simard J, et al.: RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet 81 (6): 1186-200, 2007.93He XF, Su J, Zhang Y, et al.: Need for clarification of data in the recent meta-analysis about RAD51 135G>C polymorphism and breast cancer risk. Breast Cancer Res Treat 129 (2): 649-51; author reply 652-3, 2011.94Lu W, Wang X, Lin H, et al.: Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Fam Cancer 11 (3): 381-5, 2012.95Wang WW, Spurdle AB, Kolachana P, et al.: A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10 (9): 955-60, 2001.96Wang Z, Dong H, Fu Y, et al.: RAD51 135G>C polymorphism contributes to breast cancer susceptibility: a meta-analysis involving 26,444 subjects. Breast Cancer Res Treat 124 (3): 765-9, 2010.97Zhou GW, Hu J, Peng XD, et al.: RAD51 135G>C polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 125 (2): 529-35, 2011.98Yu KD, Yang C, Fan L, et al.: RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers: evidence from a meta-analysis of 12 studies. Breast Cancer Res Treat 126 (2): 365-71, 2011.99Solyom S, Aressy B, Pylkäs K, et al.: Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions. Sci Transl Med 4 (122): 122ra23, 2012.100Thorisson GA, Smith AV, Krishnan L, et al.: The International HapMap Project Web site. Genome Res 15 (11): 1592-3, 2005.101Clarke L, Zheng-Bradley X, Smith R, et al.: The 1000 Genomes Project: data management and community access. Nat Methods 9 (5): 459-62, 2012.102Evans DM, Cardon LR: Genome-wide association: a promising start to a long race. Trends Genet 22 (7): 350-4, 2006.103Cardon LR: Genetics. Delivering new disease genes. Science 314 (5804): 1403-5, 2006.104Chanock SJ, Manolio T, Boehnke M, et al.: Replicating genotype-phenotype associations. Nature 447 (7145): 655-60, 2007.105Wellcome Trust Case Control Consortium.: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (7145): 661-78, 2007.106Easton DF, Pooley KA, Dunning AM, et al.: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447 (7148): 1087-93, 2007.107Stacey SN, Manolescu A, Sulem P, et al.: Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39 (7): 865-9, 2007.108Hunter DJ, Kraft P, Jacobs KB, et al.: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39 (7): 870-4, 2007.109Turnbull C, Ahmed S, Morrison J, et al.: Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42 (6): 504-7, 2010.110Gold B, Kirchhoff T, Stefanov S, et al.: Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci U S A 105 (11): 4340-5, 2008.111Zheng W, Long J, Gao YT, et al.: Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41 (3): 324-8, 2009.112Kibriya MG, Jasmine F, Argos M, et al.: A pilot genome-wide association study of early-onset breast cancer. Breast Cancer Res Treat 114 (3): 463-77, 2009.113Murabito JM, Rosenberg CL, Finger D, et al.: A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study. BMC Med Genet 8 (Suppl 1): S6, 2007.114Stacey SN, Manolescu A, Sulem P, et al.: Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40 (6): 703-6, 2008.115Ahmed S, Thomas G, Ghoussaini M, et al.: Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41 (5): 585-90, 2009.116Reeves GK, Travis RC, Green J, et al.: Incidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci. JAMA 304 (4): 426-34, 2010.117Haiman CA, Chen GK, Vachon CM, et al.: A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer. Nat Genet 43 (12): 1210-4, 2011.118Stevens KN, Fredericksen Z, Vachon CM, et al.: 19p13.1 is a triple-negative-specific breast cancer susceptibility locus. Cancer Res 72 (7): 1795-803, 2012.119Antoniou AC, Kartsonaki C, Sinilnikova OM, et al.: Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet 20 (16): 3304-21, 2011.120Kim HC, Lee JY, Sung H, et al.: A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study. Breast Cancer Res 14 (2): R56, 2012.121Antoniou AC, Beesley J, McGuffog L, et al.: Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res 70 (23): 9742-54, 2010.122Milne RL, Goode EL, García-Closas M, et al.: Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer. Cancer Epidemiol Biomarkers Prev 20 (10): 2222-31, 2011.123Kirchhoff T, Chen ZQ, Gold B, et al.: The 6q22.33 locus and breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev 18 (9): 2468-75, 2009.124Long J, Cai Q, Sung H, et al.: Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer. PLoS Genet 8 (2): e1002532, 2012.125Cai Q, Long J, Lu W, et al.: Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium. Hum Mol Genet 20 (24): 4991-9, 2011.126Antoniou AC, Kuchenbaecker KB, Soucy P, et al.: Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. Breast Cancer Res 14 (1): R33, 2012.127Fletcher O, Johnson N, Orr N, et al.: Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. J Natl Cancer Inst 103 (5): 425-35, 2011.128Couch FJ, Gaudet MM, Antoniou AC, et al.: Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 21 (4): 645-57, 2012.129Ghoussaini M, Fletcher O, Michailidou K, et al.: Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet 44 (3): 312-8, 2012.130Antoniou AC, Wang X, Fredericksen ZS, et al.: A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 42 (10): 885-92, 2010.131Goode EL, Chenevix-Trench G, Song H, et al.: A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 42 (10): 874-9, 2010.132Song H, Ramus SJ, Tyrer J, et al.: A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat Genet 41 (9): 996-1000, 2009.133Ramus SJ, Kartsonaki C, Gayther SA, et al.: Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 103 (2): 105-16, 2011.134Bolton KL, Tyrer J, Song H, et al.: Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat Genet 42 (10): 880-4, 2010.135Campa D, Kaaks R, Le Marchand L, et al.: Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst 103 (16): 1252-63, 2011.136Milne RL, Gaudet MM, Spurdle AB, et al.: Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study. Breast Cancer Res 12 (6): R110, 2010.137Pharoah PD, Antoniou AC, Easton DF, et al.: Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358 (26): 2796-803, 2008.138Gail MH: Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast cancer risk. J Natl Cancer Inst 100 (14): 1037-41, 2008.139Gail MH: Value of adding single-nucleotide polymorphism genotypes to a breast cancer risk model. J Natl Cancer Inst 101 (13): 959-63, 2009.140Wacholder S, Hartge P, Prentice R, et al.: Performance of common genetic variants in breast-cancer risk models. N Engl J Med 362 (11): 986-93, 2010.141Shendure J: Next-generation human genetics. Genome Biol 12 (9): 408, 2011.142Park DJ, Lesueur F, Nguyen-Dumont T, et al.: Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet 90 (4): 734-9, 2012.
Psychosocial Issues in Inherited Breast Cancer Syndromes
Psychosocial research in the context of cancer genetic testing helps to define psychological outcomes, interpersonal and familial effects, and cultural and community responses. It also identifies behavioral factors that encourage or impede screening and other health behaviors. It can enhance decision-making about risk-reduction interventions, evaluate psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification and genetic testing, provide data to help resolve ethical concerns, and predict the interest in testing of various groups.
Research in these areas is limited by few randomized controlled trials, and many reports are based on uncontrolled studies of selected high-risk populations. Research is likely to expand considerably with access to larger populations of at-risk individuals.
There have been a number of descriptions of cancer genetics programs that provide genetic susceptibility testing.  The development of such programs was encouraged by federal funding of multidisciplinary research programs that offered intensive genetic counseling for hereditary cancer syndromes, psychological assessment and back-up, and physician involvement.
Interest in and Uptake of Genetic Testing
Decisions about whether to pursue breast cancer genetic testing involve complex biologic, behavioral, and social elements. There are vast differences in interest in and actual uptake rates of testing reported in the literature. In a systematic review of 40 peer-reviewed primary clinical studies published between 1990 and May 2002, it was reported that sampling frame and other methodological variables contributed to the wide variability. On average, interest in genetic testing was 66% (range 20%–96%), while actual uptake of genetic testing was 59% (range, 25%–96%) (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.16–1.39). In multivariate analysis, personal and family history of cancer, study recruitment and setting were all associated with testing uptake. A more recent study also found that having a personal history of breast cancer and having at least some college education predicted uptake of BRCA testing. Researchers in Ontario, Canada, surveyed 416 women diagnosed with epithelial ovarian cancer or fallopian tube cancer between 2002 and 2004. Although genetic testing is freely available in Canada to women diagnosed with ovarian cancer or fallopian tube cancer, only 80 of 416 women surveyed (19%) had undergone clinical genetic testing. The researchers concluded that uptake of genetic testing may rise with increased public awareness directed at both physicians and patients. In a study of over 1,500 family members from 60 kindreds with a 25% or higher risk of carrying the family mutation, attendance at a family informational session doubled rates of mutation testing compared to non-attendees (75% vs. 34%). Those who opted for mutation testing included persons who had previously provided a blood sample for research genetic testing and persons who had not previously donated a blood sample.
Furthermore, accrual statistics in different populations are difficult to compare because there are many points in the genetic risk assessment process at which a family member can decline, and no standard method of reporting these rates has been developed. Factors that may influence uptake of testing include the following:
- Cost of genetic testing.
- How informative testing would be (e.g., presence of a known mutation in the family or ethnic group vs. lack of an identified mutation).
- Extent to which genetic test results are likely to influence clinical decision-making.
Motivations for testing include the belief that testing positive would increase one’s motivation to get regular clinical breast examinations, to do breast self-exams, and to get recommended mammograms. Women known to be at increased risk do not necessarily adhere to screening recommendations at higher rates than women at population risk, nor do they necessarily pursue or complete genetic testing, though the data on this subject are contradictory. An additional motivation for testing is to receive information that would benefit other family members.
Another motivator for testing may be recommendation by a physician. In a retrospective study of 335 women considering genetic testing, 77% reported that they wanted the opinion of the genetics physician about whether they should be tested, and 49% wanted the opinion of their primary care provider. However, there is some evidence of referral bias favoring those with a maternal family history. In a Canadian retrospective review of 315 patients, those with a maternal family history of breast cancer or ovarian cancer were 4.9 times (95% CI, 3.6–6.7) more likely to be referred for a cancer genetics consultation by their physician than were those with a paternal family history (P < .001). Studies have found that physicians may not adequately assess paternal family history  or may underestimate the significance of a paternal family history for genetic risk.
In one study of women who pursued BRCA1 and BRCA2 mutation testing and received uninformative test results, 45% (17/40) were interested in undergoing additional testing for five large rearrangements (deletions and insertions) in the BRCA1 gene. There were no significant differences in BRCAPRO scores, age at time of genetic testing, number of children, or number of siblings between individuals who chose to pursue additional testing and those who declined. Women who chose to undergo additional testing were significantly less likely to have a diagnosis of breast or ovarian cancer at the time of initial testing.
Limited data are available about the characteristics of at-risk individuals who decline to be or have never been tested. It is difficult to access samples of test decliners since they are people who also may be reluctant to participate in research studies. Studies of testing are difficult to compare because people may decline at different points and with different amounts of pretest education and counseling. One study found that 43% of affected and unaffected individuals from hereditary breast/ovarian cancer families completing a baseline interview regarding testing declined. Most individuals declining testing chose not to participate in educational sessions. Decliners were more likely to be male and unmarried and had fewer relatives affected with breast cancer. Those decliners who had high levels of cancer-related stress had higher levels of depression. Decliners lost to follow-up were significantly more likely to be affected with cancer. Another study looked at a small number (n = 13) of women decliners who carry a 25% to 50% probability of harboring a BRCA mutation and found that these nontested women were more likely to be childless and have a higher educational level. This study showed that most women had decided not to undergo the test after serious deliberation about the risks and benefits. Satisfaction with frequent surveillance was given as one reason for nontesting in most of these women. Other reasons for declining included having no children and becoming acquainted with breast/ovarian cancer in the family relatively early in their lives. A third study evaluated characteristics of 34 individuals who declined BRCA1/BRCA2 testing in a large multicenter study in the United Kingdom. Decliners were younger compared with a national sample of test acceptors, and female decliners had lower mean scores on a measure of cancer worry. Although 78% of test decliners/deferrers felt that their health was at risk, they reported that learning about their BRCA1/BRCA2 mutation status would cause them to worry about the following:
- Their children's health (76%).
- Their life insurance (60%).
- Their own health (56%).
- Loss of their job (5%).
- Receiving less screening if they did not carry a BRCA1/BRCA2 mutation (62%).
Apprehension about the impact of the test result was a more important factor in the reason to decline than concrete burdens such as time to travel to a genetics clinic and time away from work, family, and social obligations. In 15% (n = 31) of individuals from 13 hereditary breast and ovarian cancer families who underwent genetic education and counseling and declined testing for a documented mutation in the family, positive changes in family relationships were reported, specifically greater expressiveness and cohesion, compared with those who pursued testing.
Participation in breast cancer risk counseling among relatives of breast cancer patients is positively associated with higher levels of education, income, and positive health behaviors (nonsmokers, any current alcohol use, recent clinical breast exam), and perceived and objective risk perception. Other predictors of participation are being married, having a family history of cancer, presence of a daughter, fear of stigma, and believing there are more reasons to be tested than not to be tested.
Women recruited from high-risk clinics who have expressed their concern about breast cancer by seeking specialized medical attention are more likely than women recruited from registry sources to attend counseling and educational sessions about cancer genetics and genetic testing. Genetic testing uptake was influenced by eligibility for free testing, history of breast or ovarian cancer, and Ashkenazi Jewish heritage. Interest in testing declines sharply if it is not immediately available. Knowledge about the details of cancer genetic testing is not associated with the decision to be tested, suggesting a need for improved education about cancer genetics. Several studies suggest that interest in cancer genetic testing is generally high despite respondents' relative lack of knowledge regarding the pros and cons of attempting to learn one's mutation status. One U.K. study suggested that proactive approaches to offering predictive testing (telephone calls and home visits) may be useful in increasing testing uptake among at-risk men.
There are limited data on uptake of genetic counseling and testing among nonwhite populations, and further research will be needed to define factors influencing uptake in these populations. In a study of African American women at increased risk of breast cancer, those with a personal history of cancer or a greater perceived risk of developing cancer were more likely to report greater limitations or drawbacks of genetic testing. Those with more fatalistic beliefs about cancer, higher perceived risk of having a BRCA1/BRCA2 mutation, and more relatives affected with breast or ovarian cancer were more likely to consider undergoing BRCA1/BRCA2 testing. In a case-control study of women who had been seen in a university-based primary care system, African-American women with a family history of breast or ovarian cancer were less likely to undergo BRCA1/BRCA2 testing compared with white women who had similar histories. Other predictors of testing used in that study include younger age, higher anxiety, belief that testing will provide reassurance, absence of concern about discrimination, and having had a primary care doctor or gynecologist discuss genetic testing with the patient.
What People Bring to Genetic Testing: Impact of Risk Perception, Health Beliefs, and Personality Characteristics
The emerging literature in this area suggests that risk perceptions, health beliefs, psychological status, and personality characteristics are important factors in decision-making about breast/ovarian cancer genetic testing. Many women presenting at academic centers for BRCA1/BRCA2 testing arrive with a strong belief that they have a mutation, having decided they want genetic testing, but possessing little information about the risks or limitations of testing. Most mean scores of psychological functioning at baseline for subjects in genetic counseling studies were within normal limits. Nonetheless, a subset of subjects in many genetic counseling studies present with elevated anxiety, depression, or cancer worry. Identification of these individuals is essential to prevent adverse outcomes. In a study of 205 women pursuing genetic counseling, interactions among cancer worry, breast cancer risk perception, and perceived severity of having a breast cancer gene mutation were found such that those with high worry, high breast cancer risk perception, and low perceived severity were twice as likely to follow through with BRCA1/BRCA2 testing than others.
A general tendency to overestimate inherited risk of breast and ovarian cancer has been noted in at-risk populations, in cancer patients, in spouses of breast and ovarian cancer patients, and among women in the general population, but underestimation of breast cancer risk in higher-risk and average-risk women also has been reported. This overestimation may encourage a belief that BRCA1/BRCA2 genetic testing will be more informative than it is currently thought to be. There is some evidence that even counseling does not dissuade women at low to moderate risk from the belief that BRCA1 testing could be valuable. Overestimation of both breast and ovarian cancer risk has been associated with nonadherence to physician-recommended screening practices. A meta-analysis of 12 studies of outcomes of genetic counseling for breast/ovarian cancer showed that counseling improved the accuracy of risk perception.
Women appear to be the prime communicators within families about the family history of breast cancer. Higher numbers of maternal versus paternal transmission cases are reported, likely due to family communication patterns, to the misconception that breast cancer risk can only be transmitted through the mother, and to the greater difficulty in recognizing paternal family histories because of the need to identify more distant relatives with cancer. In an analysis of 2,505 women participating in the Family Healthware Impact Trial, not only was evidence of underreporting of paternal family history identified, but also women reported a lower level of perceived breast cancer risk with a paternal versus maternal breast cancer family history. Physicians and counselors taking a family history are encouraged to elicit paternal and maternal family histories of breast, ovarian, or other associated cancers.
The accuracy of reported family history of breast or ovarian cancer varies; some studies found levels of accuracy above 90%, with others finding more errors in the reporting of cancer in second-degree or more distant relatives  or in age of onset of cancer. Less accuracy has been found in the reporting of cancers other than breast cancer. Ovarian cancer history was reported with 60% accuracy in one study compared with 83% accuracy in breast cancer history. Providers should be aware that there are a few published cases of Munchausen syndrome in reporting of false family breast cancer history. Much more common is erroneous reporting of family cancer history due to unintentional errors or gaps in knowledge, related in some cases to the early death of potential maternal informants about cancer family history. (Refer to the Taking a Family History section of the Cancer Genetics Risk Assessment and Counseling summary for more information.)
Targeted written, video, CD-ROM, interactive computer program, and culturally targeted educational materials  may be an effective and efficient means of increasing knowledge about the pros and cons of genetic testing. Such supplemental materials may allow more efficient use of the time allotted for pretest education and counseling by genetics and primary care providers and may discourage individuals without appropriate indication of risk from seeking genetic testing.
Genetic Counseling for Hereditary Predisposition to Breast Cancer
Counseling for breast cancer risk typically involves individuals with family histories that are potentially attributable to BRCA1 or BRCA2. It also, however, may include individuals with family histories of Li-Fraumeni syndrome, ataxia-telangiectasia, Cowden syndrome, or Peutz-Jeghers syndrome. (Refer to the High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes section of this summary for more information.)
Management strategies for carriers may involve decisions about the nature, frequency, and timing of screening and surveillance procedures, chemoprevention, risk-reducing surgery, and use of hormone replacement therapy (HRT). The utilization of breast conservation and radiation as cancer therapy for women who are carriers may be influenced by knowledge of mutation status. (Refer to the Clinical management of BRCA mutation carriers section of this summary for more information.)
Counseling also includes consideration of related psychosocial concerns and discussion of planned family communication and the responsibility to warn other family members about the possibility of having an increased risk of breast, ovarian, and other cancers. Data are emerging that individual responses to being tested as adults are influenced by the results status of other family members. Management of anxiety and distress are important not only as quality-of-life factors, but also because high anxiety may interfere with the understanding and integration of complex genetic and medical information and adherence to screening. The limited number of medical interventions with proven benefit to mutation carriers provides further basis for the expectation that mutation carriers may experience increased anxiety, depression, and continuing uncertainty following disclosure of genetic test results. Formal, objective evaluation of these outcomes are now emerging. (Refer to the Emotional Outcomes and Behavioral Outcomes sections of this summary for more information.)
Published descriptions of counseling programs for BRCA1 (and subsequently for BRCA2) testing include strategies for gathering a family history, assessing eligibility for testing, communicating the considerable volume of relevant information about breast/ovarian cancer genetics and associated medical and psychosocial risks and benefits, and discussion of specialized ethical considerations about confidentiality and family communication. Participant distress, intrusive thoughts about cancer, coping style, and social support were assessed in many prospective testing candidates. The psychosocial outcomes evaluated in these programs have included changes in knowledge about the genetics of breast/ovarian cancer after counseling, risk comprehension, psychological adjustment, family and social functioning, and reproductive and health behaviors. A Dutch study of communication processes and satisfaction levels of counselees going through cancer genetic counseling for inherited cancer syndromes indicated that asking more medical questions (by the counselor), providing more psychosocial information, and longer eye contact by the counselor were associated with lower satisfaction levels. The provision of medical information by the counselor was most highly related to satisfaction and perception that needs have been fulfilled. Additional research is needed on how to adequately address the emotional needs and feelings of control of counselees.
Many of the psychosocial outcome studies involve specialized, highly selected research populations, some of which were utilized to map and clone BRCA1 and BRCA2. One such example is K2082, an extensively studied kindred of more than 800 members of a Utah Mormon family in which a BRCA1 mutation accounts for the observed increased rates of breast and ovarian cancer. A study of the understanding that members of this kindred have about breast/ovarian cancer genetics found that, even in breast cancer research populations, there was incomplete knowledge about associated risks of colon and prostate cancer, the existence of options for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), and the complexity of existing psychosocial risks. A meta-analysis of 21 studies found that genetic counseling was effective in increasing knowledge and improved the accuracy of perceived risk. Genetic counseling did not have a statistically significant long-term impact on affective outcomes including anxiety, distress, or cancer-specific worry and the behavioral outcome of cancer surveillance activities. These prospective studies, however, were characterized by a heterogeneity of measures of cancer-specific worry and inconsistent findings in effects of change from baseline.
It is not yet clearly established to what extent findings derived from special research populations, at least some of which have long awaited genetic testing for breast/ovarian cancer risk, are generalizable to other populations. For example, there are data to suggest that the BRCA1/BRCA2 penetrance estimates derived from these dramatically affected families are substantial overestimates and do not apply to most families presenting for counseling and possible testing.
Emotional Outcomes of Individuals
Studies conducted to date of psychological outcomes associated with genetic testing for mutations in breast/ovarian cancer predisposition genes have shown low levels of distress among those found to be carriers and even lower levels among noncarriers. A systematic review found that the studies assessing measures of distress (9 of 11 studies) found no change, or a decrease, in those parameters (including anxiety, depression, general distress, and situation distress) in people who had undergone testing at assessments done at 1 month or less, and 3 to 6 months later. One follow-up study from the United Kingdom measured levels of cancer-related worry, general mental health, risk perception, intrusive or avoidant thoughts, and risk-management behaviors at baseline and 1, 4, and 12 months after results were provided. This study included 202 unaffected women and 59 unaffected men, of whom 91 tested positive and 170 tested negative. Results showed that while female noncarriers had significant (P < .001) reductions in cancer-related worry, female carriers younger than 50 years had an increase in cancer-related worry 1 month posttesting. These levels returned to baseline by 12 months but remained higher than noncarrier levels throughout the 12-month period. Female carriers engaged in more posttest screening than noncarriers (92% vs. 30%) within 12 months of test results disclosure. Thirty carriers had RRM and/or RRSO within the same time period. A slightly smaller subset of this cohort was assessed again for cancer-related worry, general mental health and risk-management behaviors 3 years following genetic test result disclosure. One hundred fifty-four women and 39 males, including 71 carriers and 122 noncarriers, returned the questionnaire. The level of distress and cancer worry was similar between carriers and noncarriers. Female carriers had higher distress levels at 3 years versus 1 year postdisclosure, but their level of cancer worry decreased significantly over the same time period. In female noncarriers, although the level of cancer worry had decreased from baseline to 1 year postdisclosure, these levels returned to baseline by 3 years. The authors did not comment on contextual factors that might influence distress and cancer worry levels. Another study reported that, compared with pretest levels, mean scores on 1-year posttest measures of cancer-specific distress and state-anxiety decreased significantly among noncarriers, while scores on these measures and on a measure of general distress did not change among BRCA1/BRCA2 carriers. One long-term study of 65 female participants explored the psychosocial consequences of carrying a BRCA1/BRCA2 mutation 5 years after genetic testing. Carriers did not differ from noncarriers on several distress measures. Although both groups showed significant increases in depression and anxiety compared with 1 year postdisclosure, these scores remained within normal limits for the general population. Caution is advised by authors of these studies in interpretation of the results as they are all from programs in which results disclosure was preceded by extensive genetic counseling about risks and benefits of BRCA1/BRCA2 testing, psychological assessment, and in some cases exclusion of a few individuals who appeared highly distressed. Intrusive thoughts (measured by the Impact of Event Scale [IES])  about cancer diminished after results disclosure for both mutation-positive and mutation-negative individuals in one Dutch study.
Some studies have examined reactions to BRCA testing several years following the receipt of results. Two U.S.-based studies have reported similar findings among women who were surveyed more than 3 years after receipt of BRCA test results. In a cross-sectional study, 167 women who were surveyed more than 4 years after receiving BRCA test results reported low levels of genetic testing–specific concerns, as measured using the Multidimensional Impact of Cancer Risk Assessment Scale. Approximately 74% of women reported no distress; 41% reported no uncertainty about their cancer risk, screening decisions, and options for risk management and prevention; and 51% reported positive experiences suggestive of low adverse reactions pertaining to family support and communication. In multivariate regression models, mutation carriers were significantly more likely to experience distress than were noncarriers. Time since disclosure of test result significantly predicted uncertainty but not distress, such that more time since disclosure corresponded to less uncertainty. In a second study, 464 women were followed prospectively for a median of 5 years (range: 3.4–9.1 years) after testing. Among both affected and unaffected participants, BRCA carriers reported significantly higher levels of distress, uncertainty (affected only), perceived stress (affected only), and lower positive testing experiences (unaffected only) than women who received negative results. Although both studies reported greater distress among BRCA carriers than among noncarriers, the level of distress was not reflective of clinically significant dysfunction.
A prospective Australian study evaluated the psychological impact of genetic testing at baseline, 7 to 10 days, 4 months, and 12 months in 60 women of Ashkenazi Jewish heritage (ten with breast cancer, 50 unaffected). Of the 43 women who opted to learn their test results, 97% felt pleased to have had the test and, at 12 months of follow-up, none regretted having been tested. Seventeen women opted not to receive their results and had significantly lower levels of breast cancer anxiety than did those who opted to receive their results. Women with no history of cancer who opted to learn their results showed a progressive decrease in breast cancer anxiety over the 12-month study period compared with baseline measures. There was also no statistically significant difference in measures of depression and generalized anxiety from baseline to the follow-up assessments. However, these results must be interpreted in light of the fact that only 7 of 43 women had deleterious mutations.
Despite generally positive findings regarding diminished distress in tested individuals, most studies also report increased distress among small subsets of tested individuals. Most, but not all, of these increases are within the normal range of distress. Increased distress has been noted by individuals receiving both positive and negative test results. Studies suggest that the psychological impact of an individual test result is highly influenced by the test result status of other family members. A 1999 study found that an individual’s response to learning his or her own BRCA1/BRCA2 test result was significantly influenced by his or her gender and by the genetic test result status of other family members. Adverse, immediate outcomes were experienced by male carriers who were the first tested in their family or by noncarrier men whose siblings were all positive. In addition, female carriers who were the first in their families to be tested or whose siblings were all negative had significantly higher distress than other female carriers. Another study found that spousal anxiety about genetic testing and supportiveness differentiated the impact of BRCA1/BRCA2 test results. When the spouse was highly anxious and unsupportive in style, the mutation carrier had significantly higher levels of distress. These studies illustrate that genetic test results are not received in a vacuum, and that researchers need to consider the context of the tested individual in determining which individuals applying for genetic testing may require additional emotional support.
In another study, depression rates postdisclosure were unchanged for mutation carriers and markedly decreased for noncarriers. An analysis of the distress of individuals receiving BRCA1 results in the context of their siblings' results, however, revealed patterns of response suggesting that certain subgroups of tested individuals have markedly increased levels of distress after disclosure that were not apparent when the analysis focused only on comparing the mean scores for carriers versus noncarriers. Early optimistic findings may not sufficiently reflect the true complexity of response to disclosure of BRCA1/BRCA2 test results. Female carriers who had no carrier siblings had distress scores (IES) similar to those found in cancer patients 10 weeks after their diagnosis. The distress of male subjects was highly correlated with the status of their siblings’ test results or lack thereof. One pilot study suggested that women diagnosed more recently were more distressed after counseling. A survey of women enrolled in a high-risk clinic found that heightened levels of distress may be more related to living with the awareness of a familial risk of cancer than with the genetic testing process itself. Obtaining genetic testing may be less stressful than living with the awareness of familial risk of cancer. (Refer to the PDQ Supportive Care summaries on Depression and Adjustment to Cancer: Anxiety and Distress for more detailed information about depression and anxiety associated with a cancer diagnosis.) Case descriptions have supported the importance of family relationships and test outcomes in shaping the distress of tested individuals.
Although there are not yet reports of large-scale studies of the reactions of affected individuals to genetic testing, there are indications from several smaller studies that affected individuals who undergo genetic counseling and testing experience more distress than had been expected by professionals  and are less able themselves to anticipate the intensity of their reactions following result disclosure. Female mutation carriers who have had breast cancer are often surprised by their high risk of ovarian cancer. Women mutation carriers who have had breast cancer worried more than unaffected women about developing ovarian cancer, though, in general, worry about ovarian cancer risk was found to be unrealistically low. In addition, some distress related to the burden of conveying genetic information to relatives has been noted among those who are the first in their families to be tested.
The long-term effect of uninformative BRCA1/BRCA2 test results (BRCA1/BRCA2 negative, negative on a panel of three Ashkenazi founder mutations, or detecting a variant of uncertain significance) was examined in 209 women recruited from one of two comprehensive cancer centers or a community hospital. These women had a personal history of breast or ovarian cancer and were assessed at pretesting, 1-, 6-, and 12-months post-disclosure. Distress was low at each time point, and declined from pretest to post-disclosure, remaining stable and low thereafter. No clinical cut-offs were reported. Those who reported higher general distress associated with cancer risk, risk-reduction efforts, and family communication and lower confidence in dealing with these issues, and those who expected to carry a deleterious mutation, had greater decisional conflict related to managing their cancer risk through 1-year post-test. In another study of 182 women drawn from this sample, most (84%) had made a risk management decision within 6 months of test result disclosure. Those who were delayed in making a risk management decision reported greater feelings of decisional uncertainty, dissatisfaction, and lack of confidence, yet there was also a high level of reported decisional conflict even among those who were early or intermediate decision-makers. Increased depression levels post-disclosure predicted increased risk of delay in risk management decision-making.
Several studies have compared the provision of breast cancer genetics services by different providers and the psychological impact on women at high and low risk of cancer. In a study of 735 women at all hereditary breast/ovarian cancer risk levels, the services of a multidisciplinary team of genetics specialists was compared with services provided by surgeons. There were no significant differences between groups in anxiety, cancer worry, or perceived risk. In a Scottish study of 373 participants, an alternative model of cancer genetics services using genetics nurse specialists in community-based services was compared with standard genetics regional services. There was no difference in cancer worry or change in health behaviors between the two groups. Cancer worry decreased for both groups over a 6-month period. Women who dropped out of the study tended to be in the nurse provider arm or were at low risk of breast cancer. In a small U.S. study, an evaluation of nurses and genetic counselors as providers of education about breast cancer susceptibility testing was conducted to compare outcomes of pretest education about breast cancer susceptibility. Four genetic counselors and two nurses completed specialized training in cancer genetics. Women receiving pretest education from nurses were as satisfied with information received and had equal degrees of perceived autonomy and partnership. The study findings suggest that with proper training and supervision, both genetic counselors and nurses can be effective in providing pretest education to women considering genetic susceptibility testing for breast cancer risk.
There has been little empirical research in the communication of risk assessments to individuals at risk of breast/ovarian cancer syndromes. When asked to choose a preferred method, individuals undergoing genetic counseling for breast and ovarian cancer appear to prefer quantitative to qualitative presentation of risk information. One study indicated that most women wanted information given both ways. Information about the risk of developing breast cancer among women with a family history of breast cancer may be more accurately recalled when presented as odds ratios rather than in other forms.
There is a small but growing body of literature on the use of decision aids as an adjunct to standard genetic counseling to assist patients in making informed decisions about genetic testing. One study measured the effectiveness of a decision aid for BRCA1/BRCA2 genetic testing given to women at the end of their first genetic counseling consultation. At 1 week and 6 months follow-up, the decision aid had no effect on informed choice, decisional regret, or actual genetic testing decision. However, women who received the decision aid had significantly higher knowledge levels and felt more informed about genetic testing than women who received the control pamphlet. The decision aid also helped those women who did not have their blood drawn for genetic testing at the first visit to clarify their values about their testing decision.
Preferences for delivery of breast cancer genetic testing are reported in one study  to include pretest counseling conducted by a genetic counselor (42%) or oncologist (22%) rather than by a primary care physician (6%), nurse (12%), or gynecologist (5%). Patients in that study preferred results disclosure by an oncologist. Younger women especially expressed a need for individual consideration of their personal values and goals or potential emotional reactions to testing; 67% believed emotional support and counseling were a necessary part of posttest counseling. Most women (82%) wanted to be able to self-refer for genetic testing, without a physician referral.
Family communication about genetic testing and hereditary risk
Family communication about genetic testing for cancer susceptibility, and specifically about the results of BRCA1/BRCA2 genetic testing, is complex; there are few systematic data available on this topic. Gender appears to be an important variable in family communication and psychological outcomes. One study documented that female carriers are more likely to disclose their status to other family members (especially sisters and children aged 14–18 years) than are male carriers. Among males, noncarriers were more likely than carriers to tell their sisters and children the results of their tests. BRCA1/BRCA2 carriers who disclosed their results to sisters had a slight decrease in psychological distress, compared with a slight increase in distress for carriers who chose not to tell their sisters. Findings from other studies suggest that there may be more communication about inherited breast and ovarian cancer risk among female family members than between female and male relatives (e.g., between brothers and sisters and/or mothers and sons). One study found that men reported greater difficulty disclosing mutation-positive results to family members in comparison to women (90% vs. 70%).
Family communication of BRCA1/BRCA2 test results to relatives is another factor affecting participation in testing. There have been more studies of communication with first-degree relatives and second-degree relatives than with more distant family members. One study investigated the process and content of communication among sisters about BRCA1/BRCA2 test results. Study results suggest that both mutation carriers and women with uninformative results communicate with sisters to provide them with genetic risk information. Among relatives with whom genetic test results were not discussed, the most important reason given was that the affected women were not close to their relatives. Studies found that women with a BRCA mutation more often shared their results with their mother and adult sisters and daughters than with their father and adult brothers and sons. A study that evaluated communication of test results to first-degree relatives at 4 months postdisclosure found that women aged 40 years or older were more likely to inform their parents of test results compared with younger women. Participants also were more likely to inform brothers of their results if the BRCA mutation was inherited through the paternal line. Another study found that disclosure was limited mainly to first-degree relatives, and dissemination of information to distant relatives was problematic. Age was a significant factor in informing distant relatives with younger patients being more willing to communicate their genetic test result.
A few in-depth qualitative studies have looked at issues associated with family communication about genetic testing. Although the findings from these studies may not be generalizable to the larger population of at-risk persons, they illustrate the complexity of issues involved in conveying hereditary cancer risk information in families. On the basis of 15 interviews conducted with women attending a familial cancer genetics clinic, the authors concluded that while women felt a sense of duty to discuss genetic testing with their relatives, they also experienced conflicting feelings of uncertainty, respect, and isolation. Decisions on whom in the family to inform and how to inform them about hereditary cancer and genetic testing may be influenced by tensions between women's need to fulfill social roles and their responsibilities toward themselves and others. Another qualitative study of 21 women who attended a familial breast and ovarian cancer genetics clinic suggested that some women may find it difficult to communicate about inherited cancer risk with their partners and with certain relatives, especially brothers, because of those persons’ own fears and worries about cancer. This study also suggested that how genetic risk information is shared within families may depend on the existing norms for communicating about cancer in general. For example, family members may be generally open to sharing information about cancer with each other, may selectively avoid discussing cancer information with certain family members to protect themselves or other relatives from negative emotional reactions, or may ask a specific relative to act as an intermediary to disclosure of information to other family members. The potential importance of persons outside the family, such as friends, as both confidantes about inherited cancer risk information and as sources of support for coping with this information was also noted in the study.
A study of 31 mothers with a documented BRCA mutation explored patterns of dissemination to children. Of those who chose to disclose test results to their children, age of offspring was the most important factor. Fifty percent of the children who were told were aged 20 to 29 years and slightly more than 25% of the children were aged 19 years or younger. Sons and daughters were notified in equal numbers. More than 70% of mothers informed their children within a week of learning their test result. Ninety-three percent of mothers who chose not to share their results with their children indicated that it was because their children were too young. These findings were consistent with three other studies showing that children younger than 13 years were less likely to be informed about test results compared with older children. Another study of 187 mothers undergoing BRCA1/BRCA2 testing evaluated their need for resources to prepare for a facilitated conversation about sharing their BRCA1/BRCA2 testing results with their children. Seventy-eight percent of mothers were interested in three or more resources, including literature (93%), family counseling (86%), talk to prior participants (79%), and support groups (54%).
A longitudinal study of 153 women self-referred for genetic testing for BRCA1 and BRCA2 mutations and 118 of their partners evaluated communication about genetic testing and distress before testing and at 6 months posttesting. The study found that most couples discussed the decision to undergo testing (98%), most test participants felt their partners were supportive, and most women disclosed test results to their partners (97%, n = 148). Test participants who felt their partners were supportive during pretest discussions experienced less distress after disclosure, and partners who felt more comfortable sharing concerns with test participants pretest experienced less distress after disclosure. Six-month follow-up revealed that 22% of participants felt the need to talk about the testing experience with their partners in the week before the interview. Most participants (72%, n = 107) reported comfort in sharing concerns with their partners, and 5% (n = 7) reported relationship strain as a result of genetic testing. In couples in which the woman had a positive genetic test result, more relationship strain, more protective buffering of their partners, and more discussion of related concerns were reported than in couples in which the woman had a true-negative or uninformative result.
There is a small but growing body of literature regarding psychological effects in men who have a family history of breast cancer and who are considering or have had BRCA testing. A qualitative study of 22 men from 16 high-risk families in Ireland revealed that more men in the study with daughters were tested than men without daughters. These men reported little communication with relatives about the illness, with some men reporting being excluded from discussion about cancer among female family members. Some men in the study also reported actively avoiding open discussion with daughters and other relatives. In contrast, a study of 59 men testing positive for a BRCA1/BRCA2 mutation found that most men participated in family discussions about breast and/or ovarian cancer. However, fewer than half of the men participated in family discussions about risk-reducing surgery. The main reason given for having BRCA testing was concern for their children and a need for certainty about whether they could have transmitted the mutation to their children. In this study, 79% of participating men had at least one daughter. Most of these men described how their relationships had been strengthened after receipt of BRCA results, helping communication in the family and greater understanding. Men in both studies expressed fears of developing cancer themselves. Irish men especially reported fear of cancer in sexual organs.
In a study of 212 individuals from 13 hereditary breast and ovarian cancer families who received genetic counseling and were offered BRCA1/BRCA2 testing for documented mutation in the family, individuals who were not tested were found 6 to 9 months later to have significantly greater increases in expressiveness and cohesiveness compared with those who were tested. Persons who were randomized to a client-centered versus problem-solving genetic counseling intervention had a significantly greater reduction in conflict, regardless of the test decision.
Partners of high-risk women
Many studies have looked at the psychological effects in women of having a high risk of developing cancer, either on the basis of carrying a BRCA1/BRCA2 mutation or having a strong family history of cancer. Some studies have also examined the effects on the partners of such women.
A Canadian study assessed 59 spouses of women found to have a BRCA1/BRCA2 mutation. All were supportive of their spouses’ decision to undergo genetic testing and 17% wished they had been more involved in the genetic testing process. Spouses who reported that genetic testing had no impact on their relationship had long-term relationships (mean duration 27 years). Forty-six percent of spouses reported that their major concern was of their partner dying of cancer. Nineteen percent were concerned their spouse would develop cancer and 14% were concerned their children would also be BRCA1/BRCA2 mutation carriers.
In a U.S. study, 118 partners of women undergoing genetic testing for mutations in BRCA1 and BRCA2 completed a survey prior to testing and then again 6 months following result disclosure. At 6 months, only 10 partners reported that they had not been told of the test result. Ninety-one percent reported that the testing had not caused strain on their relationship. Partners who were comfortable sharing concerns prior to testing experienced less distress following testing. Protective buffering was not found to impact distress levels of partners.
An Australian study of 95 unaffected women at high risk of developing breast and/or ovarian cancer (13 mutation carriers and 82 with unknown mutation status) and their partners showed that although the majority of male partners had distress levels comparable to a normative population sample, 10% had significant levels of distress that indicated the need for further clinical intervention. Men with a high monitoring coping style and greater perceived breast cancer risk for their wives reported higher levels of distress. Open communication between the men and their partners and the occurrence of a cancer-related event in the wife’s family in the last year were associated with lower distress levels. When men were asked what kind of information and support they would like for themselves and their partners, 57.9% reported that they would like more information about breast and ovarian cancer, and 32.6% said they would like more support in dealing with their partner's risk. Twenty-five percent of men had suggestions on how to improve services for partners of high-risk women, including strategies on how to best support their partner, greater encouragement from health care professionals to attend appointments, and meeting with other partners.
A review of this literature reported that the BRCA testing process may be distressing for male partners, particularly for those with spouses identified as carriers. Male partner distress appears to be associated with their beliefs about the woman’s breast cancer risk, lack of couple communication, and feelings of alienation from the testing process.
A review of the literature on the experiences of males in BRCA1 and BRCA2 mutation–positive families reported that while the data are limited, men from mutation-positive families are less likely than females to participate in communication regarding genetics at every level, including the counseling and testing process. Men are less likely to be informed of genetic test results received by female relatives, and most men from these families do not pursue their own genetic testing.
A study of Dutch men at increased risk of having inherited a BRCA1 mutation reported a tendency for the men to deny or minimize the emotional effects of their risk status, and to focus on medical implications for their female relatives. Men in these families, however, also reported considerable distress in relation to their female relatives. In another study of male psychological functioning during breast cancer testing, 28 men belonging to 18 different high-risk families (with a 25% or 50% risk of having inherited a BRCA1/BRCA2 mutation) participated. The study purpose was to analyze distress in males at risk of carrying a BRCA1/BRCA2 mutation who applied for genetic testing. Of the men studied, most had low pretest distress; scores were lowest for men who were optimistic or who did not have daughters. Most mutation carriers had normal levels of anxiety and depression and reported no guilt, though some anticipated increased distress and feelings of responsibility if their daughters developed breast or ovarian cancer. None of the noncarriers reported feeling guilty. In one study, adherence to recommended screening guidelines after testing was analyzed. In this study, more than half of male carriers of mutations did not adhere to the screening guidelines recommended after disclosure of genetic test results. These findings are consistent with those for female carriers of BRCA1/BRCA2 mutations.
A multicenter U.K. cohort study examined prospective outcomes of BRCA1/BRCA2 testing in 193 individuals, of which 20% were men aged 28 to 86 years. Men’s distress levels were low, did not differ among carriers and noncarriers, and did not change from baseline (before genetic testing) to the 3-year follow-up. Twenty-two percent of male mutation carriers received colorectal cancer screening and 44% received prostate cancer screening; however, it is unclear whether men in this study were following age-appropriate screening guidelines.
Several studies have explored communication of BRCA test results to at-risk children. Across all studies, the rate of disclosure to children ranging in age from 4 to 25 years is approximately 50%. In general, age of offspring was the most important factor in deciding whether to disclose test results. In one study of 31 mothers disclosing their BRCA test results, 50% of the children who were informed of the results were aged 20 to 29 years and slightly more than 25% of the children were aged 19 years or younger. Sons and daughters were notified in equal numbers. Similarly, in another study of 42 female BRCA mutation carriers, 83% of offspring older than age 18 years were told of the results, while only 21% of offspring aged 13 years or younger were told.
Several studies have also looked at the timing of disclosure to children after parents receive their test results. Although the majority of children were told within a week to several months after results disclosure, some parents chose to delay disclosure. Reasons for delaying disclosure included waiting for the child to get older, allowing time for the parent to adjust to the information, and waiting until results could be shared in person (in the case of adult children living away from home).
One study looked at the reaction of children to results disclosure or the effect on the parent-child relationship of communicating the results. With regard to offspring’s understanding of the information, almost half of parents from one study reported that their child did not appear to understand the significance of a positive test result, although older children were reported to have a better understanding. This same study also showed that 48% of parents reported at least one negative reaction in their child, ranging from anxiety or concern (22%) to crying and fear (26%). It should be noted, however, that in this study children's level of understanding and reactions to the test result were measured qualitatively and based only on the parents' perception. Also, given the retrospective design of the study, there was a potential for recall bias. There were no significant differences in emotional reaction depending on age or gender of the child. Lastly, 65% of parents reported no change in their relationship with their child, while 5 parents (22%) reported a strengthening of their relationship.
Another study of 187 mothers undergoing BRCA1/BRCA2 testing evaluated their need for resources to prepare for a facilitated conversation about sharing their BRCA1/BRCA2 testing results with their children. Seventy-eight percent of mothers were interested in three or more resources, including literature (93%), family counseling (86%), talking to prior participants (79%), and support groups (54%).
Testing for BRCA1/BRCA2 has been almost universally limited to adults older than 18 years. The risks of testing children for adult-onset disorders (such as breast and ovarian cancer), as inferred from developmental data on children’s medical understanding and ability to provide informed consent, have been outlined in several reports. Surveys of parental interest in testing children for adult-onset hereditary cancers suggest that parents are more eager to test their children than to be tested themselves for a breast cancer gene, suggesting potential conflicts for providers. In a general population survey in the United States, 71% of parents said that it was moderately, very, or extremely likely that if they carried a breast-cancer predisposing mutation, they would test a 13-year-old daughter now to determine her breast cancer gene status. To date, no data exist on the testing of children for BRCA1/BRCA2, though some researchers believe it is necessary to test the validity of assumptions underlying the general prohibition of testing of children for breast/ovarian cancer and other adult-onset disease genes. In one study, 20 children (aged 11–17 years) of a selected group of mothers undergoing genetic testing (80% of whom previously had breast cancer and all of whom had discussed BRCA1/BRCA2 testing with their children) completed self-report questionnaires on their health beliefs and attitudes toward cancer, feelings related to cancer, and behavioral problems. Ninety percent of children thought they would want cancer risk information as adults; half worried about themselves or a family member developing cancer. There was no evidence of emotional distress or behavioral problems. Another study by this group  found that 1 month after disclosure of BRCA1/BRCA2 genetic test results, 53% of 42 enrolled mothers of children aged 8 to 17 years had discussed their result with one or more of their children. Age of the child rather than mutation status of the mother influenced whether they were told, as did family health communication style.
In one study, participants who told children younger than 13 years about their carrier status had increased distress, and those who did not tell their young children experienced a slight decrease in distress. Communication with young children was found to be influenced by developmental variables such as age and style of parent/child communication.
Prenatal diagnosis and preimplantation genetic diagnosis
The possibility of transmitting a mutation to a child may pose a concern to families affected by history of breast/ovarian cancer (HBOC), perhaps to the extent that some carriers may avoid childbearing. These concerns also may prompt women to consider using prenatal diagnosis methods to help reduce the risk of transmission. Prenatal diagnosis is an encompassing term used to refer to any medical procedure conducted to assess the presence of a genetic disorder in a fetus. Methods include amniocentesis and chorionic villous sampling (CVS). Both procedures carry some risk of miscarriage and some evidence suggests fetal defects may result from using these tests. Moreover, discovering the fetus is a carrier for a genetic defect may impose a difficult decision for couples regarding pregnancy continuation or termination. An alternative to these tests is preimplantation genetic diagnosis (PGD), a procedure used to test fertilized embryos for genetic disorders prior to uterine implantation, thereby avoiding the potential dangers associated with amniocentesis and CVS and the decision to terminate a pregnancy. Using the information obtained from the genetic testing, potential parents can decide whether or not to implant. PGD can be used to detect mutations in hereditary cancer predisposing genes, including BRCA.
In the United States, a series of studies have evaluated awareness, interest (e.g., would consider using PGD), and attitudes related to PGD among members of Facing Our Risk of Cancer Empowered (FORCE), an advocacy organization focused on persons at increased risk of HBOC. The first study was a web based survey of 283 members, the second included 205 attendees of the 2007 annual FORCE conference, and the third was a web based survey of 962 members. These studies have documented low levels of awareness, with 20% to 32% of study respondents reporting having heard of PGD prior to study participation. With respect to interest in PGD, the first study  found only 13% of women would be likely to use PGD, whereas, 33% of respondents in the subsequent FORCE studies reported that they would consider using PGD. In the third FORCE-based study (n = 962), multivariable analysis revealed PGD interest was associated with the desire to have more children, having previously had any prenatal genetic test, and previous awareness of PGD. Attitudinal predictors of interest in PGD included the following:
- Agreement that others at risk of HBOC should be offered PGD.
- The belief that PGD is acceptable for persons at risk of HBOC.
- The belief that PGD information should be given to individuals at risk of HBOC.
- Endorsement of PGD benefits of having children without genetic mutations and eliminating genetic diseases.
Conversely, those who indicated that PGD was “too much like playing God” and reported that they considered PGD in the context of religion, had less interest in PGD.
The U.K. Human Fertilization and Embryology authority has approved the use of PGD for hereditary breast and ovarian cancer. In a sample of 102 women with a BRCA mutation, most were supportive of PGD but only 38% of the women who had completed their families would consider it for themselves had PGD been available, and only 14% of women who were contemplating a future pregnancy would consider PGD. In a study of 77 individuals undergoing BRCA testing as part of a multicenter cohort study in Spain, 61% of respondents reported they would consider PGD. Factors associated with PGD interest were age 40 years and older and had a prior cancer diagnosis.
In France, couples who obtain authorization from a multidisciplinary prenatal diagnosis team may access PGD free of charge as a benefit of their national health care system. However, no BRCA carriers have been authorized to use PGD. In a national study of 490 unaffected BRCA mutation carriers of childbearing age (women aged 18–49 years; men aged 18–69 years), 16% stated that BRCA test results had altered their ongoing plans for childbearing. Upon qualitative analysis of written comments provided by some respondents, the primary impact was related to accelerating the timing of pregnancy, feelings of guilt about possibly passing on the mutation to offspring, and having future children. In response to a hypothetical scenario in which PGD was readily available, 33% of participants reported that they would undergo PGD. Factors associated with this intention were having no future reproductive plans at the time of the survey, feeling pregnancy termination was an acceptable option in the context of identifying a BRCA mutation, and having fewer cases of breast and/or ovarian cancer in the family. When presented with questions about expectations about delivery of PGD or prenatal diagnosis (PND) information, 85% of respondents felt it should be provided along with BRCA test results; 45% felt that it should be provided when carriers decide to have children. Respondents stated that they would expect this information to be delivered by cancer geneticists (92%), obstetrician/gynecologists (76%), and general practitioners (48%).
A small (N = 25) qualitative study of BRCA mutation–positive women of reproductive age who underwent genetic testing before having children evaluated how their BRCA status influenced their attitudes about reproductive genetic testing (both PGD and PND) and decisions about having children. In this study, the decision to undergo BRCA testing was primarily motivated by the desire to manage one’s personal cancer risk, rather than a desire to inform future reproductive decisions. The perceived severity of HBOC influenced concerns about passing on a BRCA mutation to children and also influenced willingness to consider PGD or PND and varied based on personal experience. Most did not believe that BRCA mutation–positive status was a reason to terminate a pregnancy. As observed in prior studies, knowledge of reproductive options varied; however, there was a tendency among participants to view PGD as more acceptable than PND with regard to termination of pregnancy. Decisions regarding the pros and cons of PGD versus PND with termination of pregnancy were driven primarily by personal preferences and experiences, rather than by morality judgments. For example, women were deterred from PGD based on the need to undergo in vitro fertilization and to take hormones that might increase cancer risk and based on the observed experiences of others who underwent this procedure.
One study has examined these issues among high-risk men recruited from FORCE and Craigslist (a bulletin board Web site) (N = 228). Similar to the previous studies of women, only 20% of men were aware of PGD prior to survey participation. In a multivariate analysis, those who selected the “other” option for possible benefits of PGD compared with those who selected from several predetermined options (e.g., having children without genetic mutations) and those who considered PGD in the context of religion (as opposed to health and safety) were less likely to report that they would ever consider using PGD.
The recognition that BRCA1/BRCA2 mutations are prevalent, not only in breast/ovarian cancer families but also in some ethnic groups, has led to considerable discussion of the ethical, psychological, and other implications of having one’s ethnicity be a factor in determination of disease predisposition. Fears of genetic reductionism and the creation of a genetic underclass  have been voiced. Questions about the impact on the group of being singled out as having genetic vulnerability to breast cancer have been raised. There is also confusion about who gives or withholds permission for the group to be involved in studies of their genetic identity. These issues challenge traditional views on informed consent as a function of individual autonomy.
A growing literature on the unique factors influencing a variety of cultural subgroups suggests the importance of developing culturally specific genetic counseling and educational approaches. The inclusion of members within the community of interest (e.g., breast cancer survivors, advocates, and community leaders) may enhance the development of culturally tailored genetic counseling materials. One study showed that participation in any genetic counseling (culturally mediated or standard approaches) reduced perceived risk of developing breast cancer.
The human implications of the ethical issues raised by the advent of genetic testing for breast/ovarian cancer susceptibility are described in case studies, essays, and research reports. Issues about rights and responsibilities in families concerning the spread of information about genetic risk promise to be major ethical and legal dilemmas in the coming decades.
Studies have shown that 62% of studied family members were aware of the family history and that 88% of hereditary breast/ovarian cancer family members surveyed have significant concerns about privacy and confidentiality. Expressed concern about cancer in third-degree relatives, or relatives farther removed, was about the same as that for first- or second-degree relatives of the proband. Only half of surveyed first-degree relatives of women with breast or ovarian cancer felt that written permission should be required to disclose BRCA1/BRCA2 test results to a spouse or immediate family member. Attitudes toward testing varied by ethnicity, previous exposure to genetic information, age, optimism, and information style. Altruism is a factor motivating genetic testing in some people. Many professional groups have made recommendations regarding informed consent. There is some evidence that not all practitioners are aware of or follow these guidelines. Research shows that many BRCA1/BRCA2 genetic testing consent forms do not fulfill recommendations by professional groups about the 11 areas that should be addressed, and they omit highly relevant points of information. In a study of women with a history of breast or ovarian cancer, the interviews yielded that the women reported feeling inadequately prepared for the ethical dilemmas they encountered when imparting genetic information to family members. These data suggest that more preparation about disclosure to family members before testing reduces the emotional burden of disseminating genetic information to family members. Patients and health care providers would benefit from enhanced consideration of the ethical issues of warning family members about hereditary cancer risk. (Refer to the PDQ summaries Cancer Genetics Risk Assessment and Counseling and Cancer Genetics Overview for more information about the ethics of cancer genetics and genetic testing.)
Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Ovarian Cancer
Decision aids for persons considering risk management options for hereditary breast and ovarian cancer
There is a small but growing body of literature on the use of decision aids as an adjunct to standard genetic counseling to assist patients in making informed decisions about cancer risk management. One study showed that the use of a decision aid consisting of individualized value assessment and cancer risk management information after receiving positive BRCA1/BRCA2 test results was associated with fewer intrusive thoughts and lower levels of depression at the 6-month follow-up in unaffected women. Use of the decision aid did not alter cancer risk management intentions and behaviors. Slightly detrimental effects on well-being and several decision-related outcomes, however, were noted among affected women. Another study compared responses to a tailored decision aid (including a values-clarification exercise) versus a general information pamphlet intended for women making decisions about ovarian cancer risk management. In the short term, the women receiving the tailored decision aid showed a decrease in decisional conflict and increased knowledge compared with women receiving the pamphlet, but no differences in decisional outcomes were found between the two groups. In addition, the decision aid did not appear to alter the participant’s baseline cancer risk management decisions. A third decision aid focused on breast cancer risk management decision support for women with a BRCA1/BRCA2 mutation. Pre-evaluations and postevaluations of the decision aid in 20 women showed that use of the aid resulted in a significant decrease in decisional conflict, improvement in knowledge, and a decrease in uncertainty about tamoxifen use, RRM and RRSO. No significant differences were identified in cancer-related distress following the use of the tool.
Uptake of cancer risk management options
An increasing number of studies have examined uptake and adherence to cancer risk management options among individuals who have undergone genetic counseling and testing for BRCA1 and BRCA2 gene mutations. Findings from these studies are reported in Table 10 and Table 11. Outcomes vary across studies and include uptake or adherence to screening (mammography, magnetic resonance imaging [MRI], cancer antigen [CA] 125, transvaginal ultrasound [TVUS]) and selection of RRM and RRSO. Studies generally report outcomes by mutation carrier or testing status (e.g., mutation-positive, mutation-negative, or declined genetic testing). Follow-up time after notification of genetic risk status also varied across studies, ranging from 12 months up to several years.
Findings from these studies suggest that breast screening often improves after notification of BRCA1/BRCA2 mutation carrier status; nonetheless, screening remains suboptimal. Fewer studies have examined adoption of MRI as a screening modality, probably due to the recent availability of efficacy data. Screening for ovarian cancer varied widely across studies, and also varied based on type of screening test (i.e., CA 125 serum testing vs. TVUS screening). However, ovarian cancer screening does not appear to be widely adopted by BRCA1/BRCA2 mutation carriers. Uptake of RRM varied widely across studies, and may be influenced by personal factors (such as younger age or having a family history of breast cancer), psychosocial factors (such as a desire for reduction of cancer-related distress), recommendations of the health care provider, and cultural or health care system factors. An individual’s choice to have a bilateral mastectomy also appears to be influenced by pretreatment genetic education and counseling regardless of the genetic test results. Similarly, uptake of RRSO also varied across studies, and may be influenced by similar factors, including older age, personal history of breast cancer, perceived risk of ovarian cancer, cultural factors (i.e., country), and the recommendations of the health care provider.Table 10. Uptake of Risk-reducing Mastectomy (RRM) and/or Breast Screening Among BRCA1 and BRCA2 Mutation CarriersStudy CitationStudy PopulationUptake of RRMUptake of Breast Screening Mammography and/or Breast MRI Length of Follow-up Comments MRI = magnetic resonance imaging; RRSO = risk-reducing salpingo-oophorectomy.aSelf-report as data source.bMedical records as data source.cData source not specified.United States Carriers (n = 108)aCarriers 37% MammographyMean 5.3 yPredictors of RRM were younger age, higher precounseling cancer distress, more recent diagnosis of breast or ovarian cancer, and intact ovaries.Carriers affected 92%Carriers unaffected 82%Noncarriers (n = 60)a Noncarriers 0%Noncarriers 66%Uninformative affected 89%MRI Uninformative (n = 206)a Uninformative 6.8% Carriers affected 51%Carriers unaffected 46% Noncarriers 11% Uninformative 27% Carriers (n = 146)aCarriers 13%Not applicable12 moIntentions at test result disclosure predicted RRM decisions.Carriers (n = 237)bCarriers 23%Not applicableMean 3.7 yWomen opting for RRM were <60 y, had a prior diagnosis of breast cancer, and also underwent RRSO.Median time to RRM: 124 days from receiving results.Carriers (n = 37)a Carriers 0%Mammography24 moCarriers 57%Noncarriers 49%Noncarriers (n = 92)a Noncarriers 0%Declined test 20%Declined testing (n = 15)a MRINot evaluatedInternationalCarriers (n = 101)a Carriers 6.9% Mammography5 yNoncarriers often continued screening.Carriers 59%Noncarriers aged 30–39 y 53%Noncarriers (n = 145)a Noncarriers 0% MRICarriers 31%Noncarriers 4.8%Carriers (n = 70)aCarriers 11%Mammography3 yCarriers 89%MRI Not evaluatedCarriers (N = 2,677)aCarriers 18% (unaffected) Mammography 3.9 y; range 1.5–10.3 yLarge differences in uptake of risk management options by country.Carriers 87%MRI1,294 participants had a personal history of breast cancer.Carriers 31%Table 11. Uptake of Risk-reducing Salpingo-oophorectomy (RRSO) and/or Gynecologic Screening Among BRCA1 and BRCA2 Mutation CarriersStudy CitationStudy Population Uptake of RRSOUptake of Gynecologic ScreeningLength of Follow-upCommentsCA 125 = cancer antigen 125; RRM = risk-reducing mastectomy; TVUS = transvaginal ultrasound.aSelf-report as data source.bMedical records as data source.cData source not specified.United StatesCarriers (n = 100)a Carriers 65% CA125Mean 5.3 yPredictors of RRSO were being ≥40 y and diagnosis of breast cancer more than 10 y ago.Carriers 56%Noncarriers 12%Noncarriers (n = 52)aNoncarriers 1.9% Uninformative 33%TVUSCarriers 42% Uninformative (n = 203)aUninformative 13.3%Noncarriers 20%Uninformative 26%Carriers (n = 146)aCarriers 32%Not applicable12 moCarriers (n = 240)bCarriers 51%Not applicableMean 3.7 yWomen opting for RRSO were <60 y, had a prior diagnosis of breast cancer, and also underwent RRM.Median time to RRSO: 123 days from receiving results.Carriers (n = 179)a, Carriers 50.3% CA 125 Mean 24.8 mo; range 1.6–66.0 moWomen undergoing RRSO were older and more likely to have a personal history of breast cancer. Carriers 67.6% TVUSCarriers 72.9%International Carriers (N = 306)bCarriers 57%Not evaluatedMean 47.8 mo post-oophorectomyMedian age at time of RRSO = 47 y. One occult fallopian tube cancer was detected at the time of RRSO. One peritoneal carcinoma was diagnosed 26 mo post RRSO.Carriers (n = 101)aCarriers 42.6% TVUS5 yRRSO uptake increased with age. Having undergone RRSO did not alter breast cancer risk perception Noncarriers often continued screening. Noncarriers (n = 145)aNoncarriers 2% Noncarriers 43.2% Carriers (n = 70)aCarriers 29%CA 1253 yCarriers 0% TVUSCarriers 67%Carriers (N = 160)a, bCarriers 74%Carriers 26%12 mo Women undergoing RRSO had lower education levels, viewed ovarian cancer as incurable and believed strongly in the benefits of RRSO. Specific method(s) of gynecological screening not reported.Carriers (N = 2,677)aCarriers 57%Not applicable3.9 y; range 1.5–10.3 yLarge differences in uptake of risk management options by country. Carriers (N = 537)c Carriers 55% Not applicableMinimum 6 mo; median 36 mo RRSO greatest in parous women >40 y.
On the other hand, many women found to be mutation carriers express interest in RRM in hopes of minimizing their risk of breast cancer. In one study of a number of unaffected women with no previous risk-reducing surgery who received results of BRCA1 testing following genetic counseling, 17% of carriers (2 of 12) intended to have mastectomies and 33% (4 of 12) intended to have oophorectomies. In a later study of the same population, RRM was considered an important option by 35% of women who tested positive, whereas risk-reducing oophorectomy was considered an important option by 76%. A prospective study assessed the stability of risk management preferences over five time points (pre-BRCA testing to 9 months after results disclosure) among 80 Dutch women with a documented BRCA mutation. Forty-six participants indicated a preference for screening at baseline. Of 25 women who preferred RRM at baseline, 22 indicated the same preference 9 months after test results disclosure; however, it was not reported how many women actually had RRM.
Initial interest does not always translate into the decision for surgery. Two different studies found low rates of RRM among mutation carriers in the year following result disclosure, one showing 3% (1 of 29) of carriers and the other 9% (3 of 34) of carriers having had this surgery. Among members from a large BRCA1 kindred, utilization of cancer screening and/or risk-reducing surgeries was assessed at baseline (before disclosure of results), and at 1 year and 2 years after disclosure of BRCA1 test results. Of the 269 men and women who participated, complete data were obtained on 37 female carriers and 92 female noncarriers, all aged 25 years or older. At 2 years after disclosure of test results, none of the women had undergone RRM, although 4 of the 37 carriers (10.8%) said they were considering the procedure. In contrast, of the 26 women who had not had an oophorectomy prior to baseline, 46% (12 of 26) had obtained an oophorectomy by 2 years after testing. Of those carriers aged 25 to 39 years, 29% (5 of 17) underwent oophorectomy, while 78% (7 of 9) of the carriers aged 40 years and older had this procedure. In a study assessing uptake of risk-reducing surgery 3 months following BRCA result disclosure, 7 of 62 women had undergone RRM and 13 of 62 women had undergone RRSO. Intent to have an RRSO prior to testing correlated with procedure uptake. In contrast, intent to undergo RRM did not correlate with uptake. Overall, reasons given for indecision about risk-reducing surgery included complex testing factors such as the significance of family history in the absence of a mutation, concerns over the surgical procedure, and time and uncertainty regarding early menopause and the use of HRT. In a study of patients in the United Kingdom, data were collected during observations of genetic consultations and in semistructured interviews with 41 women following their attendance at genetic counseling. The option of risk-reducing surgery was raised in 29 consultations and discussed in 35 of the postclinic interviews. Fifteen women said they would consider having an oophorectomy in the future, and nine said they would consider having a mastectomy. The implications of undergoing oophorectomy and mastectomy were discussed in postclinic interviews. Risk-reducing surgery was described by the counselees as providing individuals with a means to (a) fulfill their obligations to other family members and (b) reduce risk and contain their fear of cancer. The costs of this form of risk management were described by the respondents as follows:
- Compromising social obligations.
- Upsetting the natural balance of the body.
- Not receiving protection from cancer.
- Operative and postoperative complications.
- The onset of menopause.
- The effects of body image, gender, and personal identity.
- Potential effects on sexual relationships.
A number of women choose to undergo RRM and RRSO without genetic testing because of the following:
- Testing is not readily accessible.
- They do not wish exposure to the psychosocial risks of genetic testing.
- They do not trust that a negative genetic test result means they are not at increased risk.
- They find any level of risk, even baseline population risk, unacceptable.
Among first-degree relatives of breast cancer patients attending a surveillance clinic, women who expressed an interest in RRM and/or had undergone surgery were found to have significantly more breast cancer biopsies (P < .05) and higher subjective 10-year breast cancer risk estimates (P < .05) than women not interested in RRM. Cancer worry at the time of entry into the clinic was highest among women who subsequently underwent RRM compared with women who expressed interest but had not yet had surgery and women who did not intend to have surgery (P < .001).
Few studies have evaluated the impact of BRCA1/BRCA2 test results on risk-reducing surgery decisions among women affected with breast cancer. A study evaluating predictors of contralateral RRM among 435 breast cancer survivors found that 16% had undergone contralateral RRM (in conjunction with mastectomy of the affected breast) prior to referral for genetic counseling and BRCA1/BRCA2 genetic testing. Predictors of contralateral RRM prior to genetic counseling and testing included younger age at breast cancer diagnosis, more time since diagnosis, having at least one affected first-degree relative, and not being employed full-time. In the year following disclosure of test results, 18% of women who tested positive for a BRCA1/BRCA2 mutation and 2% of those whose test results were uninformative underwent contralateral RRM. Predictors of contralateral RRM after genetic testing included younger age at breast cancer diagnosis, higher cancer-specific distress prior to genetic counseling, and having a positive BRCA1/BRCA2 test result. In this study, contralateral RRM was not associated with distress at 1 year following disclosure of genetic test results. A retrospective chart review evaluated uptake of bilateral mastectomies in 110 women who underwent BRCA1/BRCA2 genetic testing prior to surgical decisions for the treatment of newly diagnosed breast cancer. BRCA mutation carriers were more likely to undergo bilateral mastectomies when compared to women where no mutation was detected (83% vs. 37%; P = .046). The only predictor of contralateral RRM in women without a mutation was being married (P = .03). Age, race, parity, disease stage and biomarkers, increased mammographic breast density, and breast MRI did not influence contralateral RRM decisions at the time of primary surgical treatment.
Dutch women (N = 114) who had undergone unilateral or bilateral RRM with breast reconstruction between 1994 and 2002 were retrospectively surveyed to determine their satisfaction with the procedure. Sixty-eight percent were either unaffected BRCA mutation carriers or at 50% risk of having a BRCA mutation in their family. Sixty percent of respondents indicated that they were satisfied with the procedure, 95% would opt for RRM again, and 80% would opt for the same reconstruction procedure. Less than half reported some perioperative or postoperative complications, ongoing physical complaints, or some physical limitations. Twenty-nine percent reported altered feelings of femininity following the procedure, 44% reported adverse changes in their sexual relationships, and 35% indicated that they believed their partners experienced adverse changes in their sexual relationship. Ten percent of women, however, reported positive changes in their sexual relationship following the procedure. Compared with patients who indicated satisfaction with this procedure, nonsatisfied patients were more likely to feel less informed about the procedure and its consequences, report more complications and physical complaints, feel that their breasts did not belong to their body, and indicate that they would not opt for reconstruction again. Those who reported a negative effect on their sexual relationship were more likely to:
- Feel less informed.
- Experience more physical complaints and limitations.
- Express that their breasts did not feel like their own.
- Be disinclined to opt for reconstruction again.
- State that the surgery had not met their expectations.
- Experience altered feelings of femininity and perceived adverse changes in their partner’s view of their femininity and their sexual relationship.
Ninety Swedish women who had undergone RRM between 1997 and 2005 were surveyed prior to surgery, 6 months after surgery, and 1 year after surgery to evaluate changes in health-related quality of life, depression, anxiety, sexuality, and body image. There were no significant changes in health-related quality of life or depression at the three time points; anxiety decreased over time (P = .0004). More than 80% of women reported having an intimate relationship at all three time points. Women who reported being sexually active were asked to respond to questions about sexual pleasure, discomfort, habit, and frequency of activity. There were no statistically significant differences related to frequency, habit, or discomfort. However, pleasure significantly decreased between baseline and 1 year after surgery (P = .005). At 1 year after surgery, 48% of women reported feeling less attractive, 48% reported feeling self-conscious, and 44% reported dissatisfaction with surgical scars.
Discussion of risk-reducing surgical options may not consistently occur during pretest genetic counseling. In one multi-institutional study, only one-half of genetics specialists discussed RRM and RRSO in consultations with women from high-risk breast cancer families, despite the fact that discussion of surgical options was significantly associated with meeting counselees’ expectations, and that such information was not associated with increased anxiety.
Given the increased risk of ovarian cancer faced by women with a BRCA1 or BRCA2 mutation, those who do receive information about RRSO show wide variations in surgery uptake (27%–72%). A study showed that clinical factors related to choosing RRSO versus surveillance alone are older age, parity of one or more, and a prior breast cancer diagnosis. In this study, the choice of RRSO was not related to family history of breast or ovarian cancer. Hysterectomy was presented as an option during genetic counseling and 80% of women who underwent RRSO also elected to have a hysterectomy.
Cancer screening and risk-reducing behaviors
Data are now emerging regarding uptake and adherence to cancer risk management recommendations such as screening and risk-reducing interventions. Cancer screening adherence and risk-reduction behaviors as defined by the National Comprehensive Cancer Network Guidelines were assessed in a cross-sectional study of 214 women with a personal history (n = 134) or family history (n = 80) of breast or ovarian cancer. Among unaffected women older than 40 years, 10% had not had a mammogram or clinical breast examination (CBE) in the previous year and 46% did not practice breast self-examination (BSE). Among women previously affected with breast or ovarian cancer, 21% had not had a mammogram, 32% had not had a CBE, and 39% did not practice BSE.
Three hundred and twelve women who were counseled and tested for BRCA mutations between 1997 and 2005 responded to a survey regarding their perception of genetic testing for hereditary breast and ovarian cancer. The survey included questions on risk reduction options, including screening and risk-reducing surgeries. Two hundred and seventeen (70%) of the women had been diagnosed with breast cancer, and 86 (28%) tested positive for a deleterious mutation in either the BRCA1 or BRCA2 gene. None of the BRCA-positive women agreed that mammograms are difficult procedures because of the discomfort, while 11 (5.4%) of the BRCA-negative women did agree with this statement. Both groups (BRCA-positive and BRCA-negative) agreed that risk-reducing surgeries provide the best means for lowering cancer risk and worry, and most patients in both groups expressed the belief that risk-reducing mastectomy is not too drastic, too scary, or too disfiguring.
A prospective study from the United Kingdom examined the psychological impact of mammographic screening in 1,286 women aged 35 to 49 years who have a family history of breast cancer and were participants in a multicenter screening program. Mammographic abnormalities that required additional evaluation were detected in 112 women. These women, however, did not show a statistically significant increase in cancer worry or negative psychological consequences as a result of these findings. The 1,174 women who had no mammographic abnormality detected experienced a decrease in cancer worry and a decrease in negative psychological consequences compared with baseline following receipt of their results. At 6 months, the entire cohort had experienced a decrease in measures of cancer worry and psychological consequences of breast screening.
A qualitative study explored health care professionals’ views regarding the provision of information about health protective behaviors (e.g., exercise and diet). Seven medical specialists and ten genetic counselors were interviewed during a focus group or individually. The study reported wide variation in the content and extent of information provided about health-protective behaviors and in general, participants did not consider it their role to promote such behaviors in the context of a genetic counseling session. There was agreement, however, about the need to form consensus about provision of such information both within and across risk assessment clinics.
It is important to keep in mind that not all studies specify whether screening uptake rates fall within recommended guidelines for the targeted population or the specific clinical scenario, nor do they report on other variables that may influence cancer screening recommendations. For example, women who have a history of atypical ductal hyperplasia would be advised to follow screening recommendations that may differ from those of the general population.
Psychosocial Outcome Studies
A prospective study conducted in the Netherlands found that among 26 BRCA1/BRCA2 mutation carriers, the 14 women who chose mastectomy had higher distress both before test result disclosure and 6 and 12 months later, compared with the 12 carriers who chose surveillance and compared with 53 nonmutation carriers. Overall, however, anxiety declined in women undergoing prophylactic mastectomy; at 1 year, their anxiety scores were closer to those of women choosing surveillance and to the scores of nonmutation carriers. Interestingly, women opting for prophylactic mastectomy had lower pretest satisfaction with their breasts and general body image than carriers who opted for surveillance or noncarriers of BRCA1/BRCA2 mutations. Of the women who had a prophylactic mastectomy, all but one did not regret the decision at 1 year posttest disclosure, but many had difficulties with body image, sexual interest and functioning, and self-esteem. The perception that doctors had inadequately informed them about the consequences of prophylactic mastectomy was associated with regret. At 5-year follow-up, women who had undergone RRM had less favorable body image and changes in sexual relationships, but also had a significant reduction in the fear of developing cancer. In a study of 78 women who underwent risk-reducing surgery (including BRCA1/BRCA2 carriers and women who were from high-risk families with no detectable BRCA1/BRCA2 mutation), cancer-specific and general distress were assessed 2 weeks prior to surgery and at 6 and 12 months postsurgery. The sample included women who had RRM and RRSO alone and women who had both surgeries. There was no observable increase in distress over the 1-year period.
Mixed psychosocial outcomes were reported in a follow-up study (mean 14 years) of 609 women who received prophylactic mastectomies at the Mayo Clinic. Seventy percent were satisfied with prophylactic mastectomy, 11% were neutral, and 19% were dissatisfied. Eighteen percent believed that if they had the choice to make again, they probably or definitely would not have a prophylactic mastectomy. About three quarters said their worry about cancer was diminished by surgery. Half reported no change in their satisfaction with body image; 16% reported improved body image following surgery. Thirty-six percent said they were dissatisfied with their body image following prophylactic mastectomy. About a quarter of the women reported adverse impact of prophylactic mastectomy on their sexual relationships and sense of femininity, and 18% had diminished self-esteem. Factors most strongly associated with satisfaction with prophylactic mastectomy were postsurgical satisfaction with appearance, reduced stress, no reconstruction or lack of problems with implants, and no change or improvement in sexual relationships. Women who cited physician advice as the primary reason for choosing prophylactic mastectomy tended to be dissatisfied following prophylactic mastectomy.
A study of 60 healthy women who underwent RRM measured levels of satisfaction, body image, sexual functioning, intrusion and avoidance, and current psychological status at a mean of 4 years and 4 months postsurgery. Of this group, 76.7% had either a strong family history (21.7%) or carried a BRCA1 or BRCA2 mutation (55%). Overall, 97% of the women surveyed were either satisfied (17%) or extremely satisfied (80%) with their decision to have RRM, and all but one participant would recommend this procedure to other women. Most women (66.7%) reported that surgery had no impact on their sexual life, although 31.7% reported a worsening sexual life, and 76.6% reported either no change in body image or an improvement in body image, regardless of whether reconstruction was performed. Worsening self-image was reported by 23.3% of women after surgery. Women’s mean distress levels after surgery were only slightly above normal levels, although those women who continued to perceive their postsurgery breast cancer risk as high had higher mean levels of global and cancer-related distress than those who perceived their risk as low. Additionally, BRCA1 and BRCA2 mutation carriers and women with a strong family history of breast and/or ovarian cancer had higher mean levels of cancer-related distress than women with a limited family history.
Very little is known about how the results of genetic testing affect treatment decisions at the time of cancer diagnosis. Two studies explored genetic counseling and BRCA1/BRCA2 genetic testing at the time of breast cancer diagnosis. One of these studies found that genetic testing at the time of diagnosis significantly altered surgical decision making, with more mutation carriers than noncarriers opting for bilateral mastectomy. Bilateral RRM was chosen by 48% of mutation-positive women  and by 100% of mutation-positive women in a smaller series  of women undergoing testing at the time of diagnosis. Of women in whom no mutation was found, 24% also opted for bilateral RRM. Four percent of the test decliners also underwent bilateral RRM. Among mutation carriers, predictors of bilateral RRM included whether patients reported their physicians had recommended BRCA1/BRCA2 testing and bilateral RRM prior to testing, and whether they received a positive test result. Data are lacking on quality-of-life outcomes for women undergoing RRM following genetic testing performed at the time of diagnosis.
A prospective study from the Netherlands evaluated long-term psychological outcomes of offering women with breast cancer genetic counseling and, if indicated, genetic testing at the onset of breast radiation for treatment of their primary breast cancer. Of those who were approached for counseling, some underwent genetic testing and chose to receive their result (n = 58), some were approached but did not fulfill referral criteria (n = 118), and some declined the option of counseling/testing (n = 44). Another subset of women undergoing radiation therapy was not approached for counseling (n = 182) but was followed using the same measures. Psychological distress was measured at baseline and at 4, 11, 27, and 43 weeks after initial consultation for radiation therapy. No differences were detected in general anxiety, depression or breast cancer–specific distress across all four groups.
A retrospective questionnaire study of 583 women with a personal and family history of breast cancer and who underwent contralateral prophylactic mastectomy between 1960 and 1993 measured overall satisfaction after mastectomy and factors influencing satisfaction and dissatisfaction with this procedure. The mean time of follow-up was 10.3 years after prophylactic surgery. Overall, 83% of all participants stated they were satisfied or very satisfied, 8% were neutral, and 9% were dissatisfied with contralateral prophylactic mastectomy. Most women also reported favorable effects or no change in their self-esteem, level of stress, and emotional stability after surgery (88%, 83%, and 88%, respectively). Despite the high levels of overall satisfaction, 33% reported negative body image, 26% reported a reduced sense of femininity, and 23% reported a negative effect on sexual relationships. The type of surgical procedure also affected levels of satisfaction. The authors attributed this difference to the high rate of unanticipated reoperations in the group of women having subcutaneous mastectomy (43%) versus the group having simple mastectomy (15%) (P < .0001). Limitations to this study are mostly related to the time period during which participants had their surgery (i.e., availability of surgical reconstructive option). None of these women had genetic testing for mutations in the BRCA1/BRCA2 genes. Nevertheless, this study shows that while most women in this group were satisfied with contralateral prophylactic mastectomy, all women reported at least one adverse outcome.
Another study compared long-term quality-of-life outcomes in 195 women following bilateral RRM performed between 1979 and 1999 versus 117 women at high risk of breast cancer opting for screening. No statistically significant differences were detected between the groups for psychosocial outcomes. Eighty-four percent of those opting for surgery reported satisfaction with their decision. Sixty-one percent of women from both the surgery and screening groups reported being very much or quite a bit contented with their quality of life.
In a study of psychosocial outcomes associated with RRM and immediate reconstruction, 61 high-risk women (27 mutation carriers, others with high-risk family history), 31 of whom had a prior history of breast cancer, were evaluated on average 3 to 4 years after surgery. The study utilized questions designed to elicit yes versus no responses and found that the surgery was well-tolerated with 83% of participants reporting that the results of their reconstructive surgery were as they expected, 90% reporting that they had received adequate preoperative information, none reporting that they regretted the surgery, and all reporting that they would choose the same route if they had to do it again. Satisfaction with the results ranged from 74% satisfied with the shape of their breasts to 89% satisfied with the appearance of the scarring. Comparison of this group to normative samples on quality-of-life indicators (SF-36; HAD scores) indicated no reductions in quality of life in these women.
A qualitative study examining material on the Facing Our Risk of Cancer Empowered (FORCE) Web site posted by 21 high-risk women (BRCA1/BRCA2 positive) undergoing RRM showed that these women anticipated and received negative reactions from friends and family regarding the surgery, and that they managed disclosure in ways to maintain emotional support and self-protection for their decision. Many of the women expressed a relief from intrusive breast cancer thoughts and worry, and were satisfied with the cosmetic result of their surgery.
In contrast, another study examined long-term psychosocial outcomes in 684 women who had had bilateral or contralateral RRM on average 9 years prior to assessment. A majority of women (59%) had reconstructive surgery as well. Interestingly, based on a Likert scale, 85% of women reported that they were satisfied or very satisfied with their decision to have an RRM. However, in qualitative interviews, a large number of women went on to describe dissatisfaction or negative psychosocial outcomes associated with surgery. The authors coded the responses as negative when women reported still being anxious about their breast cancer risk and/or reported negative feelings about their body image, pain, and sexuality. Seventy-nine percent of the women providing negative comments and 84% of those making mixed comments (mixture of satisfaction and dissatisfaction) responded that they were either satisfied or very satisfied with their decision. Twice as many women with bilateral mastectomy made negative and mixed comments than did women with contralateral mastectomy. The areas of most concern were body image, problems with breast implants, pain after surgery, and sexuality. The authors proposed that those who had undergone contralateral procedures had already been treated for cancer, while those who had undergone bilateral procedures had not been treated previously, and this may partially account for the differences in satisfaction between the two groups. These findings suggest that women's satisfaction with RRM may be tempered by their complex reactions over time.
In a qualitative study of 108 women who underwent or were considering RRM, more than half of those who had RRM felt that presurgical consultation with a psychologist was advisable; nearly two-thirds thought that postsurgical consultation was also appropriate. All of the women who were considering RRM believed that psychological consultation prior to surgery would facilitate decision-making.
A retrospective self-administered survey of 40 women aged 35 to 74 years at time of RRSO (57.5% were younger than 50 years), who had undergone the procedure due to a family history of ovarian cancer through the Ontario Ministry of Health, found that RRSO resulted in a significant reduction in perceived ovarian cancer risk. Fifty-seven percent identified a decrease in perceived risk as a benefit of RRSO (35% did not comment on RRSO benefits) and 49% reported that they would repeat RRSO to decrease cancer risk. The overall quality-of-life scores were consistent with those published for women who are menopausal or participating in hormone studies. Quality of life in 59 women who underwent RRSO was assessed at 24 months postprocedure. Overall quality of life was similar to the general population and breast cancer survivors, with approximately 20% reporting depression. The 30% of subjects reporting vaginal dryness and dyspareunia were more likely to report dissatisfaction with the procedure.
A Canadian prospective study examined the impact of RRSO on menopausal symptoms and sexual functioning prior to surgery and then 1 year later in a sample of 114 women with known BRCA1/2 mutations. Satisfaction with the decision to undergo RRSO was high regardless of symptoms reported. Those who were premenopausal at the time of surgery (n = 75) experienced a worsening of symptoms and a decline in sexual functioning. HRT addressed vaginal dryness and dyspareunia but not declines in sexual pleasure. HRT also resulted in fewer moderate to severe hot flashes.
Additional work reported by this group found that the majority of the 127 women who had undergone RRSO 1 year previously (75 with BRCA1 mutations; 52 with BRCA2 mutations) felt that RRSO reduced their risk of both breast and ovarian cancer. There was a wide range of risk perceptions for ovarian cancer noted in the group. Twenty percent of BRCA1 and BRCA2 mutation carriers thought that their risk of ovarian cancer was completely eliminated; others had an inflated perception of their ovarian cancer risk both before and after surgery. A small group of these women were further surveyed at about 3 years postsurgery and their risk perceptions did not change significantly during this extended time period. These findings suggest that important misperceptions about ovarian cancer risk may persist after RRSO. Additional genetic education and counseling may be warranted.
A larger study assessed quality of life in women at high risk of ovarian cancer who opted for periodic gynecologic screening (GS) versus those who underwent RRSO. Eight hundred forty-six high-risk women, 44% of whom underwent RRSO and 56% of whom chose GS, completed questionnaires evaluating quality of life, cancer-specific distress, endocrine symptoms, and sexual functioning. Women in the RRSO group were a mean of 2.8 ±1.9 years from surgery and women in the GS group were a mean of 4.3 years from their first visit to a gynecologist for high-risk management. No statistical difference in overall quality of life was detected between the RRSO and GS groups. When compared with the GS group, women who underwent RRSO had poorer sexual functioning and more endocrine symptoms such as vaginal dryness, dyspareunia, and hot flashes. Women who underwent RRSO experienced lower levels of breast and ovarian cancer distress and had a more favorable perception of cancer risk.
Women (N = 182) at risk of hereditary breast and ovarian cancer referred for genetic counseling were surveyed concerning their satisfaction with their choice of either RRSO or period screening (PS) (biannual pelvic examination with TVUS and CA 125 determination) to manage their ovarian cancer risk. Overall satisfaction with both options was extremely high, but highest among those who chose RRSO over PS. There were no other demographic or clinical factors that distinguished satisfaction level. There was higher decisional ambivalence among those who chose PS.
A retrospective study assessed 98 BRCA mutation carriers who underwent RRSO about their preoperative counseling regarding symptoms to expect following surgery. The mean age at RRSO was 45.5 years (range, ages 32–63 years). Eighty-five percent pursued RRSO after learning that they harbored a BRCA mutation, and 48.0% were premenopausal at the time of surgery. Participants reported ‘‘frequent’’ or ‘‘very frequent’’ postsurgical symptoms of vaginal dryness (52.1%), changes in interest in sex (50.0%), sleep disturbances (46.7%), changes in sex life (43.9%), and hot flashes (42.9%). Only vaginal dryness and hot flashes were commonly recalled to have been addressed preoperatively. While 96% would have the surgery again, participants reported that the discussion of the impact of surgery on their sex life (59.2%), risk of coronary heart disease (57.1%), and the availability of sex counseling (57.1%) would have been helpful.
Several psychological interventions have been proposed for women who may have hereditary risk of breast cancer, but few of these have been rigorously tested. Issues faced by these women include the following:
- Confronting the meaning of one’s risk status and venting strong feelings of fear of harm, disfigurement, pain, or death.
- Addressing guilt about passing on genetic risk or not doing enough for loved ones.
- Managing stress, cancer-related worry, and intrusive thoughts.
- Coaching in problem-solving.
- Facilitating effective decision-making strategies and teaching positive, active coping behaviors.
Psychotherapy for women interested in prophylactic mastectomy is discussed in one report. Another recommends rehearsal of affective state in the context of all potential outcomes of cancer genetic testing for BRCA1/BRCA2. As genetic testing programs grow and the psychological outcomes and behavioral impact of testing are further defined, there will be an increasing demand for interventions to maximize the benefits of cancer genetic testing and minimize the risks to carriers and family members.
A randomized trial with 126 BRCA1/BRCA2 mutation carriers evaluated whether psychological and behavioral outcomes of BRCA1/BRCA2 testing are improved among mutation carriers by providing a psychosocial telephone counseling intervention in addition to standard genetic counseling. The intervention consisted of five 60- to 90-minute telephone counseling sessions. The first session was a semistructured clinical assessment interview designed to allow the mutation carrier to describe her experiences and reactions to BRCA testing results. The second through the fourth telephone sessions were individualized to the concerns raised by the woman in the domains of making medical decisions, managing family concerns, and emotional reactions following receipt of a positive BRCA1/BRCA2 result. The final telephone session focused on integration and closure on the issues raised and implementation of a plan for short-term and long-term goals established during the telephone intervention. Women most likely to complete the intervention were those who did not have a personal history of cancer; those who had higher levels of cancer-specific distress; those who were college graduates; and those who were employed. Outcome data from this study has not yet been reported.
A pilot study demonstrated the usefulness of a six-session psychoeducational support group for women at high genetic risk of breast cancer who were considering prophylactic mastectomy. The themes for the group sessions included overestimation of and anxiety about risk, desire for hard data, emotional impact of watching a mother die of breast cancer, concerns about spouse reactions, self-image and body image, the decision-making process, and confusion over whom to trust in decision-making. Both the participants and the multidisciplinary leaders concluded that as a supplement to individual counseling, a support group is a beneficial and cost-effective treatment modality.
A prospective study from the Netherlands  involving 163 newly-identified BRCA mutation carriers with no history of cancer considered the effects of psychoeducational support sessions on completion of intended risk management preferences (breast cancer surveillance or prophylactic mastectomy). All were offered the opportunity to participate in eight sessions focused on psychosocial (five sessions) and medical information (three sessions) following the receipt of test results. The number of women with a preference for mastectomy following receipt of test results who actually had a mastectomy at follow-up (median 2 years) was higher in the group that attended the psychoeducational support sessions compared with those who did not attend (89% and 63%, respectively; OR, 4.8; P = .04).
Women who called the National Cancer Institute's Cancer Information Service seeking information about breast or ovarian cancer risk, risk assessment, or cancer genetic testing, were randomly assigned to receive (1) general information about cancer risk and a referral to testing and counseling services or (2) an educational intervention designed to increase knowledge and understanding about inherited cancer risk, personal history of cancer, and the benefits and limitations of genetic testing. In the group receiving the educational intervention, intention to obtain genetic testing decreased among women at average breast cancer risk (as determined by the Gail model) and increased among women at high risk. Among average risk women, those in the intervention group identified as high monitors (i.e., those who seek and pay greater attention to threatening health-related information) demonstrated an increase in knowledge and breast cancer risk perceptions compared with low monitors (i.e., those who avoid attending to threatening health-related information).
A study  of screening behaviors of 216 self-referred, high-risk (>10% risk of carrying a BRCA1/BRCA2 mutation) women who are members of hereditary breast cancer families found a range of screening practices. Even the presence of known mutations in their families was not associated with good adherence to recommended screening practices. Sixty-nine percent of women aged 50 to 64 years and 83% of women aged 40 to 49 years had had a screening mammogram in the previous year. Twenty percent of participants had ever had a CA 125 test and 31% had ever had a pelvic or TVUS. Further analysis of this study population  looking specifically at 107 women with informative BRCA test results found good use of breast cancer screening, though the uptake rate in younger carriers is lower. The reason for the lower uptake rate was not explored in this study. One survey of screening behaviors among women at increased risk of breast/ovarian cancer identified physician recommendations as a significant factor in adherence to screening.
While motivations cited for pursuing genetic testing often include the expectation that mutation carriers will be more compliant with breast and/or ovarian screening recommendations, limited data exist about whether participants in genetic testing alter their screening behaviors over time and about other variables that may influence those behaviors, such as insurance coverage and physician recommendations or attitudes. The impact of cancer genetic counseling on screening behaviors was assessed in a U.K. study of 293 women followed for 12 months postcounseling at four cancer genetics clinics. BSE, CBE, and mammography were significantly increased after counseling; however, gaps in adherence to recommendations were noted: 38% of women aged 35 to 49 years had not had a mammogram by 12 months postcounseling. BSE was not done by most women at the recommended time and frequency.
This is a critical issue not only for women testing positive, but also for adherence to screening for those testing negative and those who have received indeterminate results or choose not to receive their results. It is possible that adherence actually diminishes with a decrease in the perceived risk that may result from a negative genetic test result.
In addition, while there is still some question regarding the link between cancer-related worry and breast cancer screening behavior, accumulating evidence appears to support a linear rather than a curvilinear relationship. That is, for some time, the data were not consistent; some data supported the hypothesis that mild-to-moderate worry may increase adherence, while excessive worry may actually decrease the utilization of recommended screening practices. Other reports support the notion that a linear relationship is more likely; that is, more worry increases adherence to screening recommendations. Few studies, however, have followed women to assess their health behaviors following genetic testing. Thus, a negative test result leading to decreased worry could theoretically result in decreased screening adherence. A large study found that patient compliance with screening practices was not related to general or screening-specific anxiety—with the exception of BSE, for which compliance is negatively associated with procedure-specific anxiety. Further research designed to clarify this potential concern would highlight the need for comprehensive genetic counseling to discuss the need for follow-up screening.
Further complicating this area of research are issues such as the baseline rate of mammography adherence among women older than 40 or 50 years prior to genetic testing. More specifically, the ability to note a significant difference in adherence on this measure may be affected by the high adherence rate to this screening behavior before genetic testing by women undergoing such testing. It may be easier to find significant changes in mammography use among women with a family history of breast cancer who test positive. Finally, adherence over time will likely be affected by how women undergoing genetic testing and their caregivers perceive the efficacy of many of the screening options in question, such as mammography for younger women, BSE, and ovarian cancer screening (periodic vaginal ultrasound and serum CA 125 measurements), along with the value of preventive interventions.
The issue of screening decision-making and adherence among women undergoing genetic testing for breast and ovarian cancer is the subject of \several ongoing trials, and an area of much needed ongoing study.1Lynch HT, Fitzsimmons ML, Lynch J, et al.: A hereditary cancer consultation clinic. Nebr Med J 74 (12): 351-9, 1989.2Eeles RA, ed.: Genetic Predisposition to Cancer. London, England: Chapman and Hall Medical, 1996.3Baty BJ, Venne VL, McDonald J, et al.: BRCA1 testing: genetic counseling protocol development and counseling issues. J Genet Couns 6(2): 223-244, 1997.4Hoskins IA: Genetic counseling for cancer patients and their families. Oncology (Huntingt) 3 (1): 84-92; discussion 92, 95-8, 1989.5Lynch HT, Lynch J: Genetic counseling for hereditary cancer. Oncology (Huntingt) 10 (1): 27-34, 1996.6McKinnon WC, Guttmacher AE, Greenblatt MS, et al.: The Familial Cancer Program of the Vermont Cancer Center: development of a cancer genetics program in a rural area. J Genet Couns 6(2): 131-145, 1997.7Offit K: Clinical Cancer Genetics: Risk Counseling and Management. New York, NY: John Wiley and Sons, 1998.8Peters JA: Familial cancer risk, part II: breast cancer risk counseling and genetic susceptibility testing. J Oncol Manag 3 (6): 14-22, 1994.9Ponder BA: Setting up and running a familial cancer clinic. Br Med Bull 50 (3): 732-45, 1994.10Collins FS, Thomson EJ: Findings from the cancer genetic studies consortium. Cancer Epidemiol Biomarkers Prev 8 (special issue): 325, 1999.11Calzone KA, Biesecker BB: Genetic testing for cancer predisposition. Cancer Nurs 25 (1): 15-25; quiz 26-7, 2002.12Ropka ME, Wenzel J, Phillips EK, et al.: Uptake rates for breast cancer genetic testing: a systematic review. Cancer Epidemiol Biomarkers Prev 15 (5): 840-55, 2006.13Olaya W, Esquivel P, Wong JH, et al.: Disparities in BRCA testing: when insurance coverage is not a barrier. Am J Surg 198 (4): 562-5, 2009.14Metcalfe KA, Fan I, McLaughlin J, et al.: Uptake of clinical genetic testing for ovarian cancer in Ontario: a population-based study. Gynecol Oncol 112 (1): 68-72, 2009.15Lynch HT, Snyder CL, Lynch JF, et al.: Family information service participation increases the rates of mutation testing among members of families with BRCA1/2 mutations. Breast J 15 (Suppl 1): S20-4, 2009 Sep-Oct.16Bowen DJ, Patenaude AF, Vernon SW: Psychosocial issues in cancer genetics: from the laboratory to the public. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 326-8, 1999.17Lee SC, Bernhardt BA, Helzlsouer KJ: Utilization of BRCA1/2 genetic testing in the clinical setting: report from a single institution. Cancer 94 (6): 1876-85, 2002.18Durfy SJ, Buchanan TE, Burke W: Testing for inherited susceptibility to breast cancer: a survey of informed consent forms for BRCA1 and BRCA2 mutation testing. Am J Med Genet 75 (1): 82-7, 1998.19Geller G, Doksum T, Bernhardt BA, et al.: Participation in breast cancer susceptibility testing protocols: influence of recruitment source, altruism, and family involvement on women's decisions. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 377-83, 1999.20Kash KM, Holland JC, Halper MS, et al.: Psychological distress and surveillance behaviors of women with a family history of breast cancer. J Natl Cancer Inst 84 (1): 24-30, 1992.21Lerman C, Schwartz M: Adherence and psychological adjustment among women at high risk for breast cancer. Breast Cancer Res Treat 28 (2): 145-55, 1993.22Armstrong K, Calzone K, Stopfer J, et al.: Factors associated with decisions about clinical BRCA1/2 testing. Cancer Epidemiol Biomarkers Prev 9 (11): 1251-4, 2000.23Armstrong K, Stopfer J, Calzone K, et al.: What does my doctor think? Preferences for knowing the doctor's opinion among women considering clinical testing for BRCA1/2 mutations. Genet Test 6 (2): 115-8, 2002 Summer.24McCuaig JM, Greenwood CM, Shuman C, et al.: Breast and ovarian cancer: the forgotten paternal contribution. J Genet Couns 20 (5): 442-9, 2011.25Burke W, Culver J, Pinsky L, et al.: Genetic assessment of breast cancer risk in primary care practice. Am J Med Genet A 149A (3): 349-56, 2009.26Mouchawar J, Klein CE, Mullineaux L: Colorado family physicians' knowledge of hereditary breast cancer and related practice. J Cancer Educ 16 (1): 33-7, 2001.27Yong MC, Zhou XJ, Lee SC: The importance of paternal family history in hereditary breast cancer is underappreciated by health care professionals. Oncology 64 (3): 220-6, 2003.28Shannon KM, Muzikansky A, Chan-Smutko G, et al.: Uptake of BRCA1 rearrangement panel testing: in individuals previously tested for BRCA1/2 mutations. Genet Med 8 (12): 740-5, 2006.29Lerman C, Hughes C, Lemon SJ, et al.: What you don't know can hurt you: adverse psychologic effects in members of BRCA1-linked and BRCA2-linked families who decline genetic testing. J Clin Oncol 16 (5): 1650-4, 1998.30Lodder L, Frets PG, Trijsburg RW, et al.: Attitudes and distress levels in women at risk to carry a BRCA1/BRCA2 gene mutation who decline genetic testing. Am J Med Genet 119A (3): 266-72, 2003.31Foster C, Evans DG, Eeles R, et al.: Non-uptake of predictive genetic testing for BRCA1/2 among relatives of known carriers: attributes, cancer worry, and barriers to testing in a multicenter clinical cohort. Genet Test 8 (1): 23-9, 2004.32McInerney-Leo A, Biesecker BB, Hadley DW, et al.: BRCA1/2 testing in hereditary breast and ovarian cancer families II: impact on relationships. Am J Med Genet A 133 (2): 165-9, 2005.33Struewing JP, Lerman C, Kase RG, et al.: Anticipated uptake and impact of genetic testing in hereditary breast and ovarian cancer families. Cancer Epidemiol Biomarkers Prev 4 (2): 169-73, 1995.34Rimer BK, Schildkraut JM, Lerman C, et al.: Participation in a women's breast cancer risk counseling trial. Who participates? Who declines? High Risk Breast Cancer Consortium. Cancer 77 (11): 2348-55, 1996.35Jacobsen PB, Valdimarsdottier HB, Brown KL, et al.: Decision-making about genetic testing among women at familial risk for breast cancer. Psychosom Med 59 (5): 459-66, 1997 Sep-Oct.36Lerman C, Hughes C, Benkendorf JL, et al.: Racial differences in testing motivation and psychological distress following pretest education for BRCA1 gene testing. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 361-7, 1999.37Durfy SJ, Bowen DJ, McTiernan A, et al.: Attitudes and interest in genetic testing for breast and ovarian cancer susceptibility in diverse groups of women in western Washington. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 369-75, 1999.38Evans DG, Binchy A, Shenton A, et al.: Comparison of proactive and usual approaches to offering predictive testing for BRCA1/2 mutations in unaffected relatives. Clin Genet 75 (2): 124-32, 2009.39Kessler L, Collier A, Brewster K, et al.: Attitudes about genetic testing and genetic testing intentions in African American women at increased risk for hereditary breast cancer. Genet Med 7 (4): 230-8, 2005.40Armstrong K, Micco E, Carney A, et al.: Racial differences in the use of BRCA1/2 testing among women with a family history of breast or ovarian cancer. JAMA 293 (14): 1729-36, 2005.41Winer E, Winer N, Bluman L, et al.: Attitudes and risk perceptions of women with breast cancer considering testing for BRCA1/2. [Abstract] Proceedings of the American Society of Clinical Oncology 16: A1937, 537a, 1997.42Braithwaite D, Emery J, Walter F, et al.: Psychological impact of genetic counseling for familial cancer: a systematic review and meta-analysis. J Natl Cancer Inst 96 (2): 122-33, 2004.43Mikkelsen EM, Sunde L, Johansen C, et al.: Psychosocial conditions of women awaiting genetic counseling: a population-based study. J Genet Couns 17 (3): 242-51, 2008.44Dorval M, Bouchard K, Maunsell E, et al.: Health behaviors and psychological distress in women initiating BRCA1/2 genetic testing: comparison with control population. J Genet Couns 17 (4): 314-26, 2008.45Wang C, Gonzalez R, Janz N, et al.: The role of cognitive appraisal and worry in BRCA1/2 testing decisions among a clinic population. Psychol Health 22 (6): 719-36, 2007.46Hallowell N, Statham H, Murton F: Women's understanding of their risk of developing breast/ovarian cancer before and after genetic counseling. J Genet Couns 7(4): 345-364, 1998.47MacDonald DJ, Choi J, Ferrell B, et al.: Concerns of women presenting to a comprehensive cancer centre for genetic cancer risk assessment. J Med Genet 39 (7): 526-30, 2002.48Matloff ET, Moyer A, Shannon KM, et al.: Healthy women with a family history of breast cancer: impact of a tailored genetic counseling intervention on risk perception, knowledge, and menopausal therapy decision making. J Womens Health (Larchmt) 15 (7): 843-56, 2006.49Bluman LG, Rimer BK, Berry DA, et al.: Attitudes, knowledge, and risk perceptions of women with breast and/or ovarian cancer considering testing for BRCA1 and BRCA2. J Clin Oncol 17 (3): 1040-6, 1999.50Iglehart JD, Miron A, Rimer BK, et al.: Overestimation of hereditary breast cancer risk. Ann Surg 228 (3): 375-84, 1998.51Bluman LG, Rimer BK, Regan Sterba K, et al.: Attitudes, knowledge, risk perceptions and decision-making among women with breast and/or ovarian cancer considering testing for BRCA1 and BRCA2 and their spouses. Psychooncology 12 (5): 410-27, 2003 Jul-Aug.52McCaul KD, O'Donnell SM: Naive beliefs about breast cancer risk. Womens Health 4 (1): 93-101, 1998 Spring.53Huiart L, Eisinger F, Stoppa-Lyonnet D, et al.: Effects of genetic consultation on perception of a family risk of breast/ovarian cancer and determinants of inaccurate perception after the consultation. J Clin Epidemiol 55 (7): 665-75, 2002.54Davis S, Stewart S, Bloom J: Increasing the accuracy of perceived breast cancer risk: results from a randomized trial with Cancer Information Service callers. Prev Med 39 (1): 64-73, 2004.55Katapodi MC, Dodd MJ, Lee KA, et al.: Underestimation of breast cancer risk: influence on screening behavior. Oncol Nurs Forum 36 (3): 306-14, 2009.56Lindberg NM, Wellisch D: Anxiety and compliance among women at high risk for breast cancer. Ann Behav Med 23 (4): 298-303, 2001 Fall.57Ritvo P, Irvine J, Robinson G, et al.: Psychological adjustment to familial-genetic risk assessment for ovarian cancer: predictors of nonadherence to surveillance recommendations. Gynecol Oncol 84 (1): 72-80, 2002.58Meiser B, Halliday JL: What is the impact of genetic counselling in women at increased risk of developing hereditary breast cancer? A meta-analytic review. Soc Sci Med 54 (10): 1463-70, 2002.59Green J, Richards M, Murton F, et al.: Family communication and genetic counseling: the case of hereditary breast and ovarian cancer. J Genet Couns 6(1): 45-60, 1997.60Quillin JM, Ramakrishnan V, Borzelleca J, et al.: Paternal relatives and family history of breast cancer. Am J Prev Med 31 (3): 265-8, 2006.61O'Neill SM, Rubinstein WS, Wang C, et al.: Familial risk for common diseases in primary care: the Family Healthware Impact Trial. Am J Prev Med 36 (6): 506-14, 2009.62Rubinstein WS, O'neill SM, Rothrock N, et al.: Components of family history associated with women's disease perceptions for cancer: a report from the Family Healthware™ Impact Trial. Genet Med 13 (1): 52-62, 2011.63Theis B, Boyd N, Lockwood G, et al.: Accuracy of family cancer history in breast cancer patients. Eur J Cancer Prev 3 (4): 321-7, 1994.64Breuer B, Kash KM, Rosenthal G, et al.: Reporting bilaterality status in first-degree relatives with breast cancer: a validity study. Genet Epidemiol 10 (4): 245-56, 1993.65Parent ME, Ghadirian P, Lacroix A, et al.: The reliability of recollections of family history: implications for the medical provider. J Cancer Educ 12 (2): 114-20, 1997 Summer.66Kelly KM, Shedlosky-Shoemaker R, Porter K, et al.: Cancer family history reporting: impact of method and psychosocial factors. J Genet Couns 16 (3): 373-82, 2007.67Kerber RA, Slattery ML: Comparison of self-reported and database-linked family history of cancer data in a case-control study. Am J Epidemiol 146 (3): 244-8, 1997.68Kerr B, Foulkes WD, Cade D, et al.: False family history of breast cancer in the family cancer clinic. Eur J Surg Oncol 24 (4): 275-9, 1998.69Schwartz MD, Peshkin BN, Hughes C, et al.: Impact of BRCA1/BRCA2 mutation testing on psychologic distress in a clinic-based sample. J Clin Oncol 20 (2): 514-20, 2002.70Mancini J, Noguès C, Adenis C, et al.: Impact of an information booklet on satisfaction and decision-making about BRCA genetic testing. Eur J Cancer 42 (7): 871-81, 2006.71Green MJ, Biesecker BB, McInerney AM, et al.: An interactive computer program can effectively educate patients about genetic testing for breast cancer susceptibility. Am J Med Genet 103 (1): 16-23, 2001.72Green MJ, Peterson SK, Baker MW, et al.: Effect of a computer-based decision aid on knowledge, perceptions, and intentions about genetic testing for breast cancer susceptibility: a randomized controlled trial. JAMA 292 (4): 442-52, 2004.73Green MJ, McInerney AM, Biesecker BB, et al.: Education about genetic testing for breast cancer susceptibility: patient preferences for a computer program or genetic counselor. Am J Med Genet 103 (1): 24-31, 2001.74Dabney MK, Huelsman K: Counseling by computer: breast cancer risk and genetic testing. Developed by the University of Wisconsin-Madison Department of Medicine and the Program in Medical Ethics. Genet Test 4 (1): 43-4, 2000.75Green MJ, Peterson SK, Baker MW, et al.: Use of an educational computer program before genetic counseling for breast cancer susceptibility: effects on duration and content of counseling sessions. Genet Med 7 (4): 221-9, 2005.76Baty BJ, Kinney AY, Ellis SM: Developing culturally sensitive cancer genetics communication aids for African Americans. Am J Med Genet 118A (2): 146-55, 2003.77Permuth-Wey J, Vadaparampil S, Rumphs A, et al.: Development of a culturally tailored genetic counseling booklet about hereditary breast and ovarian cancer for Black women. Am J Med Genet A 152A (4): 836-45, 2010.78Pal T, Stowe C, Cole A, et al.: Evaluation of phone-based genetic counselling in African American women using culturally tailored visual aids. Clin Genet 78 (2): 124-31, 2010.79Calzone KA: Predisposition testing for breast and ovarian cancer susceptibility. Semin Oncol Nurs 13 (2): 82-90, 1997.80Smith KR, West JA, Croyle RT, et al.: Familial context of genetic testing for cancer susceptibility: moderating effect of siblings' test results on psychological distress one to two weeks after BRCA1 mutation testing. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 385-92, 1999.81Wylie JE, Smith KR, Botkin JR: Effects of spouses on distress experienced by BRCA1 mutation carriers over time. Am J Med Genet 119C (1): 35-44, 2003.82Kelly PT: Understanding Breast Cancer Risk. Philadelphia, Pa: Temple University Press, 1991.83Hubbard R, Lewontin RC: Pitfalls of genetic testing. N Engl J Med 334 (18): 1192-4, 1996.84Richards MP, Hallowell N, Green JM, et al.: Counseling families with hereditary breast and ovarian cancer: a psychosocial perspective. J Genet Couns 4(3): 219-233, 1995.85Hoskins KF, Stopfer JE, Calzone KA, et al.: Assessment and counseling for women with a family history of breast cancer. A guide for clinicians. JAMA 273 (7): 577-85, 1995.86Schneider KA: Genetic counseling for BRCA1/BRCA2 testing. Genet Test 1 (2): 91-8, 1997.87McKinnon WC, Baty BJ, Bennett RL, et al.: Predisposition genetic testing for late-onset disorders in adults. A position paper of the National Society of Genetic Counselors. JAMA 278 (15): 1217-20, 1997.88Cummings S, Olopade O: Predisposition testing for inherited breast cancer. Oncology (Huntingt) 12 (8): 1227-41; discussion 1241-2, 1998.89Lipkus IM, Klein WM, Rimer BK: Communicating breast cancer risks to women using different formats. Cancer Epidemiol Biomarkers Prev 10 (8): 895-8, 2001.90Butow PN, Lobb EA: Analyzing the process and content of genetic counseling in familial breast cancer consultations. J Genet Couns 13 (5): 403-24, 2004.91Lerman C, Audrain J, Croyle RT: DNA-testing for heritable breast cancer risks: lessons from traditional genetic counseling. Ann Behav Med 16(4): 327-333, 1994.92Pieterse AH, van Dulmen AM, Beemer FA, et al.: Cancer genetic counseling: communication and counselees' post-visit satisfaction, cognitions, anxiety, and needs fulfillment. J Genet Couns 16 (1): 85-96, 2007.93Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.94Lerman C, Narod S, Schulman K, et al.: BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes. JAMA 275 (24): 1885-92, 1996.95Croyle RT, Smith KR, Botkin JR, et al.: Psychological responses to BRCA1 mutation testing: preliminary findings. Health Psychol 16 (1): 63-72, 1997.96Reichelt JG, Heimdal K, Møller P, et al.: BRCA1 testing with definitive results: a prospective study of psychological distress in a large clinic-based sample. Fam Cancer 3 (1): 21-8, 2004.97Reichelt JG, Møller P, Heimdal K, et al.: Psychological and cancer-specific distress at 18 months post-testing in women with demonstrated BRCA1 mutations for hereditary breast/ovarian cancer. Fam Cancer 7 (3): 245-54, 2008.98Broadstock M, Michie S, Marteau T: Psychological consequences of predictive genetic testing: a systematic review. Eur J Hum Genet 8 (10): 731-8, 2000.99Watson M, Foster C, Eeles R, et al.: Psychosocial impact of breast/ovarian (BRCA1/2) cancer-predictive genetic testing in a UK multi-centre clinical cohort. Br J Cancer 91 (10): 1787-94, 2004.100Foster C, Watson M, Eeles R, et al.: Predictive genetic testing for BRCA1/2 in a UK clinical cohort: three-year follow-up. Br J Cancer 96 (5): 718-24, 2007.101Claes E, Evers-Kiebooms G, Denayer L, et al.: Predictive genetic testing for hereditary breast and ovarian cancer: psychological distress and illness representations 1 year following disclosure. J Genet Couns 14 (5): 349-63, 2005.102van Oostrom I, Meijers-Heijboer H, Lodder LN, et al.: Long-term psychological impact of carrying a BRCA1/2 mutation and prophylactic surgery: a 5-year follow-up study. J Clin Oncol 21 (20): 3867-74, 2003.103Horowitz M, Wilner N, Alvarez W: Impact of Event Scale: a measure of subjective stress. Psychosom Med 41 (3): 209-18, 1979.104DudokdeWit AC, Tibben A, Duivenvoorden HJ, et al.: Predicting adaptation to presymptomatic DNA testing for late onset disorders: who will experience distress? Rotterdam Leiden Genetics Workgroup. J Med Genet 35 (9): 745-54, 1998.105Halbert CH, Stopfer JE, McDonald J, et al.: Long-term reactions to genetic testing for BRCA1 and BRCA2 mutations: does time heal women's concerns? J Clin Oncol 29 (32): 4302-6, 2011.106Graves KD, Vegella P, Poggi EA, et al.: Long-term psychosocial outcomes of BRCA1/BRCA2 testing: differences across affected status and risk-reducing surgery choice. Cancer Epidemiol Biomarkers Prev 21 (3): 445-55, 2012.107Cella D, Hughes C, Peterman A, et al.: A brief assessment of concerns associated with genetic testing for cancer: the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire. Health Psychol 21 (6): 564-72, 2002.108Andrews L, Meiser B, Apicella C, et al.: Psychological impact of genetic testing for breast cancer susceptibility in women of Ashkenazi Jewish background: a prospective study. Genet Test 8 (3): 240-7, 2004.109Wood ME, Mullineaux L, Rahm AK, et al.: Impact of BRCA1 testing on women with cancer: a pilot study. Genet Test 4 (3): 265-72, 2000.110Coyne JC, Kruus L, Racioppo M, et al.: What do ratings of cancer-specific distress mean among women at high risk of breast and ovarian cancer? Am J Med Genet 116A (3): 222-8, 2003.111DudokdeWit AC, Tibben A, Frets PG, et al.: BRCA1 in the family: a case description of the psychological implications. Am J Med Genet 71 (1): 63-71, 1997.112Macke E: A family history of breast and ovarian cancer. In: Marteau T, Richards M, eds.: The Troubled Helix: Social and Psychological Implications of the New Human Genetics. Cambridge, England: Cambridge University Press, 1996, pp 31-37.113Bonadona V, Saltel P, Desseigne F, et al.: Cancer patients who experienced diagnostic genetic testing for cancer susceptibility: reactions and behavior after the disclosure of a positive test result. Cancer Epidemiol Biomarkers Prev 11 (1): 97-104, 2002.114Bish A, Sutton S, Jacobs C, et al.: Changes in psychological distress after cancer genetic counselling: a comparison of affected and unaffected women. Br J Cancer 86 (1): 43-50, 2002 Jan 7.115Dorval M, Patenaude AF, Schneider KA, et al.: Anticipated versus actual emotional reactions to disclosure of results of genetic tests for cancer susceptibility: findings from p53 and BRCA1 testing programs. J Clin Oncol 18 (10): 2135-42, 2000.116Hallowell N, Foster C, Ardern-Jones A, et al.: Genetic testing for women previously diagnosed with breast/ovarian cancer: examining the impact of BRCA1 and BRCA2 mutation searching. Genet Test 6 (2): 79-87, 2002 Summer.117O'Neill SC, Rini C, Goldsmith RE, et al.: Distress among women receiving uninformative BRCA1/2 results: 12-month outcomes. Psychooncology 18 (10): 1088-96, 2009.118Rini C, O'Neill SC, Valdimarsdottir H, et al.: Cognitive and emotional factors predicting decisional conflict among high-risk breast cancer survivors who receive uninformative BRCA1/2 results. Health Psychol 28 (5): 569-78, 2009.119Brain K, Norman P, Gray J, et al.: A randomized trial of specialist genetic assessment: psychological impact on women at different levels of familial breast cancer risk. Br J Cancer 86 (2): 233-8, 2002.120Fry A, Cull A, Appleton S, et al.: A randomised controlled trial of breast cancer genetics services in South East Scotland: psychological impact. Br J Cancer 89 (4): 653-9, 2003.121Bernhardt BA, Geller G, Doksum T, et al.: Evaluation of nurses and genetic counselors as providers of education about breast cancer susceptibility testing. Oncol Nurs Forum 27 (1): 33-9, 2000 Jan-Feb.122Hallowell N, Statham H, Murton F, et al.: "Talking about chance": the presentation of risk information during genetic counseling for breast and ovarian cancer. J Genet Couns 6(3): 269-286, 1997.123Audrain J, Rimer B, Cella D, et al.: Genetic counseling and testing for breast-ovarian cancer susceptibility: what do women want? J Clin Oncol 16 (1): 133-8, 1998.124Watson M, Duvivier V, Wade Walsh M, et al.: Family history of breast cancer: what do women understand and recall about their genetic risk? J Med Genet 35 (9): 731-8, 1998.125Wakefield CE, Meiser B, Homewood J, et al.: A randomized controlled trial of a decision aid for women considering genetic testing for breast and ovarian cancer risk. Breast Cancer Res Treat 107 (2): 289-301, 2008.126Lerman C, Peshkin BN, Hughes C, et al.: Family disclosure in genetic testing for cancer susceptibility: determinants and consequences. Journal of Health Care Law and Policy 1(2): 353-373, 1998.127Kenen R, Arden-Jones A, Eeles R: Healthy women from suspected hereditary breast and ovarian cancer families: the significant others in their lives. Eur J Cancer Care (Engl) 13 (2): 169-79, 2004.128Finlay E, Stopfer JE, Burlingame E, et al.: Factors determining dissemination of results and uptake of genetic testing in families with known BRCA1/2 mutations. Genet Test 12 (1): 81-91, 2008.129Hughes C, Lerman C, Schwartz M, et al.: All in the family: evaluation of the process and content of sisters' communication about BRCA1 and BRCA2 genetic test results. Am J Med Genet 107 (2): 143-50, 2002.130Wagner Costalas J, Itzen M, Malick J, et al.: Communication of BRCA1 and BRCA2 results to at-risk relatives: a cancer risk assessment program's experience. Am J Med Genet 119C (1): 11-8, 2003.131Patenaude AF, Dorval M, DiGianni LS, et al.: Sharing BRCA1/2 test results with first-degree relatives: factors predicting who women tell. J Clin Oncol 24 (4): 700-6, 2006.132MacDonald DJ, Sarna L, van Servellen G, et al.: Selection of family members for communication of cancer risk and barriers to this communication before and after genetic cancer risk assessment. Genet Med 9 (5): 275-82, 2007.133Claes E, Evers-Kiebooms G, Boogaerts A, et al.: Communication with close and distant relatives in the context of genetic testing for hereditary breast and ovarian cancer in cancer patients. Am J Med Genet 116A (1): 11-9, 2003.134Foster C, Eeles R, Ardern-Jones A, et al.: Juggling roles and expectations: dilemmas faced by women talking to relatives about cancer and genetic testing. Psychol Health 19 (4): 439-55, 2004.135Kenen R, Arden-Jones A, Eeles R: We are talking, but are they listening? Communication patterns in families with a history of breast/ovarian cancer (HBOC). Psychooncology 13 (5): 335-45, 2004.136Segal J, Esplen MJ, Toner B, et al.: An investigation of the disclosure process and support needs of BRCA1 and BRCA2 carriers. Am J Med Genet A 125 (3): 267-72, 2004.137Bradbury AR, Dignam JJ, Ibe CN, et al.: How often do BRCA mutation carriers tell their young children of the family's risk for cancer? A study of parental disclosure of BRCA mutations to minors and young adults. J Clin Oncol 25 (24): 3705-11, 2007.138Bradbury AR, Patrick-Miller L, Pawlowski K, et al.: Learning of your parent's BRCA mutation during adolescence or early adulthood: a study of offspring experiences. Psychooncology 18 (2): 200-8, 2009.139Manne S, Audrain J, Schwartz M, et al.: Associations between relationship support and psychological reactions of participants and partners to BRCA1 and BRCA2 testing in a clinic-based sample. Ann Behav Med 28 (3): 211-25, 2004.140McAllister MF, Evans DG, Ormiston W, et al.: Men in breast cancer families: a preliminary qualitative study of awareness and experience. J Med Genet 35 (9): 739-44, 1998.141Liede A, Metcalfe K, Hanna D, et al.: Evaluation of the needs of male carriers of mutations in BRCA1 or BRCA2 who have undergone genetic counseling. Am J Hum Genet 67 (6): 1494-504, 2000.142Metcalfe KA, Liede A, Trinkaus M, et al.: Evaluation of the needs of spouses of female carriers of mutations in BRCA1 and BRCA2. Clin Genet 62 (6): 464-9, 2002.143Mireskandari S, Sherman KA, Meiser B, et al.: Psychological adjustment among partners of women at high risk of developing breast/ovarian cancer. Genet Med 9 (5): 311-20, 2007.144Sherman KA, Kasparian NA, Mireskandari S: Psychological adjustment among male partners in response to women's breast/ovarian cancer risk: a theoretical review of the literature. Psychooncology 19 (1): 1-11, 2010.145Daly MB: The impact of social roles on the experience of men in BRCA1/2 families: implications for counseling. J Genet Couns 18 (1): 42-8, 2009.146DudokdeWit AC, Tibben A, Frets PG, et al.: Males at-risk for the BRCA1 gene, the psychological impact. Psychooncology 5(3): 251-257, 1996.147Lodder L, Frets PG, Trijsburg RW, et al.: Men at risk of being a mutation carrier for hereditary breast/ovarian cancer: an exploration of attitudes and psychological functioning during genetic testing. Eur J Hum Genet 9 (7): 492-500, 2001.148Lerman C, Hughes C, Croyle RT, et al.: Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing. Prev Med 31 (1): 75-80, 2000.149Hughes C, Lynch H, Durham C, et al.: Communication of BRCA1/2 Test Results in Hereditary Breast Cancer Families. Cancer Research in Therapy and Control Vol. 8, 1999, pp. 51-59.150Tercyak KP, Hughes C, Main D, et al.: Parental communication of BRCA1/2 genetic test results to children. Patient Educ Couns 42 (3): 213-24, 2001.151Tercyak KP, Peshkin BN, DeMarco TA, et al.: Parent-child factors and their effect on communicating BRCA1/2 test results to children. Patient Educ Couns 47 (2): 145-53, 2002.152McGivern B, Everett J, Yager GG, et al.: Family communication about positive BRCA1 and BRCA2 genetic test results. Genet Med 6 (6): 503-9, 2004 Nov-Dec.153Tercyak KP, Peshkin BN, Demarco TA, et al.: Information needs of mothers regarding communicating BRCA1/2 cancer genetic test results to their children. Genet Test 11 (3): 249-55, 2007.154Patenaude AF: Cancer susceptibility testing: risks, benefits, and personal beliefs. In: Clarke A, ed.: The Genetic Testing of Children. Oxford, England: BIOS Scientific, 1998, pp 145-156.155Richards M: The genetic testing of children: adult attitude's and children's understanding. In: Clarke A, ed.: The Genetic Testing of Children. Oxford, England: BIOS Scientific, 1998, pp 169-179.156Wertz DC, Fanos JH, Reilly PR: Genetic testing for children and adolescents. Who decides? JAMA 272 (11): 875-81, 1994.157Borry P, Stultiëns L, Nys H, et al.: Attitudes towards predictive genetic testing in minors for familial breast cancer: a systematic review. Crit Rev Oncol Hematol 64 (3): 173-81, 2007.158Wertz DC: International perspectives. In: Clarke A, ed.: The Genetic Testing of Children. Oxford, England: BIOS Scientific, 1998, pp 271-287.159Benkendorf JL, Reutenauer JE, Hughes CA, et al.: Patients' attitudes about autonomy and confidentiality in genetic testing for breast-ovarian cancer susceptibility. Am J Med Genet 73 (3): 296-303, 1997.160Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 57 (5): 1233-41, 1995.161Michie S, Marteau TM: Predictive genetic testing in children: the need for psychological research. In: Clarke A, ed.: The Genetic Testing of Children. Oxford, England: BIOS Scientific, 1998, pp 169-182.162MacDonald DJ, Lessick M: Hereditary cancers in children and ethical and psychosocial implications. J Pediatr Nurs 15 (4): 217-25, 2000.163Tercyak KP, Peshkin BN, Streisand R, et al.: Psychological issues among children of hereditary breast cancer gene (BRCA1/2) testing participants. Psychooncology 10 (4): 336-46, 2001 Jul-Aug.164Staton AD, Kurian AW, Cobb K, et al.: Cancer risk reduction and reproductive concerns in female BRCA1/2 mutation carriers. Fam Cancer 7 (2): 179-86, 2008.165Friedman LC, Kramer RM: Reproductive issues for women with BRCA mutations. J Natl Cancer Inst Monogr (34): 83-6, 2005.166Smith KR, Ellington L, Chan AY, et al.: Fertility intentions following testing for a BRCA1 gene mutation. Cancer Epidemiol Biomarkers Prev 13 (5): 733-40, 2004.167Quinn G, Vadaparampil S, Wilson C, et al.: Attitudes of high-risk women toward preimplantation genetic diagnosis. Fertil Steril 91 (6): 2361-8, 2009.168Cunniff C; American Academy of Pediatrics Committee on Genetics.: Prenatal screening and diagnosis for pediatricians. Pediatrics 114 (3): 889-94, 2004.169Rappaport VJ: Prenatal diagnosis and genetic screening--integration into prenatal care. Obstet Gynecol Clin North Am 35 (3): 435-58, ix, 2008.170Baruch S, Kaufman D, Hudson KL: Genetic testing of embryos: practices and perspectives of US in vitro fertilization clinics. Fertil Steril 89 (5): 1053-8, 2008.171Ogilvie CM, Braude PR, Scriven PN: Preimplantation genetic diagnosis--an overview. J Histochem Cytochem 53 (3): 255-60, 2005.172Vadaparampil ST, Quinn GP, Knapp C, et al.: Factors associated with preimplantation genetic diagnosis acceptance among women concerned about hereditary breast and ovarian cancer. Genet Med 11 (10): 757-65, 2009.173Quinn GP, Vadaparampil ST, King LM, et al.: Conflict between values and technology: perceptions of preimplantation genetic diagnosis among women at increased risk for hereditary breast and ovarian cancer. Fam Cancer 8 (4): 441-9, 2009.174Menon U, Harper J, Sharma A, et al.: Views of BRCA gene mutation carriers on preimplantation genetic diagnosis as a reproductive option for hereditary breast and ovarian cancer. Hum Reprod 22 (6): 1573-7, 2007.175Fortuny D, Balmaña J, Graña B, et al.: Opinion about reproductive decision making among individuals undergoing BRCA1/2 genetic testing in a multicentre Spanish cohort. Hum Reprod 24 (4): 1000-6, 2009.176Julian-Reynier C, Fabre R, Coupier I, et al.: BRCA1/2 carriers: their childbearing plans and theoretical intentions about having preimplantation genetic diagnosis and prenatal diagnosis. Genet Med 14 (5): 527-34, 2012.177Ormondroyd E, Donnelly L, Moynihan C, et al.: Attitudes to reproductive genetic testing in women who had a positive BRCA test before having children: a qualitative analysis. Eur J Hum Genet 20 (1): 4-10, 2012.178Quinn GP, Vadaparampil ST, Miree CA, et al.: High risk men's perceptions of pre-implantation genetic diagnosis for hereditary breast and ovarian cancer. Hum Reprod 25 (10): 2543-50, 2010.179Struewing JP, Abeliovich D, Peretz T, et al.: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11 (2): 198-200, 1995.180Rothenberg KH: Breast cancer, the genetic "quick fix," and the Jewish community. Ethical, legal, and social challenges. Health Matrix Clevel 7 (1): 97-124, 1997 Winter.181Foster MW, Bernsten D, Carter TH: A model agreement for genetic research in socially identifiable populations. Am J Hum Genet 63 (3): 696-702, 1998.182Burhansstipanov L, Bemis LT, Dignan MB: Native American cancer education: genetic and cultural issues. J Cancer Educ 16 (3): 142-5, 2001 Autumn.183Hughes C, Fasaye GA, LaSalle VH, et al.: Sociocultural influences on participation in genetic risk assessment and testing among African American women. Patient Educ Couns 51 (2): 107-14, 2003.184Julian-Reynier CM, Bouchard LJ, Evans DG, et al.: Women's attitudes toward preventive strategies for hereditary breast or ovarian carcinoma differ from one country to another: differences among English, French, and Canadian women. Cancer 92 (4): 959-68, 2001.185Phillips KA, Warner E, Meschino WS, et al.: Perceptions of Ashkenazi Jewish breast cancer patients on genetic testing for mutations in BRCA1 and BRCA2. Clin Genet 57 (5): 376-83, 2000.186Vadaparampil ST, Quinn GP, Small BJ, et al.: A pilot study of hereditary breast and ovarian knowledge among a multiethnic group of Hispanic women with a personal or family history of cancer. Genet Test Mol Biomarkers 14 (1): 99-106, 2010.187Halbert CH, Kessler L, Troxel AB, et al.: Effect of genetic counseling and testing for BRCA1 and BRCA2 mutations in African American women: a randomized trial. Public Health Genomics 13 (7-8): 440-8, 2010.188Freedman TG: Genetic susceptibility testing: ethical and social quandaries. Health Soc Work 23 (3): 214-22, 1998.189Parens E: Glad and terrified: on the ethics of BRACA1 and 2 testing. Cancer Invest 14 (4): 405-11, 1996.190Winter PR, Wiesner GL, Finnegan J, et al.: Notification of a family history of breast cancer: issues of privacy and confidentiality. Am J Med Genet 66 (1): 1-6, 1996.191Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010.192Burke W, Daly M, Garber J, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 277 (12): 997-1003, 1997.193Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol 14 (5): 1730-6; discussion 1737-40, 1996.194Hallowell N, Foster C, Eeles R, et al.: Balancing autonomy and responsibility: the ethics of generating and disclosing genetic information. J Med Ethics 29 (2): 74-9; discussion 80-3, 2003.195Metcalfe KA, Poll A, O'Connor A, et al.: Development and testing of a decision aid for breast cancer prevention for women with a BRCA1 or BRCA2 mutation. Clin Genet 72 (3): 208-17, 2007.196Tiller K, Meiser B, Gaff C, et al.: A randomized controlled trial of a decision aid for women at increased risk of ovarian cancer. Med Decis Making 26 (4): 360-72, 2006 Jul-Aug.197van Roosmalen MS, Stalmeier PF, Verhoef LC, et al.: Randomized trial of a shared decision-making intervention consisting of trade-offs and individualized treatment information for BRCA1/2 mutation carriers. J Clin Oncol 22 (16): 3293-301, 2004.198Culver JO, MacDonald DJ, Thornton AA, et al.: Development and evaluation of a decision aid for BRCA carriers with breast cancer. J Genet Couns 20 (3): 294-307, 2011.199Schwartz MD, Lerman C, Brogan B, et al.: Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients. J Clin Oncol 22 (10): 1823-9, 2004.200Schwartz MD, Isaacs C, Graves KD, et al.: Long-term outcomes of BRCA1/BRCA2 testing: risk reduction and surveillance. Cancer 118 (2): 510-7, 2012.201O'Neill SC, Valdimarsdottir HB, Demarco TA, et al.: BRCA1/2 test results impact risk management attitudes, intentions, and uptake. Breast Cancer Res Treat 124 (3): 755-64, 2010.202Beattie MS, Crawford B, Lin F, et al.: Uptake, time course, and predictors of risk-reducing surgeries in BRCA carriers. Genet Test Mol Biomarkers 13 (1): 51-6, 2009.203Botkin JR, Smith KR, Croyle RT, et al.: Genetic testing for a BRCA1 mutation: prophylactic surgery and screening behavior in women 2 years post testing. Am J Med Genet A 118 (3): 201-9, 2003.204Julian-Reynier C, Mancini J, Mouret-Fourme E, et al.: Cancer risk management strategies and perceptions of unaffected women 5 years after predictive genetic testing for BRCA1/2 mutations. Eur J Hum Genet 19 (5): 500-6, 2011.205Phillips KA, Jenkins MA, Lindeman GJ, et al.: Risk-reducing surgery, screening and chemoprevention practices of BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Clin Genet 70 (3): 198-206, 2006.206Metcalfe KA, Birenbaum-Carmeli D, Lubinski J, et al.: International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int J Cancer 122 (9): 2017-22, 2008.207Scheuer L, Kauff N, Robson M, et al.: Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 20 (5): 1260-8, 2002.208Rhiem K, Foth D, Wappenschmidt B, et al.: Risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers. Arch Gynecol Obstet 283 (3): 623-7, 2011.209Madalinska JB, van Beurden M, Bleiker EM, et al.: Predictors of prophylactic bilateral salpingo-oophorectomy compared with gynecologic screening use in BRCA1/2 mutation carriers. J Clin Oncol 25 (3): 301-7, 2007.210Friebel TM, Domchek SM, Neuhausen SL, et al.: Bilateral prophylactic oophorectomy and bilateral prophylactic mastectomy in a prospective cohort of unaffected BRCA1 and BRCA2 mutation carriers. Clin Breast Cancer 7 (11): 875-82, 2007.211van Dijk S, van Roosmalen MS, Otten W, et al.: Decision making regarding prophylactic mastectomy: stability of preferences and the impact of anticipated feelings of regret. J Clin Oncol 26 (14): 2358-63, 2008.212Claes E, Evers-Kiebooms G, Decruyenaere M, et al.: Surveillance behavior and prophylactic surgery after predictive testing for hereditary breast/ovarian cancer. Behav Med 31 (3): 93-105, 2005.213Ray JA, Loescher LJ, Brewer M: Risk-reduction surgery decisions in high-risk women seen for genetic counseling. J Genet Couns 14 (6): 473-84, 2005.214Hallowell N: 'You don't want to lose your ovaries because you think 'I might become a man". Women's perceptions of prophylactic surgery as a cancer risk management option. Psychooncology 7 (3): 263-75, 1998 May-Jun.215Schneider KA, Stopfer JE, Peters JA, et al.: Complexities in cancer risk counseling: presentation of three cases. J Genet Couns 6(2): 147-168, 1997.216Tarkan L: My Mother's Breast: Daughters Face Their Mothers' Cancer. Dallas, TX: Taylor Publishing, 1999.217Stefanek ME, Helzlsouer KJ, Wilcox PM, et al.: Predictors of and satisfaction with bilateral prophylactic mastectomy. Prev Med 24 (4): 412-9, 1995.218Graves KD, Peshkin BN, Halbert CH, et al.: Predictors and outcomes of contralateral prophylactic mastectomy among breast cancer survivors. Breast Cancer Res Treat 104 (3): 321-9, 2007.219Howard-McNatt M, Schroll RW, Hurt GJ, et al.: Contralateral prophylactic mastectomy in breast cancer patients who test negative for BRCA mutations. Am J Surg 202 (3): 298-302, 2011.220Bresser PJ, Seynaeve C, Van Gool AR, et al.: Satisfaction with prophylactic mastectomy and breast reconstruction in genetically predisposed women. Plast Reconstr Surg 117 (6): 1675-82; discussion 1683-4, 2006.221Brandberg Y, Sandelin K, Erikson S, et al.: Psychological reactions, quality of life, and body image after bilateral prophylactic mastectomy in women at high risk for breast cancer: a prospective 1-year follow-up study. J Clin Oncol 26 (24): 3943-9, 2008.222Lobb E, Meiser B: Genetic counselling and prophylactic surgery in women from families with hereditary breast or ovarian cancer. Lancet 363 (9424): 1841-2, 2004.223Lobb EA, Butow PN, Meiser B, et al.: Tailoring communication in consultations with women from high risk breast cancer families. Br J Cancer 87 (5): 502-8, 2002.224Lobb EA, Butow PN, Barratt A, et al.: Communication and information-giving in high-risk breast cancer consultations: influence on patient outcomes. Br J Cancer 90 (2): 321-7, 2004.225Schwartz MD, Kaufman E, Peshkin BN, et al.: Bilateral prophylactic oophorectomy and ovarian cancer screening following BRCA1/BRCA2 mutation testing. J Clin Oncol 21 (21): 4034-41, 2003.226Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002.227Meijers-Heijboer EJ, Verhoog LC, Brekelmans CT, et al.: Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355 (9220): 2015-20, 2000.228Schmeler KM, Sun CC, Bodurka DC, et al.: Prophylactic bilateral salpingo-oophorectomy compared with surveillance in women with BRCA mutations. Obstet Gynecol 108 (3 Pt 1): 515-20, 2006.229MacDonald DJ, Sarna L, Uman GC, et al.: Cancer screening and risk-reducing behaviors of women seeking genetic cancer risk assessment for breast and ovarian cancers. Oncol Nurs Forum 33 (2): E27-35, 2006.230Litton JK, Westin SN, Ready K, et al.: Perception of screening and risk reduction surgeries in patients tested for a BRCA deleterious mutation. Cancer 115 (8): 1598-604, 2009.231Tyndel S, Austoker J, Henderson BJ, et al.: What is the psychological impact of mammographic screening on younger women with a family history of breast cancer? Findings from a prospective cohort study by the PIMMS Management Group. J Clin Oncol 25 (25): 3823-30, 2007.232Rees G, Young MA, Gaff C, et al.: A qualitative study of health professionals' views regarding provision of information about health-protective behaviors during genetic consultation for breast cancer. J Genet Couns 15 (2): 95-104, 2006.233Lodder LN, Frets PG, Trijsburg RW, et al.: One year follow-up of women opting for presymptomatic testing for BRCA1 and BRCA2: emotional impact of the test outcome and decisions on risk management (surveillance or prophylactic surgery). Breast Cancer Res Treat 73 (2): 97-112, 2002.234Bresser PJ, Seynaeve C, Van Gool AR, et al.: The course of distress in women at increased risk of breast and ovarian cancer due to an (identified) genetic susceptibility who opt for prophylactic mastectomy and/or salpingo-oophorectomy. Eur J Cancer 43 (1): 95-103, 2007.235Frost MH, Schaid DJ, Sellers TA, et al.: Long-term satisfaction and psychological and social function following bilateral prophylactic mastectomy. JAMA 284 (3): 319-24, 2000.236Metcalfe KA, Esplen MJ, Goel V, et al.: Psychosocial functioning in women who have undergone bilateral prophylactic mastectomy. Psychooncology 13 (1): 14-25, 2004.237Weitzel JN, McCaffrey SM, Nedelcu R, et al.: Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis. Arch Surg 138 (12): 1323-8; discussion 1329, 2003.238Schlich-Bakker KJ, Ausems MG, Schipper M, et al.: BRCA1/2 mutation testing in breast cancer patients: a prospective study of the long-term psychological impact of approach during adjuvant radiotherapy. Breast Cancer Res Treat 109 (3): 507-14, 2008.239Frost MH, Slezak JM, Tran NV, et al.: Satisfaction after contralateral prophylactic mastectomy: the significance of mastectomy type, reconstructive complications, and body appearance. J Clin Oncol 23 (31): 7849-56, 2005.240Schwartz MD: Contralateral prophylactic mastectomy: efficacy, satisfaction, and regret. J Clin Oncol 23 (31): 7777-9, 2005.241Geiger AM, Nekhlyudov L, Herrinton LJ, et al.: Quality of life after bilateral prophylactic mastectomy. Ann Surg Oncol 14 (2): 686-94, 2007.242Isern AE, Tengrup I, Loman N, et al.: Aesthetic outcome, patient satisfaction, and health-related quality of life in women at high risk undergoing prophylactic mastectomy and immediate breast reconstruction. J Plast Reconstr Aesthet Surg 61 (10): 1177-87, 2008.243Kenen RH, Shapiro PJ, Hantsoo L, et al.: Women with BRCA1 or BRCA2 mutations renegotiating a post-prophylactic mastectomy identity: self-image and self-disclosure. J Genet Couns 16 (6): 789-98, 2007.244Altschuler A, Nekhlyudov L, Rolnick SJ, et al.: Positive, negative, and disparate--women's differing long-term psychosocial experiences of bilateral or contralateral prophylactic mastectomy. Breast J 14 (1): 25-32, 2008 Jan-Feb.245Patenaude AF, Orozco S, Li X, et al.: Support needs and acceptability of psychological and peer consultation: attitudes of 108 women who had undergone or were considering prophylactic mastectomy. Psychooncology 17 (8): 831-43, 2008.246Elit L, Esplen MJ, Butler K, et al.: Quality of life and psychosexual adjustment after prophylactic oophorectomy for a family history of ovarian cancer. Fam Cancer 1 (3-4): 149-56, 2001.247Robson M, Hensley M, Barakat R, et al.: Quality of life in women at risk for ovarian cancer who have undergone risk-reducing oophorectomy. Gynecol Oncol 89 (2): 281-7, 2003.248Finch A, Metcalfe KA, Chiang JK, et al.: The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation. Gynecol Oncol 121 (1): 163-8, 2011.249Finch A, Metcalfe K, Lui J, et al.: Breast and ovarian cancer risk perception after prophylactic salpingo-oophorectomy due to an inherited mutation in the BRCA1 or BRCA2 gene. Clin Genet 75 (3): 220-4, 2009.250Madalinska JB, Hollenstein J, Bleiker E, et al.: Quality-of-life effects of prophylactic salpingo-oophorectomy versus gynecologic screening among women at increased risk of hereditary ovarian cancer. J Clin Oncol 23 (28): 6890-8, 2005.251Westin SN, Sun CC, Lu KH, et al.: Satisfaction with ovarian carcinoma risk-reduction strategies among women at high risk for breast and ovarian carcinoma. Cancer 117 (12): 2659-67, 2011.252Campfield Bonadies D, Moyer A, Matloff ET: What I wish I'd known before surgery: BRCA carriers' perspectives after bilateral salipingo-oophorectomy. Fam Cancer 10 (1): 79-85, 2011.253Massie MJ, Muskin PR, Stewart DE: Psychotherapy with a woman at high risk for developing breast cancer. Gen Hosp Psychiatry 20 (3): 189-97, 1998.254Shoda Y, Mischel W, Miller SM, et al.: Psychological interventions and genetic testing: facilitating informed decisions about BRCA1/2 cancer susceptibility. J Clin Psychol Med Settings 5(1): 3-17, 1998.255Halbert CH, Wenzel L, Lerman C, et al.: Predictors of participation in psychosocial telephone counseling following genetic testing for BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 13 (5): 875-81, 2004.256Karp J, Brown KL, Sullivan MD, et al.: The prophylactic mastectomy dilemma: a support group for women at high genetic risk for breast cancer. J Genet Counsel 8 (3): 163-73, 1999.257Landsbergen KM, Prins JB, Kamm YJ, et al.: Female BRCA mutation carriers with a preference for prophylactic mastectomy are more likely to participate an educational-support group and to proceed with the preferred intervention within 2 years. Fam Cancer 9 (2): 213-20, 2010.258Miller SM, Fleisher L, Roussi P, et al.: Facilitating informed decision making about breast cancer risk and genetic counseling among women calling the NCI's Cancer Information Service. J Health Commun 10 (Suppl 1): 119-36, 2005.259Isaacs C, Peshkin BN, Schwartz M, et al.: Breast and ovarian cancer screening practices in healthy women with a strong family history of breast or ovarian cancer. Breast Cancer Res Treat 71 (2): 103-12, 2002.260Peshkin BN, Schwartz MD, Isaacs C, et al.: Utilization of breast cancer screening in a clinically based sample of women after BRCA1/2 testing. Cancer Epidemiol Biomarkers Prev 11 (10 Pt 1): 1115-8, 2002.261Tinley ST, Houfek J, Watson P, et al.: Screening adherence in BRCA1/2 families is associated with primary physicians' behavior. Am J Med Genet A 125 (1): 5-11, 2004.262Lerman C, Seay J, Balshem A, et al.: Interest in genetic testing among first-degree relatives of breast cancer patients. Am J Med Genet 57 (3): 385-92, 1995.263Watson M, Kash KM, Homewood J, et al.: Does genetic counseling have any impact on management of breast cancer risk? Genet Test 9 (2): 167-74, 2005.
Changes to This Summary (03/04/2013)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Updated statistics with estimated new cases and deaths of breast cancer and ovarian cancer for 2013 (cited American Cancer Society as reference 1).
Added Figure 1, Classic BRCA1 Pedigree.
Added Figure 2, Classic BRCA2 Pedigree.
Revised text to state that studies examining the impact of radiation exposure, including, but not limited to, mammography, in BRCA1 and BRCA2 mutation carriers have had conflicting results (cited Goldfrank et al., Gronwald et al., and Pijpe et al. as references 44, 45, and 46, respectively). Also added text to state that a large European study showed a dose-response relationship of increased risk with total radiation exposure, but this was primarily driven by nonmammographic radiation exposure before age 20 years.
High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes
Added text to state that the inclusion of breast tumor markers, such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, has been shown to improve the performance of BRCAPRO and the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (cited Biswas et al., Mavaddat et al., and Tai et al. as references 104, 105, and 106, respectively).
Added Liu et al. as reference 252.
Added text to state that two studies failed to find convincing evidence of an association between ionizing radiation exposure and breast cancer risk in BRCA1 and BRCA2 mutation carriers (cited Narod et al. and Goldfrank et al. as references 282 and 283, respectively). Also added text about two large international studies that found evidence of an increased risk due to chest x-rays (cited Andrieu et al. as reference 284) or estimates of total exposure to diagnostic radiation (cited Pijpe et al. as reference 285).
Added text about a study that suggested that the most cost-effective screening strategy in BRCA1 and BRCA2 mutation carriers may be annual magnetic resonance imaging (MRI) beginning at age 25 years, with alternating MRI and digital mammography beginning at age 30 years (cited Lowry et al. as reference 287); the National Comprehensive Cancer Network currently recommends annual mammography and MRI screening beginning at age 25 years.
Added text about the timing of mammography and MRI and described a cost-effectiveness study that suggested annual MRI beginning at age 25 years, with alternating MRI and digital mammography beginning at age 30 years in BRCA1 and BRCA2 mutation carriers.
Low- and Moderate-Penetrance Genes Associated With Breast and/or Ovarian Cancer
Added text to state that among 559 cases with contralateral breast cancer and 565 matched controls with unilateral breast cancer, pathogenic (truncating) PALB2 mutations were identified in 0.9% of cases and in none of the controls (cited Tischkowitz et al. as reference 71).
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and ovarian cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Genetics of Breast and Ovarian Cancer are:
- Kathleen A. Calzone, PhD, RN, APNG, FAAN (National Cancer Institute)
- Ilana Cass, MD (Cedars-Sinai Medical Center)
- Mary B. Daly, MD, PhD (Fox Chase Cancer Center)
- Susan Domchek, MD (University of Pennsylvania Cancer Center)
- Donald W. Hadley, MS, CGC (National Human Genome Research Institute)
- Jennifer Lynn Hay, PhD (Memorial Sloan-Kettering Cancer Center)
- Karen H. Lu, MD (University of Texas, M.D. Anderson Cancer Center)
- Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)
- Tuya Pal, MD, FAAP, FABMG (H. Lee Moffitt Cancer Center & Research Institute)
- Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
- Jeffery P. Struewing, MD (National Human Genome Research Institute)
- Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
- Catharine Wang, PhD, MSc (Boston University School of Public Health)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Genetics of Breast and Ovarian Cancer. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional. Accessed <MM/DD/YYYY>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.
More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site’s Contact Form.
Get More Information From NCI
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
Write to us
For more information from the NCI, please write to this address:
- NCI Public Inquiries Office
- 9609 Medical Center Dr.
- Room 2E532 MSC 9760
- Bethesda, MD 20892-9760
Search the NCI Web site
The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).
This information was last updated on 2013-03-04