Genetics of Breast and Ovarian Cancer

Summary Type: Genetics
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the genetics of breast and ovarian cancer, including information about specific genes and family cancer syndromes. The summary also contains information about interventions that may influence the risk of developing breast and ovarian cancer in individuals who may be genetically susceptible to these diseases. Psychosocial issues associated with genetic testing are also discussed.

Genetics of Breast and Ovarian Cancer

Introduction

General Information

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.

Among women, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and is the second leading cause of cancer deaths after lung cancer. In 2007, an estimated 180,510 new cases will be diagnosed, and 40,910 deaths from breast cancer will occur. Ovarian cancer is the seventh most common cancer, with an estimated 22,430 new cases in 2007, but is the fourth most deadly, with an estimated 15,280 deaths in 2007.¹ (Refer to the PDQ summary 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 rare families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with autosomal dominant inheritance of 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 cancer-prone 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 or a second-degree relative with breast cancer.^2,^3,^4,⁵ 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.⁶ In a pooled analysis of 38 studies, the relative risk of breast cancer conferred by a first-degree relative with breast cancer was 2.1 (95% confidence interval [CI], 2.0-2.2).⁶ Risk increases with the number of affected relatives and age at diagnosis.^3,^4,^6,

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 first-degree relative with ovarian cancer.^7,

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 and shows no evidence of it can still pass the altered gene on to his sons and daughters.

Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. Those most strongly associated with these 2 cancers are BRCA1 or BRCA2 mutation syndromes, but breast cancer is also associated with Li-Fraumeni syndrome due to TP53 mutations, and Cowden syndrome due to PTEN mutations.⁸ Mutations in each of these genes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

Other genetic syndromes that may include breast cancer as an associated feature include ataxia telangiectasia (AT) and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with basal cell nevus (Gorlin) syndrome, multiple endocrine neoplasia type 1 (MEN1), and hereditary nonpolyposis colon cancer (HNPCC).⁸ The specific phenotypic characteristics are discussed later in this section.

The family characteristics that suggest hereditary breast and ovarian cancer predisposition include the following:

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 and ovarian cancer in the same individual).

Cases of male breast cancer.

Possible increased risk of other selected cancers and benign features for males and females. (Refer to the Major Genes section of this summary for more information.)

Based on typical histopathological characteristics, breast and ovarian cancers occurring in BRCA1/2 mutation carriers generally do not differ dramatically from sporadic cases occurring in noncarriers and thus far have no known pathognomonic features. [Refer to the Pathology/Prognosis of Breast Cancer and Pathology/Prognosis of Ovarian Cancer sections 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%.^9,^10,

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 Prevention of Breast Cancer for more information.) These factors are considered in more detail in numerous reviews,^11,¹² including among BRCA1/BRCA2 mutation carriers.¹³ Brief summaries are given below, highlighting, where possible, the effect of these risk factors in women who are genetically susceptible to breast cancer. (More information about their effects in BRCA1/BRCA2 mutation carriers can be found in the section on Interventions later in this document.)

Age

Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.¹⁴ 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

Breast cancer risk increases with early menarche and late menopause, and is reduced by early first full-term pregnancy. Although results have been complex and may be gene dependent, several studies have suggested that the influence of these factors on risk in BRCA1/BRCA2 mutation carriers appear to be similar to noncarriers.^13,

Oral contraceptives

Oral contraceptives 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 oral contraceptive use did not vary according to a family history of breast cancer.^15,

Oral contraceptives are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers, but studies of their effect on breast cancer risk have been inconsistent.^16,^17,¹⁸

Hormone Replacement Therapy

Data exist from both observational and randomized clinical trials regarding the association between postmenopausal hormone replacement therapy (HRT) and breast cancer. A meta-analysis of data from 51 observational studies indicated a relative risk 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.¹⁹ The Women's Health Initiative (WHI), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of strategies that may reduce the incidence of heart disease, breast and colorectal cancer, and fractures, including dietary interventions and 2 trials of HRT. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined HRT or placebo, was halted early because health risks exceeded benefits.^20,²¹ One of the adverse outcomes prompting closure was a 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) in women randomized to receive estrogen and progestin.²¹ 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.^21,

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.^22,^23,^24,^25,²⁶ ¹⁹ 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 BRCA1/2 mutations.²¹ Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.^19,²⁷ The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has only been studied in the context of bilateral prophylactic oophorectomy, where short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk.^28,

Radiation exposure

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 and BRCA2 mutations,^29,^30,^31,³² and in association with germline ATM and TP53 mutations.^33,³⁴ Since BRCA1/2 mutation carriers are heterozygotes, however, radiation sensitivity might occur only after a somatic mutation has damaged the normal copy of the gene.

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.³⁵ Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of mammography and chest x-ray exposure in BRCA1 and BRCA2 mutation carriers have had conflicting results.^36,^37,

Alcohol intake

The risk of breast cancer increases by approximately 10% for each 10g of daily alcohol intake (approximately 1 drink or less) in the general population.^38,³⁹ One study of BRCA1/BRCA2 mutation carriers found no increased risk associated with alcohol consumption.⁴⁰

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.⁴¹ 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.^42,

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).⁴³ There may also be an association between benign breast disease and family history of breast cancer.^44,

An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram,^43,^45,⁴⁶ and breast density may have a genetic component to its etiology.^47,^48,^49,

Other factors

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 subgroups of women defined according to genotype. For example, some studies have suggested that certain N-acetyl transferase alleles may influence female smokers’ risk of developing breast cancer.⁵⁰ One study ⁵¹ found a reduced risk of breast cancer among BRCA1/2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.⁵²

Other Risk Factors for Ovarian Cancer

Factors that increase risk for ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and oral contraceptives.^53,⁵⁴ (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 Risk Modification section for more information.)

Age

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.^55,

Reproductive

Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers.⁵⁶ Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.^53,⁵⁷ 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.^58,^59,^60,^61,

Surgical History

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,^53,^62,⁶³ including in BRCA1/BRCA2 mutation carriers.⁶⁴ Ovarian cancer risk is reduced >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.^65,⁶⁶ For further information on these studies refer to the Risk-Reducing Salpingo-Oophorectomy section of this summary.

Oral Contraceptives

Use of oral contraceptives for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population.⁵³ ⁵⁴ A majority of, but not all, studies also support oral contraceptives being protective among BRCA1/ BRCA2 mutation carriers.^56,^67,^68,^69,^70,

Models for Prediction of Breast Cancer Risk

Models to predict an individual’s lifetime risk for developing breast cancer are available. In addition, models exist to predict an individual’s likelihood of having a BRCA1 or BRCA2 mutation. For further information on these models refer to the Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation section of this summary. 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. The table, Characteristics of the Gail and Claus Models, summarizes the salient aspects of the risk assessment models and is designed to aid in choosing the one that best applies to a particular individual.

Two models for predicting breast cancer risk, the Claus model ⁷¹ and the Gail model,⁷² are widely used in research studies and clinical counseling . Both have limitations, and the risk estimates derived from the 2 models may differ for an individual patient. These models, however, represent the best methods currently available for individual risk assessment.

It is important to note that these models will significantly underestimate breast cancer risk for women in families with hereditary breast cancer susceptibility syndromes. In those cases, Mendelian risks would apply. A 3-generation cancer family history is taken before applying any model. (Refer to the PDQ summary on Elements of Cancer Genetics Risk Assessment and Counseling for more information on Taking a Family History.) Generally, the Claus or Gail models should not be used for families with 1 of the following characteristics:

Three individuals with breast or ovarian cancer (especially when 1 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 1 case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).

Table 1. Characteristics of the Gail and Claus Models*
Gail ModelClaus Model*Adapted from Domchek et al.,⁷³ Rubenstein et al.,⁷⁴ and Rhodes.^75,Data derived from Breast Cancer Detection Demonstration Project (BCDDP) Study Cancer and Steroid Hormone (CASH) Study Study population 2,852 cases, age ≥35 years 4,730 cases, age 20-54 years In situ and invasive cancer Invasive cancer 3,146 controls 4,688 controls Caucasian Caucasian Annual breast screening Not routinely screened Family history characteristics First-degree relatives with breast cancer First-degree or second-degree relatives 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) Strengths Incorporates: Incorporates: Risk factors other than family history Paternal as well as 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 ⁷⁵ Best application For individuals with no family history of breast cancer or 1 first-degree relative with breast cancer at ≥age 50 years For individuals with 0, 1, or 2 first-degree or second-degree relatives with breast cancer For determining eligibility for chemoprevention studies

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.^76,^77,^78,^79,⁸⁰ While the model is reliable in predicting the number of breast cancer cases expected in a group of women from the same age-risk strata, it is less reliable in predicting risk for individual patients. Risk can be overestimated in:

Noncompliant women (i.e., not compliant with screening).^76,^77,

Women in the highest risk strata.^79,

Risk could be underestimated in the lowest risk strata.⁷⁹ Earlier studies ^76,⁷⁷ suggested risk was overpredicted in younger women and underpredicted in older women. More recent studies ^78,⁷⁹ 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.^80,

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.⁸¹ The 2 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 Gail model is the basis for the Breast Cancer Risk Assessment Tool, a computer program that is available from the NCI 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.

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⁶¹ Anderson 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.

⁶² Tortolero-Luna G, Mitchell MF: The epidemiology of ovarian cancer. J Cell Biochem Suppl 23: 200-7, 1995.

⁶³ Hankinson SE, Hunter DJ, Colditz GA, et al.: Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA 270 (23): 2813-8, 1993.

⁶⁴ Rutter 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.

⁶⁵ Kauff 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.

⁶⁶ Rebbeck 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.

⁶⁷ Narod 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.

⁶⁸ Narod 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.

⁶⁹ Whittemore 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.

⁷⁰ McGuire 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.

⁷¹ Claus EB, Risch N, Thompson WD: Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73 (3): 643-51, 1994.

⁷² Gail 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.

⁷³ Domchek 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.

⁷⁴ Rubinstein 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.

⁷⁵ Rhodes DJ: Identifying and counseling women at increased risk for breast cancer. Mayo Clin Proc 77 (4): 355-60; quiz 360-1, 2002.

⁷⁶ Bondy 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.

⁷⁷ Spiegelman 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.

⁷⁸ Rockhill 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.

⁷⁹ Costantino 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.

⁸⁰ Bondy ML, Newman LA: Breast cancer risk assessment models: applicability to African-American women. Cancer 97 (1 Suppl): 230-5, 2003.

⁸¹ McTiernan 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.

Major Genes

Introduction

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. In most cases an extensive family history (more than 4 relatives in the same biologic line affected) is not present. In some families, however, inherited factors are clearly the major component of an individual’s cancer risk. We now know that some of these “cancer families” can be explained by specific mutations in single cancer susceptibility genes . The recent isolation of several of these genes associated with a significantly increased risk of breast/ovarian cancer make it possible to identify families who carry mutations in these genes . Mutation carriers who have a risk of developing breast cancer that may exceed 50% comprise no more than 5% to 10% of all breast cancer cases.

Hereditary breast cancer is characterized by early age at onset (on average 5-15 years earlier than in sporadic cases), bilaterality, vertical transmission through both maternal and paternal lines, and familial association with tumors of other organs, particularly the ovary and prostate gland.^1,^2,³

The clinical evidence of an autosomal dominant inherited predisposition to breast cancer has been supported by segregation analysis, a statistical genetics method to determine whether a particular trait follows a Mendelian pattern of inheritance. (For more information on criteria of autosomal dominant inheritance, refer to the Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition section of this summary.)

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families.⁴ When segregation analysis was applied to the Cancer and Steroid Hormone (CASH) data set, goodness-of-fit tests of genetic models provided additional evidence for the existence of a rare autosomal dominant allele associated with increased susceptibility to breast cancer.^5,

The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by the study 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.

BRCA1

In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21.⁶ 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.¹ The BRCA1 gene (OMIM: 113705) was subsequently identified by positional cloning methods, and has been found to contain 24 exons that encode a protein of 1,863 amino acids. BRCA1 appears 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.^7,

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: 600185) are thought to account for approximately 35% of multiple case breast cancer families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.^8,⁹ BRCA2 is also a large gene with 27 exons that encode a protein of 3,418 amino acids.¹⁰ 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, with loss of the unmutated allele found in tumor specimens.

BRCA1 and BRCA2 Function

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on 1 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, however, the normal allele is deleted, resulting in loss of all function. This finding strongly suggests that BRCA1 and BRCA2 are in the class of tumor suppressor genes, i.e., genes whose loss of function can result in neoplastic growth.^11,^12,

Additional evidence that BRCA1 is a tumor suppressor gene is that overexpression of the BRCA1 protein leads to tumor growth suppression in vitro and in a mouse model, in a fashion similar to the tumor suppressor gene TP53 and the retinoblastoma (RB) gene.¹³ While this provides a conceptual framework for understanding the role of mutations in cancer progression, it does little to indicate how these genes normally function to prevent cancer.

However, a variety of evidence now points to BRCA1 and BRCA2 being directly involved in the DNA repair process. Several strategies are used to evaluate gene function. These include comparing the sequence and structure of the protein product to other known genes; determining the tissues, cell types, and stages of the cell cycle in which the protein is expressed; and identifying other proteins with which the protein interacts. Animal models also provide an important tool; in particular, knockout mice provide a way to study the effects of different gene mutations. In this approach, the normal mouse gene coding for the analogous function has been removed, and normal or mutated human genes are then inserted to assess their biological effects. Epidemiological studies can provide important evidence for other factors, both genetic and nongenetic, that modify the effect of BRCA1 and BRCA2 gene mutations. New technical tools for study of gene function are now being developed; for example, microarray techniques that permit the assessment of gene variants or gene expression at multiple gene sites may allow the identification of other gene proteins that interact with or modify the effect of the BRCA1 and BRCA2 protein products.

Taken together, current data suggest that the BRCA1 and BRCA2 protein products interact with each other and with RAD51 and other proteins known to be involved in DNA repair. Loss of DNA repair function is assumed to lead to the accumulation of additional mutations and ultimately to carcinogenesis. Several review articles are available in the literature on BRCA1 and BRCA2 gene function.^14,^15,

Mutations in BRCA1 and BRCA2

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.¹⁶ 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.¹⁷ In addition, large genomic rearrangements are missed by most of the techniques, including direct DNA sequencing. Such rearrangements are believed to be responsible for 10% to 15% of BRCA1 inactivating mutations.^18,^19,^20,

Variants of uncertain significance

Germline deleterious (disease-associated) 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, classifying deleterious nucleotide changes to predict their functional impact 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 problems 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, as well as the likelihood that the VUS is significant.

African Americans appear to have a higher rate of VUS.²¹ A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratory over a three-year period.²² 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 individuals had sequence alterations that were once considered VUS, but were reclassified, usually as a polymorphism though occasionally as a deleterious mutation. As additional information is accumulated, VUS are reclassified and 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.^23,²⁴ Genetics clinics should make all efforts to track the VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. Parents and all affected family members should be tested for the variant (which is generally covered by Myriad Genetic Laboratory). The Myriad Genetic Laboratory typically provides additional information when a VUS is reported, including available data on cosegregation and whether the VUS has been seen in conjunction with a known deleterious mutation. In general, a VUS observed in subjects who also have a deleterious mutation, especially when it occurs with different mutations, is not felt to be in itself deleterious, although there are rare exceptions. Models based on sequence conservation and the biochemical properties of amino acid changes exist ^23,^25,^26,^27,²⁸ and are an adjunct to the clinical information. An attempt at further refining such models has also incorporated information on pathologic characteristics of BRCA1- and BRCA2- related tumors (such as the fact that BRCA1-related breast cancers are usually estrogen receptor negative).²⁹ Functional studies that measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 have been employed as well.^30,³¹ When attempting to interpret a VUS, all available information should be examined.

Prevalence and Founder Effects

Approximately 1 in 800 individuals in the general population may carry a pathogenic mutation in BRCA1. The frequency of carriers in selected groups has been measured. Among cases identified from the Cancer Surveillance System of Western Washington, the frequency of BRCA1 mutations was highest in cases diagnosed before age 30 years (23% carriers, 95% confidence interval (CI), 5.0-53.8), and in those with more than 3 relatives with breast cancer (20%, 95% CI, 6%-44%). A family history of ovarian cancer in a first-degree relative was also associated with an increased prevalence of BRCA1 mutations (25%, 95% CI, 3.2%-65.1%).³² In a second study, 263 women with familial breast cancer were analyzed.³³ BRCA1 mutations were found in 7% (95% CI, 0.3%-39%) of families with site-specific breast cancer, 18% of families with bilateral breast cancer, and 40% (95% CI, 1.7%-80.0%) of families with both breast and ovarian cancer. In a population-based series of incident cases of ovarian cancer in Canada, the overall prevalence of BRCA1/2 mutations was 11.7%; among women with a first-degree relative with breast or ovarian cancer, it was 19%. Of note, 6.5% of women with no affected first-degree relative carried a mutation, suggesting a higher overall prevalence of mutations in women with a diagnosis of ovarian cancer than in those with breast cancer.^34,^35,^36,

In some cases the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect. This occurs when a contemporary population can be traced back to a small, isolated group of founders. Most notably, 2 specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews (those tracing their roots to Central and Eastern Europe). Carrier frequencies for these mutations have been determined in the general Jewish population: 0.9% (95% CI, 0.7%-1.1%) for the 185delAG mutation, 0.3% (95% CI, 0.2%-0.4%) for the 5382insC mutation, and 1.3% (95% CI, 1.0%-1.5%) for the BRCA2 6174delT mutation.^37,^38,^39,⁴⁰ Altogether, the frequency of these 3 mutations approximates 1 in 40 among Ashkenazi Jews; they account for 25% of early-onset breast cancer, and up to 90% of families with multiple cases of both breast and ovarian cancer in this population.^41,⁴² Additional founder mutations have been described in the Netherlands (BRCA1 2804delAA and several large deletion mutations), Iceland (BRCA2, 999del5), and Sweden (BRCA1, 3171ins5).^43,^44,^45,⁴⁶

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 pitfalls. It is estimated that 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.^22,

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 BRCA1/2 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.

Estimates of penetrance by age 70 years for BRCA1 and BRCA2 mutations show a large range, from 14% to 87% for breast cancer and 10% to 68% for ovarian cancer.^7,^34,^36,^39,^47,^48,^49,^50,^51,^52,^53,^54,^55,^56,^57,^58,^59,^60,^61,^62,^63, Initial penetrance estimates for BRCA1 and BRCA2 mutations were derived from multiple-case families from the Breast Cancer Linkage Consortium (BCLC), families studied to localize and clone the genes.^7,^47,^48, For breast cancer, the estimates ranged from 50% to 73% by age 50 years and 65% to 87% by age 70 years for BRCA1, and 59% and 82% at ages 50 years and 70 years, respectively, for BRCA2. For ovarian cancer, the estimates were as high as 29% by age 50 years and 63% by age 70 years.^47,^48, For many patients currently seeking genetic testing for BRCA1 and BRCA2, the family history will not be as strong as this study by the BCLC (e.g., more than 4 affected relatives in the same biologic lineage). Thus, the penetrance figures derived from the BCLC may not provide a high level of accuracy for individual patients seeking genetic counseling and testing.

There are now several lines of evidence indicating that primary fallopian tube cancer should be considered a part of the BRCA1/2 phenotype . Epidemiologic evidence points to an increased risk of early-onset breast and/or ovarian cancer among first-degree relatives of women with fallopian tube cancers.⁶⁴ Histopathologic examination 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.^65,⁶⁶ A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%.⁶⁷ While the true incidence of fallopian tube tumors in BRCA carriers is not known, there is a growing consensus that risk-reducing oophorectomy should be accompanied by prophylactic removal of the fallopian tubes.

In addition to the estimates from multiple-case families and patients from high-risk genetics clinics,^7,^47,^48,^50,^52,^56,^62,^68, at least 13 studies have estimated penetrance by studying the families of mutation carriers who were not specifically recruited and studied because of a positive family history.^34,^36,^39,^51,^53,^54,^55,^56,^57,^58,^59,^60,^61, Often these studies have concentrated on founder populations in which testing of larger, more population-based subjects are possible owing to a reduced number of mutations that require testing,^39,^49,^51,^54,^57,^58,⁶⁰ compared with complete sequencing of the 2 genes required in most populations. The first study of a community-based series was carried out in the Washington, D.C., area. Blood samples and family medical histories were collected from more than 5,000 Ashkenazi Jewish individuals.³⁹ Study participants were tested for 3 founder mutations: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. The prevalence of breast cancer in the relatives of carriers was compared with that reported by mutation-negative individuals. The risk of breast cancer in carriers of these mutations was estimated to be 56% (95% CI, 40%-73%) by age 70 years. Ovarian cancer risk was estimated to be 16% (95% CI, 6%-28%). These values were lower than most prior risk estimates. Men carrying BRCA1 and BRCA2 mutations were at modestly increased risk of prostate cancer, reaching 16% by age 70 years. Subsequent studies have provided additional support for an approximately 2-fold increased risk of prostate cancer in BRCA2 mutation carriers.^54,^69,^70,.

Many subsequent studies, whether in founder or predominantly outbred populations, have estimated breast cancer risks by age 70 years of approximately 60% or lower and ovarian cancer risks of approximately 40% or lower, though often with large confidence limits because, even in studies of founder populations, the number of identified mutation carriers is relatively small. Most studies have done molecular testing on the proband only and have done no,^34,^39,^49,^51,^54,^55,^56,^57,^58,^60,^61, or limited,^53,⁶² testing among relatives. Instead, the mutation status of relatives is modeled on simple Mendelian principles that on average, one half of first-degree relatives of mutation carriers will themselves be carriers. Such modeling may lead to imprecision in the penetrance estimates; by chance, more than or less than half the relatives of some families will be carriers. In the New York Breast Cancer Study of 104 mutation-positive Ashkenazi Jews with breast cancer, penetrance estimates were based only on relatives whose mutation status was known.³⁶ These estimates were 69% and 74% for breast cancer by age 70 years for BRCA1 and BRCA2 mutation carriers, respectively, and 46% and 12% for ovarian cancer for BRCA1 and BRCA2, respectively.

The largest study to date to estimate penetrance involved a pooled analysis of 22 studies of over 8,000 breast and ovarian cancer cases unselected for family history.⁶¹ Subjects were from 12 different countries and had a broad spectrum of mutations. Using modified segregation analysis on the families of the nearly 500 cases found to carry a BRCA1/2 mutation, the cumulative risk of breast cancer by age 70 years was 65% (95% CI, 44%-78%) for BRCA1 and 45% (95% CI, 31%-56%) for BRCA2. The penetrances for ovarian cancer are somewhat higher for BRCA1 mutation carriers, especially for ovarian cancer and early-onset breast cancer. These estimates are average risks of cancer among mutation carriers, assuming there is at least one family member with breast cancer or ovarian cancer (since all probands had these cancers), the situation likely to be encountered in clinical genetics situations. A case series of 491 women with stage I or stage II breast cancer and a known or suspected deleterious BRCA1/2 mutation was reviewed for incidence of ovarian cancer. The actuarial risk of developing ovarian cancer at 10 years following diagnosis of breast cancer was 12.7% for BRCA1 mutation carriers and 6.8% for BRCA2 mutation carriers. Eight of 83 cancer deaths (9.6%) in this series were because of ovarian cancer. Systemic treatment for the primary breast cancer did not alter these findings.⁷¹ Several studies have suggested that cancer risks in BRCA1/BRCA2 mutation carriers are affected by the type of cancer of the index case. Relatives of breast cancer index cases were more likely to develop breast cancer, and relatives of ovarian cancer index cases were more likely to develop ovarian cancer.^61,^72,^73,⁷⁴ Risk of breast cancer appears increased in more recent birth cohorts.^36,^72,

The continuing uncertainty as to the exact penetrance for breast and ovarian cancer among BRCA1/2 mutation carriers may be due to several factors, including differences owing to study design, allelic heterogeneity (differing risks for different mutations within either of the genes), and to modifying genetic and/or environmental factors, such as differing rates of oophorectomy.^36,^61,^75,^76,^77,⁷⁸ While the average breast and ovarian cancer penetrances may not be as high as initially estimated, they are very high, both in relative and absolute terms, and additional studies will be required to further characterize potential modifying factors in order to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.

The tables titled “Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Breast Cancer” and “Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Ovarian Cancer” review the incidence of breast and ovarian cancer among BRCA1 and BRCA2 mutation carriers.

Table 2. Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Breast Cancer
Cumulative Incidence of Breast Cancer to Given Age# - Outcome is breast OR ovarian cancer * - Incidence to age 55 years& - Incidence to age 75 years@ - Incidence to age 80 yearsBRCA1 BRCA2 BRCA1/2 Population 50 yr 70 yr 50 yr 70 yr 50 yr 70 yr Linkage analysis-maximization of logarithm of the odd (LOD) score —214 breast-ovary families (BCLC) ⁷ 59%82%—BRCA1-linked families (BCLC) ^48,51%85%—237 breast and breast-ovarian cancer families (BCLC) ⁵⁰ 49%71%28%84%Incidence of second cancers after breast cancer —33 BRCA1-linked families (BCLC) ⁴⁷ 73%87%—BRCA1-linked families (BCLC) ⁴⁸ 50%65%Analysis of family members —Jewish ovarian cancer cases, 7 BRCA1, 3 BRCA2 ^49,30%#50%#16%#23%#—Jewish breast-ovary families, 16 BRCA1, 9 BRCA2 ^49,37%#64%#18%#49%#Kin cohort using family and cancer registries —Unselected Icelandic breast cancer patients, 56 female and 13 male BRCA2 995del5 ⁵¹ 17%37%Second or contralateral cancer incidence; focus was on nonbreast and ovary outcomes —173 breast-ovarian cancer families either BRCA2-positive or BRCA2-linked (BCLC) ^52,37%52%Modified segregation analysis - all available relatives tested (MENDEL) —Australian population-based breast cancer age <40 years, 9 BRCA1, 9 BRCA2 ^53,10%40%Kin cohort —Community-based Washington area Jews, 61 BRCA1, 59 BRCA2 ³⁹ 38%59%26%51%33%56%—Jewish women with breast cancer, 34 BRCA1, 15 BRCA2 ⁵⁴ 60%28%—Jewish women with ovarian cancer, 44 BRCA1, 24 BRCA2 ⁵⁷ 31%*44%&6%*37%&—Unselected cases ovarian cancer, 39 BRCA1, 21 BRCA2 ³⁴ 68%@14%@Modified segregation analysis (MENDEL) —Breast cancer cases age <55 years, 8 BRCA1, 16 BRCA2 ^55,32%47%18%56%21%54%—Families with 2+ cases ovarian cancer, 40 BRCA1, 11 BRCA2 ⁵⁶ 39%72%19%71%—Unselected cases ovarian cancer, 12 BRCA1 ^56,34%50%—164 BRCA2-positive families from BCLC ⁵⁹ 41%—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 ^61,38%65%15%45%—Australian multiple-case families, 28 BRCA1, 23 BRCA2 ⁶² 48%74%Relative risk times population rates —Jewish hospital-based ovarian cancer patients, 103 BRCA1, 44 BRCA2 founder mutations ^58,18%59%6%38%Direct Kaplan-Meier estimates restricted to relatives known to be mutation positive —Unselected Jewish breast cancer patients from NY, 67 BRCA1, 37 BRCA2 ^36,39%69%34%74%Mendelian retrospective likelihood approach —U.S.-based through the Cancer Genetics Network, most counseling clinic-based, although smaller number population-based, 238 BRCA1, 143 BRCA2 ^63,46%43%

Table 3. Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Ovarian Cancer
Cumulative Incidence of Ovarian Cancer to Given Age & - Incidence to age 75 years@ - Incidence to age 80 yearsBRCA1 BRCA2 BRCA1/2 Population 50 yr 70 yr 50 yr 70 yr 50 yr 70 yr Incidence of second cancers after breast cancer —33 BRCA1-linked families (BCLC) ^47,29%44%—BRCA1-linked families (BCLC) ^48,29%44%Linkage analysis - maximization of LOD score —BRCA1-linked families (BCLC) ^48,23%63%—237 breast and breast-ovarian cancer families (BCLC) ^50,0%27%Kin cohort —Community-based Washington area Jews, 61 BRCA1, 59 BRCA2 ^39,8%16%5%18%7%16%—Unselected cases ovarian cancer, 39 BRCA1, 21 BRCA2 ^34,36%@10%@Second or contralateral cancer incidence; focus was on nonbreast and ovary outcomes —173 breast-ovarian cancer families either BRCA2-positive or BRCA2-linked (BCLC) ^52,3%16%Modified segregation analysis (MENDEL) —Breast cancer cases age <55 years, 8 BRCA1, 16 BRCA2 ^55,11%36%3%10%4%16%—Families with 2+ cases ovarian cancer, 40 BRCA1, 11 BRCA2 ^56,17%53%1%31%—Unselected cases ovarian cancer, 12 BRCA1 ^56,21%68%—164 BRCA2-positive families from BCLC ^59,14%—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 ^61,13%39%1%11%Relative risk times population rates —Jewish women with ovarian cancer, 44 BRCA1, 24 BRCA2 ^57,>40%&20%&—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 ^60,11%37%3%21%Direct Kaplan-Meier estimates restricted to relatives known to be mutation positive —Unselected Jewish breast cancer patients from NY, 67 BRCA1, 37 BRCA2 ^36,21%46%2%12%Mendelian retrospective likelihood approach —U.S.-based through the Cancer Genetics Network, most counseling clinic-based, although smaller number population-based, 238 BRCA1, 143 BRCA2 ^63,40%22%

Population Estimates of the Likelihood of Having a BRCA1 or BRCA2 Mutation

Statistics regarding the percentage of women 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 family history characteristics.

Among non-Ashkenazi Jewish individuals (likelihood of having any BRCA mutation):

General non-Ashkenazi Jewish population: 1 in 500 (.002%).^79,

Women with breast cancer (all ages): 1 in 50 (2%).^80,

Women with breast cancer (younger than 40 years): 1 in 11 (9%).^81,

Men with breast cancer (regardless of age): 1 in 20 (5%).^82,

Women with ovarian cancer (all ages): 1 in 10 (10%).^34,^83,

Among Ashkenazi Jewish individuals (likelihood of having one of 3 founder mutations):

General Ashkenazi Jewish population: 1 in 40 (2.5%).^39,

Women with breast cancer (all ages): 1 in 10 (10%).^36,

Women with breast cancer (younger than 40 years): 1 in 3 (30%-35%).^36,^84,^85,

Men with breast cancer (regardless of age): 1 in 5 (19%).^86,

Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%-41%).^57,^67,^87,

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. These studies have used populations derived from clinical referral centers.^33,^88,^89,^90,^91,^92,⁹³ Personal characteristics associated with an increased likelihood of a BRCA1 or BRCA2 mutation include the following:

Breast cancer diagnosed at an early age.

Bilateral breast cancer.

A history of both breast and ovarian cancer.

The presence of breast cancer in 1 or more male family members.^33,^88,^89,^90,^93,

Family history characteristics associated with an increased likelihood of carrying a BRCA1 or BRCA2 mutation include the following:

Multiple cases of breast cancer in the family.

Both breast and ovarian cancer in the family.

One or more family members with 2 primary cancers.

Ashkenazi Jewish background.^33,^88,^89,^90,

The likelihood of having a BRCA mutation can vary from one individual to the next based on their country of origin, ethnicity, and family history of cancer. The models outlined in the table titled Characteristics of Common Models for Estimating the Likelihood of a BRCA Mutation take these factors into account and assist in providing tailored risk assessments . Another model, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), was developed in 2004 to assess both breast and ovarian cancer risks and the probabilities of carrying a BRCA1/2 mutation.⁹⁴ This model appears to perform well, particularly in the situation of a family history of breast cancer, compared to the Claus and BRCAPRO models, but because of its complexity, it is not readily applied in a clinical setting and is not included in the following table.

Table 4. Characteristics of Common Models for Estimating the Likelihood of a BRCA Mutation
Couch ^33,Shattuck-Eidens ^88,Frank ^90,Parmigiani ^93,CSGE = conformation sensitive gel electrophoresis Gene BRCA1BRCA1BRCA1 and BRCA2BRCA1 and BRCA2Study population 169 women with breast cancer and family history of breast cancer and/or ovarian cancer 798 women with either early-onset breast cancer or ovarian cancer, or with family history of breast or ovarian cancer 238 women with breast cancer diagnosed at age <50 years or with ovarian cancer, with at least 1 first-degree or second-degree relative with breast cancer <50 years or ovarian cancer Statistical model (BRCAPRO) Proband characteristics Proband may or may not have breast or ovarian cancer Proband must be affected with breast cancer and/or ovarian cancer Proband must be affected with breast cancer <50 years or ovarian cancer Proband may or may not have breast or ovarian cancer Takes into account bilateral breast cancer and age of onset of proband Takes into account probands with bilateral breast cancer and those with both breast and ovarian cancer Consideration of proband’s current age or age at diagnosis of breast or ovarian cancer Special consideration for probands with breast cancer <40 years Takes into account: - Bilateral breast cancer and those with breast cancer, ovarian cancer, or breast and ovarian cancer at any age - Male breast cancer - BRCA1/2 mutation status Family history characteristics Family must have >2 cases of breast cancer May or may not have affected relatives Must have first-degree relative with breast cancer <50 years or ovarian cancer Includes all first-degree relatives and second-degree relatives with and without cancer Takes into account proband or relatives with breast and/or ovarian cancer Takes into account relatives with breast and/or ovarian cancer Takes into account additional relatives with breast cancer <50 years or ovarian cancer Takes into account:Uses average age at diagnosis of breast cancers Does not take into account age of onset of cancer or bilateral breast cancer in relatives - Relatives with male or female breast cancer Takes into account Ashkenazi Jewish ancestry Takes into account Ashkenazi Jewish ancestry - Female relatives with ovarian cancer or breast and ovarian cancer - Current age or age at death and age at diagnosis of breast cancer and ovarian cancer - Ashkenazi Jewish ancestry - BRCA1/2 mutation status Provides risk estimate for Composite family probability Proband (who has breast or ovarian cancer) Proband (who has breast cancer <50 years or ovarian cancer) Any affected or unaffected family member Limitations Does not estimate likelihood of BRCA2 mutation Does not estimate likelihood of BRCA2 mutation Not applicable to women diagnosed with breast cancer at ≥ 50 years Requires computer software and time-consuming data entryNot applicable to families with site-specific ovarian cancer Further calculation required for unaffected relatives Further calculation required for unaffected relatives Incorporates only first-degree relatives and second-degree relatives; may need to change proband to best capture risk Does not take into account bilaterality or male breast cancer Underestimates risk with multiple affected members Combined data for Ashkenazi Jewish and non-Jewish families so it may overestimate risk for non-Jewish probands and underestimate risk for Jewish probands Has been validated in a high-risk genetic counseling clinic ^95,Some estimates are based on small sample size Validity in moderate family histories unknown Further calculation required for unaffected relatives Because testing used CSGE, may underestimate mutation likelihood Best application Families with 1 or more cases of breast cancer, Ashkenazi Jewish families, and families with multiple affected members Families with small number of affected members Families with 2 first-degree relatives with breast cancer <50 years or ovarian cancer Widely applicable. Performs equally well in African American families as in Caucasian families.^21,Provides likelihood of either BRCA1 or BRCA2 mutation Only model to incorporate unaffected relatives, male breast cancer, bilateral breast cancer, and age at diagnosis for all affected individuals Provides likelihood of either BRCA1 or BRCA2 mutation Program also provides Couch, Shattuck-Eidens and Frank risk estimates

Genetic testing for BRCA1 and BRCA2 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 in practitioners’ selection of the best model to fit their individual patient’s circumstances and consideration of factors that might limit the ability to provide an accurate risk assessment (i.e., small family size or paucity of women).

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. To date, only weak connections have been made between these genes and sporadic breast and ovarian cancer. Studies of tumor tissue from sporadic breast cancers have detected no somatic BRCA1 mutations and a very low frequency of BRCA2 mutations.^96,^97,^98,^99,¹⁰⁰ In ovarian cancer tumor tissue, however, BRCA1 mutations appear to occur with some frequency. In an unselected series of 103 ovarian cancers, 7 disease-causing mutations in BRCA1 were found that were not present in normal tissue of these patients.¹⁰¹ Another series of 221 ovarian cancers analyzed for mutations in BRCA1 identified 15 somatic mutations and 18 tumors with evidence of BRCA1 dysfunction due to hypermethylation.^102,

Since few somatic BRCA1 and BRCA2 mutations are seen in sporadic breast tumors, other mechanisms for the inactivation of these tumor suppressor genes have been investigated. In particular, decreased expression of wild-type BRCA1 may occur on an epigenetic basis, i.e., as a result of DNA methylation or other physiological change that results in loss of gene expression, an event that in turn leads to cancer. In support of this hypothesis, artificially decreasing expression of BRCA1 using antisense oligonucleotides resulted in accelerated growth of mammary epithelial cells in culture.¹⁰³ Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter.^103,^104,^105,^106,¹⁰⁷ Similar findings have not been reported for BRCA2, though the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer.^108,^109,

Taken together, current pathologic, cytogenetic, and gene expression data suggest not only that inactivation of BRCA1 and BRCA2 plays a role in sporadic cancer, but also that there are biologic differences between BRCA1-related, BRCA2-related, and sporadic breast cancers. A clear understanding of these differences (and similarities) has not yet been reached.^110,^111,^112,^113,^114,

Genotype-Phenotype Correlations

Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629.^9,⁵⁰ This is the region of the gene containing the BRC repeats, which have 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.^59, 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 4,191.¹¹⁵ These observations have generally been confirmed in subsequent studies.^61,^62,¹¹⁶ 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.^60,¹¹⁷ 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 in BRCA2:6174delT mutation carriers.^60,¹¹⁷ 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.

Additional evidence exists that this region of BRCA2 contains a specific functional domain. Of the 5 different homozygous BRCA2 knockout mice constructed by independent laboratories, 3 lead to embryonic lethality during the first 10 days of gestation.^118,^119,¹²⁰ The other 2 knockouts yield viable full-term mice that can survive to adulthood.^121,¹²² The dramatic difference in phenotype correlates with the position of the BRCA2 mutation. The mice that die in utero contain a truncation in the BRCA2 gene before a series of repeated sequences in the large exon 11, while in those mice that can come to term, some copies of these repeats are retained. The repeats themselves have been shown to be the site of interaction of the Rad51 protein, suggesting that Rad51 binding is critical in determining the function of BRCA2 both during development and neoplasia.¹²³

Genetic changes associated with BRCA1- and BRCA2-related cancers are just beginning to be examined. Mutations in TP53 seem to be much more frequent in BRCA1 breast cancers (20/26) and somewhat more frequent in BRCA2-associated breast cancers (10/22) than in grade-matched sporadic cancers (7/20).¹²⁴ BRCA mutation-associated cancers contain TP53 mutations not typically found in sporadic breast cancer, and 12 individual hereditary breast cancers were shown to contain more than a single TP53 mutation. This raised the issue that mutations of BRCA1 and BRCA2 may confer a mutator phenotype allowing the general accumulation of a high rate of genetic abnormalities. Analysis of the coding sequence from the I-ran and Pancho oncogenes and the a-globin gene revealed no increase in mutations in BRCA mutation-associated breast cancers. In addition, no evidence was seen of the microsatellite instability characteristic of HNPCC associated cancers. Therefore, TP53 inactivation (or perhaps gain of function mutations) may be specifically selected for during BRCA1 and BRCA2 tumor progression.

A genome-wide screening for chromosomal gains or losses was performed on BRCA1 and BRCA2 breast cancers to determine the presence of other associated genetic hot-spots.¹¹¹ On the whole, BRCA-associated cancers had more regions that were amplified or deleted compared with controls (not stage matched and grade matched), suggesting a generalized increase in large-scale genomic instability. Specifically, chromosomes 5q, 4q, and 4p had very frequent LOH in BRCA1 tumors, while BRCA2 tumors were characterized by losses at 13q (near the BRCA2 locus itself) and 6q and chromosomal gains at 17q (outside of the HER2/neu locus) and 20q. LOH of both chromosomes 13 and 17 have been found simultaneously in a series of sporadic ovarian cancers, suggesting a synergistic mechanism.¹²⁵ In addition, the oncogene MYC on chromosome 8q24 was found to be amplified in 48% of 60 BRCA1-related breast cancers versus 14% of non-BRCA1 tumors.^126,

Pathology/Prognosis of Breast Cancer

BRCA1

Pathology

The identification of a histologic pattern characterizing hereditary breast cancer has been elusive, though historically, medullary, tubular, and lobular histologies have been associated with familial breast cancer.¹²⁷ Other studies have noted an excess of medullary histology in multicase families.^128,¹²⁹ Since the identification of the BRCA1 and BRCA2 genes, several studies have evaluated the distinct pathologic patterns seen in known hereditary breast cancers. Medullary histology was significantly more common (19% vs. 0%) in a series of BRCA1-associated breast cancer compared with sporadic cases in a study from France,¹³⁰ in carriers from the Breast Cancer Linkage Consortium,^131,, in a Swedish population-based study of breast cancer cases from high-risk families,¹³² and among women with early-onset breast cancer in a population-based study,¹³³ suggesting that medullary histology itself may be an indication for BRCA1 testing.

The Breast Cancer Linkage Consortium reported a relative lack of an in situ component in BRCA1-associated breast cancers.¹³¹ Data from the Mayo Clinic cohort of women undergoing mastectomy, however, found a significantly lower prevalence of hyperplastic lesions in BRCA1/2 mutations, but no difference in the prevalence of in situ lesions.¹³⁴ A population-based case-control study of ductal carcinoma in situ patients also found the prevalence of BRCA mutations to be similar in these women, as previously reported in studies of invasive breast cancer patients.¹³⁵ Therefore, it appears that ductal carcinoma in situ is a component of the hereditary breast ovarian cancer syndrome.

The recent development of gene-expression technology has created the potential to increase the specificity of the classification of breast cancer at the molecular level. Global gene expression profiles of tumors with BRCA1 and BRCA2 mutations and sporadic tumors differed significantly from each other in one small series.¹³⁶ Using comparative genomic hybridization (CGH), investigators from the Netherlands were able to develop a profile of distinct somatic genetic alterations, which can identify BRCA1-associated tumors with an accuracy of 84%.¹³⁷ Another study using tissue microarray technology to compare BRCA1, BRCA2, and sporadic tumors found that BRCA1 tumors were more likely to be BCL2-negative and to express high levels of P-cadherin.^138,

One potentially unifying hypothesis is 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. These tumors characteristically exhibit higher-grade features, areas of necrosis, and frequent TP53 mutations.¹³⁹ They are typically estrogen receptor–negative, are HER2-negative, and they stain positive for cytokeratin 5/6, 14, or 17, which are markers of basal epithelium.^140,^141,¹⁴² A study of 76 estrogen receptor–negative breast cancers found that those occurring in BRCA1 mutation carriers were significantly more likely (88% vs. 45% in BRCA1-negative subjects) to have a basal epithelial phenotype as determined by cytokeratin 5/6 expression.¹³⁹ Two additional studies of invasive breast cancers occurring in BRCA1 mutation carriers not selected for estrogen receptor status found that 78% of 27 tumors ¹⁴² and 61% of 182 tumors ¹⁴³ were positive for basal epithelial markers. 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.¹⁴⁴ If, in fact, the basal epithelial cells of the breast represent the breast stem cells, the suggested regulatory role for wild-type BRCA1, it may partly explain the aggressive phenotype of BRCA1-associated breast cancer when BRCA1 function is damaged.¹⁴⁵ Further studies are needed to fully appreciate the significance of this subtype of breast cancer within the hereditary syndromes .

Prognosis

The phenotypic expression of BRCA1-related breast cancer indicates distinctive prognostic features. A large study of 1,555 women with invasive breast cancer in 10 North American centers failed to find the expected correlation of tumor size with lymph node status among carriers of a deleterious BRCA1 mutation, suggesting that these tumors are characterized by an accelerated growth rate.¹⁴⁶ Investigators from the Mayo Clinic reached similar conclusions based on the risk-reducing mastectomy cohort, in whom both in situ and invasive lesions from BRCA1/2 carriers had higher-grade tumors and higher proliferations indices.¹³⁴ A Norwegian study reported that breast cancers occurring in BRCA1 mutation carriers were more likely to be invasive, high grade, and estrogen receptor negative.¹⁴⁷ A case-control study among women of Jewish descent also found that BRCA1-associated tumors were significantly more likely to be grade III and estrogen receptor negative.¹⁴⁸ Analysis of tumors from the North American study indicates that the estrogen receptor–negative status of the BRCA1 tumors is an intrinsic feature and not simply a correlate of younger age or higher grade.¹⁴⁹ The Breast Cancer Linkage Consortium compared the histopathologic features of breast cancer in women with BRCA1 mutations to a control group and found an excess of high-grade tumors, high mitotic rates, high proliferative fractions, and increased aneuploidy.¹³¹ They also found an increased frequency of high-intensity immunostaining for p53 in tumors from BRCA1 mutation carriers.¹⁵⁰ A population-based study confirmed the excess of high-grade tumors with high mitotic rates in BRCA1 carriers, but did not find a relative absence of in situ cancers in this group.¹³³ In a separate study of tumors from women with 1 of the 3 Ashkenazi founder mutations, immunohistochemical analysis demonstrated a relatively low rate of HER2/neu positivity and no differences in p53, epidermal growth factor receptor, cathepsin D, bcl-2, or cyclin D staining compared to a control group.^151,

In accordance with the poor prognostic features noted histologically for BRCA1-related breast cancer, 2 European studies reported survival rates that were similar to or worse than sporadic cases, with a significantly increased risk of contralateral breast cancer.^152,^153,¹⁵⁴ A case series report found higher rates of both ipsilateral and contralateral breast cancers among BRCA1/2 mutation carriers than among mutation-negative cases.¹⁵⁵ Higher rates of ipsilateral and contralateral breast cancers were also seen in the cohort of Ashkenazi women with founder mutations.¹⁵⁶ That study failed, however, to show a significantly different event-free or overall survival at 5 years compared with nonmutation carriers. A retrospective cohort study of 496 Ashkenazi breast cancer patients from 2 centers compared the relative survival among the 56 BRCA1/2 mutation carriers followed for a median 116 months. BRCA1 mutations were independently associated with worse disease-specific survival; there was no effect for BRCA2. The poorer prognosis associated with BRCA1 was not observed in women who received chemotherapy.^157,

In summary, there is a growing consensus that BRCA1-related breast cancer presents with clinical, histopathologic, and molecular features, suggesting a more aggressive phenotype. Most clinical outcome studies are consistent with there being a somewhat worse prognosis, especially among women who do not receive chemotherapy. There is no consensus about whether these differences should alter the approach to treating women with BRCA1-related breast tumors.

BRCA2

Pathology

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well-characterized than that of BRCA1. A report from Iceland, where a BRCA2 founder mutation (999del5) accounts for nearly all hereditary breast cancer, found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors compared with sporadic controls.¹⁵⁸ 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.¹⁵⁹ Other reports suggest that BRCA2 related tumors include an excess of lobular and tubulolobular histology.^133,^160,

Prognosis

Studies of the prognosis of BRCA2 associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer.^161,

Pathology/Prognosis of Ovarian Cancer

Pathology

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.¹⁶² Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease.⁶⁷ 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.¹⁰¹ Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/2 carriers in a Dutch case-control study.¹⁶³ 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.^162,¹⁶⁴ 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, which may ultimately distinguish them histologically.^165,

Prognosis

Despite generally poor prognostic factors, several studies have found an improved survival among ovarian cancer patients with BRCA mutations.^148,^166,¹⁶⁷ One study found that survival of 43 BRCA1 carriers with advanced ovarian cancer was significantly better than that of matched sporadic cases.¹⁶⁶ Median survival was 77 months in the BRCA1 carriers, versus 29 months in noncarriers. 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.¹⁶⁷ In a retrospective, hospital-based study (n = 71), BRCA Ashkenazi heterozygotes had a better response to platinum-based chemotherapy, as measured by response to primary therapy, disease-free survival, and overall survival, compared with sporadic cases.¹⁶⁸ A similar study in Japanese patients also found a survival advantage in stage III BRCA1-associated ovarian cancers treated with cisplatin regimens compared with nonhereditary cancers treated in a similar manner.¹⁶⁹ In a study of 103 ovarian cancers unselected for family history, the cancers in the 11 BRCA1 mutation carriers had prognostic features consistent with better survival, including a high rate of negative second-look surgeries after the primary chemotherapy and more well-differentiated pathologic features.^101,

In contrast, 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 to sporadic controls, but no difference in longer-term survival.¹⁷⁰ 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.^153,¹⁷¹ 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 2 groups.

Further large studies with appropriate control populations will be required to determine whether there is a survival advantage in either BRCA1- or BRCA2-related ovarian cancers.

Li-Fraumeni Syndrome

Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS) (OMIM: 151623), in which germline mutations of the TP53 gene (OMIM: 191170) on chromosome 17p have been documented.¹⁷² This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.^173,¹⁷⁴ 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.¹⁷⁵ 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.

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. In response to DNA damage, p53 protein arrests cells in the G1 phase of the cell cycle, allowing DNA repair mechanisms to proceed before DNA synthesis. The p53 protein is also an active component of programmed cell death.¹⁷⁶ 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.¹⁷⁴ 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.^177,

CHEK2

CHEK2 (OMIM: 604373), a gene involved in the DNA damage repair response pathway, was initially evaluated as a potential cause of LFS.¹⁷⁸ While it does not appear to be a common cause of LFS,¹⁷⁹ based on numerous studies, a single mutation, 1100delC, appears to be a rare, low-penetrance susceptibility allele.^180,^181,^182,^183,^184,¹⁸⁵ The deletion was present in 1.2% of the European controls, 4.2% of the European BRCA1/2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases.¹⁸⁰ In both Europe and the United States (where the mutation appears to be slightly less common), additional studies have detected the mutation in 4% to 11% of familial cases of breast cancer and overall have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer,^186,^187,^188,¹⁸⁹ including a large prospective study.¹⁹⁰ A multicenter combined analysis/reanalysis of nearly 20,000 subjects from 10 case-control studies, however, has verified a significant, 2.3-fold excess of breast cancer among mutation carriers.¹⁹¹ One study suggests the risk associated with a CHEK2 1100delC mutation was stronger in the families of probands ascertained because of bilateral breast cancer.¹⁹² At least one study has also suggested that the mutation may be associated with both breast and colorectal cancer.¹⁸⁷ Although the initial report suggested that male mutation carriers were at a significantly increased risk of breast cancer,¹⁸⁵ several follow-up studies have failed to confirm the association.^193,^194,^195,¹⁹⁶ The contribution of CHEK2 mutations to breast cancer may be dependent on the population studied. A study of 3,228 women diagnosed with breast cancer before age 51, along with 5,496 population controls demonstrated that three founder alleles in CHEK2 contributed to 8% of early onset breast cancer in Poland.¹⁹⁷ Additional, larger studies will be required to more precisely define the absolute risk of female breast and other cancers in individuals who carry germline CHEK2 variants.

Cowden Syndrome

One of the more than 50 cancer-related genodermatoses, Cowden syndrome (OMIM: 158350) is characterized by an excess of breast cancer, gastrointestinal malignancies, endometrial cancer, and thyroid disease, both benign and malignant.¹⁹⁵ 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 young ages and may be bilateral.¹⁹⁶ 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. Germline mutations in PTEN (OMIM: 601728), a protein tyrosine phosphatase with homology to tensin, located on chromosome 10q23, are responsible for this 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.¹⁹⁸ Disruption of PTEN appears to occur late in tumorigenesis and may act as a regulatory molecule of cytoskeletal function. Although PTEN accounts 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.^199,²⁰⁰ (Refer to the PDQ summary Genetics of Colorectal Cancer Major Genes section for more information on Cowden syndrome.)

Ataxia Telangiectasia

Ataxia telangiectasia (AT) (OMIM: 208900) 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 the ATM gene (OMIM: 607585), which has been localized to chromosome 11q22-23.²⁰¹ More than 300 mutations in the gene have been identified to date, most of which are truncating mutations.²⁰² (Refer to ATM online database for more information on AT mutations) ATM proteins have been shown to play a role in cell cycle control.²⁰³ In vitro, AT cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.²⁰⁴

Although study design and mutation testing strategies may be contributing factors, past studies searching for an excess of ATM mutations among breast cancer patients have provided conflicting results.^205,^206,^207,^208,^209,^210,^211,^212,^213,^214,²¹⁵ Two large epidemiologic studies have suggested a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated relative risk of approximately 2.0.^215,^216,.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome (PJS) (OMIM: 175200) is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, perioral, and buccal regions, and multiple gastrointestinal polyps, both hamartomatous and adenomatous.^217,^218,²¹⁹ Mutations in the STK11 gene (OMIM: 602216) at chromosome 19p13.3, which appears to function as a tumor suppressor gene,²²⁰ have been identified as one cause of PJS.^221,²²² Germline mutations in STK11, also known as LKB1, have been reported and appear to be responsible for about 50% of the cases of PJS.^221,^222,^223,^224,^225,²²⁶ A large series of 419 patients had a cumulative incidence of cancer of 85% by age 70, commonly affecting the GI tract. In addition, the cumulative risk of breast cancer was 31% by age 60; only two ovarian cancers were seen in this series.²²⁷ Elevated cancer risks have also been seen in smaller series and a meta-analysis, including a higher risk of sex cord stromal tumors of the ovary.^228,^229,^230,^231,^232,

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¹⁷¹ Buller RE, Shahin MS, Geisler JP, et al.: Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin Cancer Res 8 (5): 1196-202, 2002.

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¹⁷⁵ Olivier 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.

¹⁷⁶ Harris CC, Hollstein M: Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329 (18): 1318-27, 1993.

¹⁷⁷ Sidransky D, Tokino T, Helzlsouer K, et al.: Inherited p53 gene mutations in breast cancer. Cancer Res 52 (10): 2984-6, 1992.

¹⁷⁸ Bell DW, Varley JM, Szydlo TE, et al.: Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286 (5449): 2528-31, 1999.

¹⁷⁹ Sodha N, Houlston RS, Bullock S, et al.: Increasing evidence that germline mutations in CHEK2 do not cause Li-Fraumeni syndrome. Hum Mutat 20 (6): 460-2, 2002.

¹⁸⁰ Meijers-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.

¹⁸¹ Kuschel 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.

¹⁸² Sodha 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.

¹⁸³ Ingvarsson 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.

¹⁸⁴ Vahteristo 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.

¹⁸⁵ Meijers-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.

¹⁸⁶ Offit 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.

¹⁸⁷ Oldenburg 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.

¹⁸⁸ Neuhausen 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.

¹⁸⁹ Ohayon T, Gal I, Baruch RG, et al.: CHEK2*1100delC and male breast cancer risk in Israel. Int J Cancer 108 (3): 479-80, 2004.

¹⁹⁰ Weischer 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.

¹⁹¹ CHEK2 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.

¹⁹² Johnson 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.

¹⁹³ Osorio 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.

¹⁹⁴ Syrjäkoski 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.

¹⁹⁵ Tsou 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.

¹⁹⁶ Olopade 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.

¹⁹⁷ Cybulski C, Górski B, Huzarski T, et al.: CHEK2-positive breast cancers in young Polish women. Clin Cancer Res 12 (16): 4832-5, 2006.

¹⁹⁸ Lynch 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.

¹⁹⁹ Myers MP, Tonks NK: PTEN: sometimes taking it off can be better than putting it on. Am J Hum Genet 61 (6): 1234-8, 1997.

²⁰⁰ Pilarski 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.

²⁰¹ Savitsky 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.

²⁰² Telatar 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.

²⁰³ Uhrhammer N, Bay JO, Bignon YJ: Seventh International Workshop on Ataxia-Telangiectasia. Cancer Res 58 (15): 3480-5, 1998.

²⁰⁴ Gilad S, Chessa L, Khosravi R, et al.: Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 62 (3): 551-61, 1998.

²⁰⁵ FitzGerald 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.

²⁰⁶ Chen J, Birkholtz GG, Lindblom P, et al.: The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res 58 (7): 1376-9, 1998.

²⁰⁷ Bay 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.

²⁰⁸ Laake K, Vu P, Andersen TI, et al.: Screening breast cancer patients for Norwegian ATM mutations. Br J Cancer 83 (12): 1650-3, 2000.

²⁰⁹ Dörk 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.

²¹⁰ Teraoka 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.

²¹¹ Chenevix-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.

²¹² Thorstenson YR, Roxas A, Kroiss R, et al.: Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63 (12): 3325-33, 2003.

²¹³ Cavaciuti 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.

²¹⁴ Olsen 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.

²¹⁵ Renwick 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.

²¹⁶ Thompson 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.

²¹⁷ Peutz 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.

²¹⁸ Jeghers 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.

²¹⁹ Spigelman AD, Murday V, Phillips RK: Cancer and the Peutz-Jeghers syndrome. Gut 30 (11): 1588-90, 1989.

²²⁰ Gruber SB, Entius MM, Petersen GM, et al.: Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 58 (23): 5267-70, 1998.

²²¹ Hemminki A, Markie D, Tomlinson I, et al.: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (6663): 184-7, 1998.

²²² Jenne 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.

²²³ Ylikorkala A, Avizienyte E, Tomlinson IP, et al.: Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer. Hum Mol Genet 8 (1): 45-51, 1999.

²²⁴ Yoon KA, Ku JL, Choi HS, et al.: Germline mutations of the STK11 gene in Korean Peutz-Jeghers syndrome patients. Br J Cancer 82 (8): 1403-6, 2000.

²²⁵ Westerman AM, Entius MM, Boor PP, et al.: Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families. Hum Mutat 13 (6): 476-81, 1999.

²²⁶ Lim 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.

²²⁷ Hearle 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.

²²⁸ Giardiello FM, Brensinger JD, Tersmette AC, et al.: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119 (6): 1447-53, 2000.

²²⁹ Humphries AL Jr, Shepherd MH, Peters HJ: Peutz-Jeghers syndrome with colonic adenocarcinoma and ovarian tumor. JAMA 197(4): 138-140, 1966.

²³⁰ Christian CD, McLoughlin TG, Cathcart ER, et al.: Peutz-Jeghers syndrome associated with functioning ovarian tumor. JAMA 190(10):157-160, 1964.

²³¹ Solh HM, Azoury RS, Najjar SS: Peutz-Jeghers syndrome associated with precocious puberty. J Pediatr 103 (4): 593-5, 1983.

²³² Scully RE: Sex cord tumor with annular tubules a distinctive ovarian tumor of the Peutz-Jeghers syndrome. Cancer 25 (5): 1107-21, 1970.

Genetic Polymorphisms and Breast Cancer Risk

Background

The search for genetic markers for breast cancer susceptibility has led to an increasing number of epidemiologic studies of relatively common genetic markers referred to as genetic polymorphisms .¹ Although the clinical significance and causality of associations with breast cancer is unclear, genetic polymorphisms may account for why some women are more sensitive than others to environmental carcinogens such as replacement estrogens or cigarette smoke.

Although varied definitions of low-penetrance exist, the term is often applied to sequence variants associated with a small-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 autosomal dominant inheritance patterns in a family. The definition of a “moderate” risk of cancer is also arbitrary, but is usually considered to be in the range of a relative risk of 1.5–2. Because these types of sequence variants (also called low-penetrance genes, alleles, mutations, and polymorphisms) are relatively common in the population, their contribution to total cancer risk is estimated to be much higher 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.² It is unknown whether there are low-penetrance variants in BRCA1/BRCA2; what was initially thought to be a low-penetrance allele, the N372H variation in BRCA2, was not verified in a large combined analysis.^3,

Summary of Evidence

Evidence of associations between genetic polymorphisms and breast cancer risk in women has been obtained from case-control or cohort (nested case-control) analytic studies, usually with just a single center or research group (level of evidence: 3). The endpoint in these studies has sometimes been prevalent breast cancer rather than the more satisfactory endpoint of incident breast cancer. In several studies of genetic polymorphisms and breast cancer, convenience samples of cases and controls have been used. Some studies have been population based, however, with incident cases of breast cancer and with adequate control of confounding factors. Results have largely been inconsistent, and none of the markers has had clinical applications.

¹ Nathanson KL, Weber BL: "Other" breast cancer susceptibility genes: searching for more holy grail. Hum Mol Genet 10 (7): 715-20, 2001.

² Pharoah PD, Antoniou A, Bobrow M, et al.: Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31 (1): 33-6, 2002.

³ Breast 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.

Interventions

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.^1,^2,^3,^4,⁵ 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.

Breast Cancer

Screening

Refer to the PDQ summary on Screening for Breast Cancer for information on screening in the general population, and to the PDQ summary Cancer Genetics Overview for information on levels of evidence related to screening and prevention.

Breast Self-Examination

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.⁶ 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 Screening for Breast Cancer for more information.)

Little direct prospective evidence exists regarding BSE among female carriers of a BRCA1 or BRCA2 high-risk mutation , male carriers of a BRCA2 mutation, or women at inherited 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, 5 breast cancers were detected by self-examination less than a year after a previous screen (as compared with 1 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.⁷ In another series of BRCA1/2 mutation carriers, 4 of 9 incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting the potential value of self-examination.⁸ 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) to establish a regular habit and allow familiarity with the normal characteristics of breast tissue. Education and instruction in self-examination are recommended.”⁹

Level of evidence: 5

Clinical Breast Examination

Few prospective data exist regarding clinical breast examination (CBE) among female carriers of a BRCA1 or BRCA2 high-risk mutation, male carriers of a BRCA2 mutation, or women at inherited risk of breast cancer.

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.^9,

Level of evidence: 5

Mammography

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 Screening for Breast Cancer 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.¹⁰ 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.¹¹ Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers.⁸ 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.¹² Higher PPVs may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity.^13, 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 2 of whom had a BRCA2 mutation. Pushing margins, characteristic of medullary histology, is associated with an absence of fibrotic reaction.¹⁴ 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 BRCA1/2 carriers was 45 days, compared with 84 days in noncarriers.¹⁵ 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.^16,

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.¹⁷ Although mammography detected smaller primary invasive tumors and more invasive as well as 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 to 1.33). One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE.

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 6 women at a mean of 20.2 months after receipt of BRCA results.⁷ 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.”⁹ 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, given accumulating evidence that the BRCA1 and BRCA2 gene products are involved in repair of DNA damage from radiation.^18,^19,^20,

Level of evidence: 5

The limited sensitivity of mammography and an interest in methods of screening that do not involve ionizing radiation has led to evaluation of other screening techniques, including magnetic resonance imaging (MRI), breast ultrasound, breast ductal lavage, and digital mammography.

Magnetic Resonance Imaging

Because of the relative insensitivity of mammography in women at hereditary risk for 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 for 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 4 large studies are presented in Table 5, Summary of MRI Screening Studies in Women at Hereditary Risk for Breast Cancer.^21,^22,^23,^24,²⁵ 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, 82% of the cancers were identified by MRI compared to 40% by mammography.

Concerns have been raised about the reduced specificity of MRI compared to 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.²⁵ 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.²⁴ The benign biopsy rates in the first study were 11% at first round, 6.6% at second round, and 4.7% at third round.²⁵ 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.²⁴ 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 not detected by screening. However, mammography clearly identifies some cancers that are not identified by MRI. Most of these mammographically detected cancers in women with a negative MRI appear to be ductal carcinomas in situ , presumably presenting as microcalcifications without significant ductal enhancement. 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 to mammography alone. One screening study demonstrated that patients were more likely to be diagnosed with small tumors and node-negative disease than women in 2 nonrandomized control groups.²² 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.

Table 5. Summary of MRI Screening Studies in Women at Hereditary Risk for Breast Cancer
SeriesKriege^22,Warner^25,MARIBS^24,Kuhl^26,Totals*2 additional cancers detected at planned 6-month interval ultrasound screening (not included in ultrasound detection proportion)**Restricted to studies in which ultrasound was performedN PatientsOverall1,9092366495293,323BRCA 1/2 Carriers35423612043753N Screening Episodes4,1694571,8811,5428,049N CancersBaseline2213201469Subsequent239152976Annual Incidence9.5/1,00019/1,00025/1,000Detected at Planned Screening41213340*135 (93%)N Detected by Each ModalityMammography188141454 (37%)MRI32172739115 (79%)Ultrasound**71724 (37%)

Ultrasound

Several studies have reported instances of breast cancer detected by ultrasound that were missed by mammography, as discussed in one review.²⁷ In a pilot study of ultrasound as an adjunct to mammography in 149 women with moderately increased risk based on family history, 1 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 8 were based on abnormalities on ultrasound alone.²⁷ Uncertainties about ultrasound include the effect of screening on mortality, the rate and outcome of false-positive results , and access to experienced breast ultrasonographers.

Digital Mammography

Digital mammography refers to the use of a digital detector to detect and record x-ray images. This technology improves contrast resolution,²⁸ 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;²⁹ however, digital mammography resulted in fewer recalls.

Risk modification

Refer to the PDQ summary on Prevention of Breast Cancer for information on prevention in the general population, and to the PDQ summary Cancer Genetics Overview for information on levels of evidence related to screening and prevention.

Reproductive Factors

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 Prevention of Breast Cancer 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.³⁰ 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 3 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 5 or more; however, increasing parity appeared to be associated with an increased risk of ovarian cancer.^31,³² 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.^33,

Studies of the effect of pregnancy on breast cancer risk have revealed complex results. Although the relationship of parity has been inconsistent, several studies have shown that among parous women, an increased number of full-term births is associated with a decrease in breast cancer risk. The influence of age at first birth may differ between BRCA1 and BRCA2 mutation carriers.^34,^35,³⁶ Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.^34,^37,

Level of evidence: 3

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,³⁸ 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 1 year or more was associated with approximately a 45% reduced risk of breast cancer.³⁹ No such reduced risk was observed among BRCA2 mutation carriers. A second study failed to confirm this association.^34,

Oral Contraceptives

Among the general population, oral contraceptives may produce a slight, short-term increase in breast cancer risk. (Refer to the PDQ summary on Prevention of Breast Cancer for more information.) In a meta-analysis of data from 54 studies, family history of breast cancer was not associated with any variation in risk associated with oral contraceptive use.⁴⁰ In a study of 50 Jewish women younger than 40 years with breast cancer, those with a BRCA1 or BRCA2 high-risk mutation had a higher likelihood of long-term oral contraceptive use (>48 months) before their first pregnancy.⁴¹ The authors concluded that oral contraceptive use might increase the risk of breast cancer among carriers of a BRCA1 or BRCA2 mutation more than in noncarriers. In a case-control study of more than 1,300 pairs of women, each case was matched to a woman with a mutation in the same gene, born within 2 years of the case, and in the same country, who had not developed cancer. Oral contraceptive use was associated with a statistically significant 20% (CI, 2%-40%) increase in risk of breast cancer among BRCA1 mutation carriers, particularly if use:

Began before 1975, a period when estrogen doses were relatively high (38% increase, CI 11%-72%).

Began before age 30 years (29% increase, CI, 9%-52%).

Lasted for 5 or more years (33% increase, CI, 11%-60%).^42,

There was no increased risk associated with use among BRCA2 mutation carriers. A Swedish population-based study of 245 women with breast cancer diagnosed before age 41, 19 of whom were BRCA1/BRCA2 mutation carriers, suggested that oral contraceptive use before age 20 was associated with increased breast cancer risk in both mutation carriers and noncarriers, though the small number of carriers limits the conclusions for this subgroup.^43,

In contrast, a population-based study of 47 BRCA1- and 36 BRCA2 mutation carriers with breast cancer diagnosed before age 40, matched to population controls without mutations, found no increased risk of early-onset breast cancer associated with ever use of low-dose contraceptive pills for BRCA2 mutation carriers (OR = 1.02) and a significantly reduced risk for BRCA1 mutation carriers (OR = 0.22; 95% CI, 0.10-0.49).^44,

One study examined proliferation of normal breast epithelium among women undergoing reduction mammoplasty.⁴⁵ The study found a substantially higher cellular proliferation rate among women who used oral contraceptives before their first full-term pregnancy. In addition, among women currently on oral contraceptives, women with a family history of breast cancer had much higher cellular proliferation rates than those women without a family history. These findings are consistent with increased breast cancer risk among women with a family history of breast cancer who use oral contraceptives.

In considering contraceptive options and preventive actions, the potential impact of oral contraceptive use upon the risk of both breast and ovarian cancer, as well as other health-related effects of oral contraceptives, needs to be considered. With regard to breast cancer risk associated with oral contraceptive use, despite conflicting results based on small numbers of carriers, several studies have found a significantly increased risk. A number of important issues remain unresolved including the potential differences between BRCA1/2 mutation carriers, age and duration of exposure, and formulation.

Levels of evidence for oral contraceptive studies: 3B, 3

Hormone Replacement Therapy

Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with hormone replacement therapy (HRT) in the general population.^46,^47,^48,⁴⁹ The Women’s Health Initiative (WHI) is a randomized controlled trial of approximately 160,000 postmenopausal women investigating the risks and benefits of strategies that may reduce the incidence of heart disease, breast and colorectal cancer, and fractures, including dietary interventions and 2 trials of hormone therapy. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits.^48,⁴⁹ 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 randomized to receive estrogen and progestin.⁴⁹ 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.^49,

Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased ^50,^51,⁵² or unaffected by a family history of breast cancer;^31,^53,^54, risk did not vary by family history in the meta-analysis.⁴⁰ The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations.⁴⁹ Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.^55,

The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 mutation has only been studied in the context of bilateral oophorectomy, a procedure known to reduce the risk of breast cancer. In a prospective study of 462 women with BRCA1 or BRCA2 mutations, 155 who had undergone bilateral oophorectomy (139 before age 50), the breast cancer risk reduction of 37% was essentially the same among the 93 women who took HRT compared to the reduction of 38% among those without HRT.⁵⁶ This finding needs to be confirmed in a larger study but suggests that HRT in this particular setting does not negate the protective effect of oophorectomy on breast cancer risk.

Level of evidence: 4B

Risk Reduction

Tamoxifen

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-P1), a prospective randomized double-blind trial, compared tamoxifen (20 mg/day) to 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.⁵⁷ Similar reductions were noted in the risk of preinvasive breast cancer. Reductions in breast cancer risk were noted among women with a family history of breast cancer and those without a family history. These benefits were associated with an increased incidence among women older than 50 years of endometrial cancers and thrombotic events. Interim data from 2 European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months ⁵⁸ or 70 months,⁵⁹ respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used HRT.⁵⁸ These trials varied considerably in study design and populations. (Refer to the PDQ summary on Prevention of Breast Cancer for more information.)

A substudy of the NSABP-P1 trial evaluated the effectiveness of tamoxifen in preventing breast cancer in BRCA1/2 mutation carriers older than 35 years. BRCA2-positive women benefited from tamoxifen to the same extent as BRCA1/2 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).^60,

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.^61,^62,⁶³ In one study involving approximately 600 BRCA1/2 mutation carriers, tamoxifen use was associated with a 51% reduction in contralateral breast cancer.⁶¹ An update to this report examined 285 BRCA1/2 mutation carriers with bilateral breast cancer and 751 BRCA1/2 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.⁶³ Another study involving 160 BRCA1/2 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.⁶² These studies are limited by their retrospective, case-control designs and the absence of information regarding estrogen-receptor status in the primary tumor.

Risk-Reducing Mastectomy

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.⁶⁴ 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 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, 3 women were diagnosed with breast cancer after bilateral risk-reducing mastectomy, with a median follow-up of 14 years.⁶⁵ 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, 8 variants of uncertain significance). None of those women had developed breast cancer after a median follow-up of 13.4 years.⁶⁶ Two of the 3 women diagnosed with breast cancer after risk-reducing mastectomy 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 risk-reducing mastectomy and followed prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas 8 were identified in women undergoing regular surveillance (HR for breast cancer after risk-reducing mastectomy = 0 [95% CI, 0–0.36]).⁶⁷

The Prevention and Observation of Surgical End Points (PROSE) study group estimated the degree of breast cancer risk reduction after risk-reducing mastectomy in BRCA1/2 mutation carriers. The rate of breast cancer in 105 mutation carriers who underwent bilateral risk-reducing mastectomy 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%.^68,

Another study evaluated the effectiveness of contralateral risk-reducing mastectomy in affected women with hereditary breast cancer. In a group of 148 BRCA1 or BRCA2 mutation carriers, 79 of whom underwent risk-reducing mastectomy, the risk of contralateral cancer was reduced by 91% and was independent of the effect of prophylactic oophorectomy. Survival was better among women undergoing risk-reducing mastectomy, but this result was apparently caused by higher mortality due to the index cancer or metachronous ovarian cancer in the group not undergoing surgery.^69,

Studies describing histopathologic findings in risk-reducing mastectomy specimens from women with BRCA1 or BRCA2 mutations have been somewhat inconsistent. In 2 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 43% to 46% of women with mutations undergoing either unilateral or bilateral risk-reducing mastectomy.^70,^71, 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, 3 (6%) cancers were detected at surgery.^72,

These findings were not replicated in a third retrospective cohort study. In this study, proliferative fibrocystic changes were noted in 0 of 11 bilateral mastectomies from patients with deleterious mutations and in only 2 of 7 contralateral unilateral risk-reducing mastectomies in affected mutation carriers.^73,

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 risk-reducing mastectomy as a treatment option, uptake varies according to culture, geography, healthcare system, insurance coverage, provider attitudes, and other social factors. For example, in one setting where the providers made 1 to 2 field trips to family gatherings for family information sessions and individual counseling, only 3% of unaffected carriers obtained risk-reducing mastectomy within 1 year of follow-up.⁷⁴ Among women at increased risk of breast cancer due to family history, fewer than 10% opted for mastectomy.⁷⁵ 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 addition, self-perceived risk has been closely linked to interest in risk-reducing mastectomy.^75,

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, risk-reducing mastectomy would result in an average increased life expectancy of 2.9 to 5.3 years.⁷⁶ 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 risk-reducing mastectomy.⁷⁷ 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.^78,

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 risk-reducing mastectomy. Almost 90% of the risk-reducing mastectomy surgeries were performed within 1 year of DNA testing. In this study, those most likely to have risk-reducing mastectomy were women younger than 55 years and with children.⁷⁹

Individual psychological factors have an important role in decision-making about risk-reducing mastectomy by unaffected women. Research is emerging about psychosocial outcomes of risk-reducing mastectomy. (Refer to the Psychological Aspects of Medical Interventions section of this summary.)

Level of evidence: 3B

Risk-Reducing Salpingo-Oophorectomy

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 Prevention of Breast Cancer for more information.) In a study of 680 women, who were at various levels of familial risk, from the Mayo Clinic who had bilateral oophorectomy before age 60, the likelihood of breast cancers developing was reduced for all risk groups.⁸⁰ 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,^81,⁸² 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) as well as ovarian cancer (HR 0.04, 95% CI, 0.01–0.16) after risk-reducing salpingo-oophorectomy.⁸³ A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend. With risk-reducing salpingo-oophorectomy (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).^84,

Levels of evidence: 3, 4

Ovarian Cancer

Screening

Refer to the PDQ summary on Screening for Ovarian Cancer for information on screening in the general population, and to the PDQ summary Cancer Genetics Overview for information on levels of evidence related to screening and prevention.

Clinical Examination

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

Serum CA 125

Limited data are available on the potential benefit of screening with serum CA 125 in women at inherited risk of ovarian cancer. When 180 women considered at high risk of ovarian cancer based on family history were screened for ovarian cancer by gynecologic examination, transvaginal ultrasound (TVUS), and serum CA 125, 1 granulosa cell tumor, 3 tumors of low malignant potential, and 5 epithelial ovarian tumors (1 stage II and 4 stage III) were detected. CA 125 levels were elevated in 1 of the tumors of low malignant potential and 3 of the 4 stage III ovarian carcinomas.^85,

A 10-year observational study of 2,500 asymptomatic women with a family history of ovarian cancer who underwent transvaginal ultrasound screening and retrospective analysis of serum CA 125 levels is described in more detail in the Pelvic Ultrasound section of this summary.^86,

Another study found elevated CA 125 levels in 68 of 597 (11.4%) women screened for ovarian cancer. Most of these women had a first-degree or second-degree relative with ovarian cancer, though 51 had a pedigree consistent with inherited susceptibility to breast or ovarian cancer, and 7 had a pedigree consistent with HNPCC. Among the premenopausal patients, the elevations in CA 125 were associated with ultrasonographic evidence of endometriosis, adenomyosis, or leiomyomas. Among the 8 postmenopausal patients, all had normal ovarian architecture on ultrasound.^87,⁸⁸ No data are available to address the effectiveness of ovarian cancer screening in preventing deaths from ovarian cancer.

In 1994, 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. The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo annual or semiannual screening for ovarian cancer with TVUS and serum CA 125.⁸⁹ The Cancer Genetics Studies Consortium task force recommended that female carriers of a BRCA1 high-risk mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years.^9,

A phase II trial evaluating annual TVUS and serial CA 125 levels in 3,000 high-risk women registered in the United Kingdom Familial Ovarian Cancer Registry is under way. In the United States, the National Cancer Institute (NCI) is conducting a large controlled clinical trial in which 74,000 women are randomized to regular medical care or research-based screening for lung, colorectal, and ovarian cancer. The ovarian cancer screening consists of yearly serum CA 125 and TVUS.^90,

Level of evidence: 5

Pelvic Ultrasound

In the general population, TVUS appears to be superior to transabdominal ultrasound in preoperative diagnosis of adnexal masses. Either technique has lower specificity in premenopausal women than in postmenopausal women due to the cyclic menstrual changes in premenopausal ovaries that can cause difficulty in interpretation. A screening trial of TVUS in 1,300 postmenopausal, asymptomatic women detected abnormalities in 2.5%. More than 90% of the lesions found were benign. Women with a family history of ovarian cancer were more likely to be found with an ovarian malignancy (RR = 4.0). No such association was noted for those with a family history of breast cancer or colon cancer.^91,

One study reported on the use of transvaginal color Doppler ultrasonography in the evaluation of 126 women with adnexal masses who subsequently underwent surgery. Twenty epithelial ovarian cancers were detected, as well as 2 dysgerminomas, 2 ovarian tumors of low malignant potential, 1 immature teratoma, and 1 Sertoli-Leydig cell tumor. It was concluded that color Doppler ultrasonography was able to increase the positive and negative predictive value due to increased sensitivity and specificity of ultrasound evaluation.^92,

Another study reported that the addition of color Doppler ultrasonography was able to increase the PPV of ultrasound imaging from 25% to 60% among women with a personal history of breast cancer undergoing screening for ovarian cancer.⁹³ As noted, however, clinical studies of color Doppler imaging have shown that normal physiologic changes in the premenopausal ovary near the time of ovulation have low impedance flow characteristics similar to those seen in malignancy.^87,

Data are limited regarding the potential benefit of pelvic ultrasound in screening women at inherited risk of ovarian cancer. A 10-year observational study in the United Kingdom of 2,500 asymptomatic women with at least one relative with ovarian cancer has evaluated TVUS and reported sensitivity and specificity with 10 years of follow-up and retrospective analysis of serum CA 125 levels.⁸⁶ Most women were screened once only, unless the initial scan was positive or the family history was especially strong. There were 11 screening-detected cancers, 1 false-negative stage III cancer (occurring within 12 months of ultrasound screening), and 93 false-positive tests, for a test sensitivity of 92% and a specificity of 97.8%. Among the 11 screening-detected cancers, 4 were stage Ia invasive, 4 borderline stage Ia, 1 invasive stage Ic, and 2 stage II/III serous carcinomas. Sixty-five percent of the subjects were premenopausal, and 9 of the 12 cancers occurred in this group. TVUS was quite sensitive in this high-risk group, but there were still a large number of women screened (n = 227) and false positives (n = 9) for each cancer were detected. The retrospective analysis of serum CA 125 levels in this study also allowed its evaluation as a potential first-stage screen to reduce both the number of ultrasound tests required and false positives.⁸⁶ If only women with CA 125 levels of 20 or higher underwent ultrasound screening, an additional 4 cancers would have been missed (sensitivity of 58%), but only 22% of the subjects would have undergone ultrasound screening, reducing the number of false positives to 21. Ultrasound screening only of those with CA 125 levels of 35 would have resulted in a sensitivity of 33% (7 additional cancers missed). Another study evaluated 383 high-risk women (152 BRCA1/2 mutation carriers) with annual transvaginal ultrasound and CA 125.⁹⁴ Abnormal screening results were noted in 74 women (19.3%) but resolved spontaneously in 47 women (63.5%). Of the 20 women undergoing exploratory surgery, only 1 had cancer, which was metastatic breast cancer to the ovary. No epithelial ovarian cancers were found as a result of screening.

Another study used gynecologic examination, TVUS, and CA 125 to screen 180 women at high risk of ovarian cancer with or without breast cancer. (Refer to the Serum CA 125 section in this summary.) Abnormal ultrasounds were noted in all 5 women with invasive epithelial ovarian carcinomas. Of these, however, 1 had stage II disease and 4 had stage III disease.^85, A study from the Netherlands used annual TVUS and CA 125 to screen 269 women at high risk of hereditary ovarian cancer. Of the 4 prevalent and 4 incident cancers found, 6 were advanced stage.^95,

One study screened 597 women at risk of ovarian cancer with serum CA 125, TVUS, and color Doppler (described in the Serum CA 125 section). No epithelial ovarian cancers were found. One case of an ovarian tumor of low malignant potential, however, was identified.^87,^88,

Another study reported screening 386 women with first- or second-degree relatives with ovarian cancer. The study used TVUS, color flow Doppler, and serum CA 125. Initial ultrasound was abnormal in 89 of 381 women (23%). Ovarian masses persisted in 15 patients; all of these were benign at surgery. CA 125 levels were higher than 35 U/mL in 42 of 386 women (11%). Two patients who underwent surgery for rising CA 125 levels had normal ovaries.^96,

The NIH Consensus Statement on Ovarian Cancer recommended against routine screening of the general population with TVUS and serum CA 125. The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA 125 every 6 to 12 months, commencing at age 35 years.⁸⁹ The Cancer Genetics Studies Consortium task force has recommended that female carriers of a BRCA1 high-risk mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years.^9,

In the United States, NCI is conducting a large controlled clinical trial in which 74,000 women are randomized to regular medical care or research-based screening for lung, colorectal, and ovarian cancer. The ovarian cancer screening consists of yearly serum CA 125 and TVUS.⁹⁰ NCI's Clinical Genetics Branch, the Gynecologic Oncology Group, and the Cancer Genetics Network are collaborating on a prospective study (GOG-0199) ⁹⁷ of women at increased genetic risk of ovarian cancer in which risk-reducing surgery and a novel CA 125-based screening strategy are being evaluated.^98,

Level of evidence: 5

Risk modification

Refer to the PDQ summary on Prevention of Ovarian Cancer for information on prevention in the general population, and to the PDQ summary Cancer Genetics Overview for information on levels of evidence related to screening and prevention.

Reproductive Factors

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.⁹⁹ 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.

Pregnancy

Among the general population, parity decreases the risk of ovarian cancer by 45% compared with nulliparous women. Subsequent pregnancies after the first appear to decrease ovarian cancer risk by 15%.¹⁰⁰ In women with BRCA1/2 mutations, studies have shown that parity decreases the risk of ovarian cancer.^101,^102,

One study analyzed the reproductive histories of 333 women with a BRCA1 high-risk mutation. Among these women, the risk of ovarian cancer increased with increasing parity. Each birth was associated with an additional 40% increase in risk up to 5 births. Late birth, however, appeared to convey a protective effect. Each 5-year interval in age at last birth was associated with a risk reduction of 18%. Women who had all their children after age 30 years, or who were nulliparous, formed a low-risk group for ovarian cancer (RR = 0.30).^33,

Lactation and Tubal Ligation

In the general population, breast feeding is associated with a decrease in ovarian cancer risk.¹⁰³ In BRCA mutation carriers, data are limited. One study found no protective effect with breast feeding.¹⁰¹ A case-control study among women with BRCA1 or BRCA2 mutations demonstrates a significant reduction in risk of ovarian cancer (odds ratio (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 oral contraceptive pill use, parity, history of breast cancer, and ethnicity.¹⁰⁴ 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).¹⁰⁵ 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.¹⁰⁶ (Refer to the PDQ summary on Prevention of Ovarian Cancer for information relevant to the general population.)

Oral Contraceptives

Oral contraceptives have been shown to have a protective effect against ovarian cancer in the general population. Several studies conducted in high-risk, multiple-case family clinic settings showed a protective effect,^46,^104,¹⁰⁷ as did a small population-based study,¹⁰⁸ while a large population-based study from Israel failed to demonstrate a protective effect.^102,

A case-control study drawn from multiple-case families from high-risk clinics was performed evaluating oral contraceptive use among 207 women with a BRCA1 high-risk mutation and ovarian cancer, and as controls, 161 of their sisters who had not been diagnosed with ovarian cancer. Oral contraceptive use was associated with a reduced risk of ovarian cancer, and the magnitude of the association appeared to exist between oral contraceptive use and decreased risk of ovarian cancer. The association increased with duration of use. Women who took oral contraceptives for more than 6 years had a 60% reduction in risk. This reduction was similar for BRCA1 and BRCA2 high-risk mutation carriers.⁴⁶ A large, population-based case-control study of ovarian cancer among 244 Jewish women in Israel found the risk of ovarian cancer among BRCA1 or BRCA2 mutation carriers decreased with each birth, but not with use of oral contraceptives (OR = 1.07 for 5 or more years of use), though they were protective, as expected, among noncarriers (OR = 0.53 for 5 or more years of use).¹⁰² A small population-based case-control study of 36 BRCA1 mutation carriers from the San Francisco Bay Area, however, observed a similar, protective effect in both mutation carriers and noncarriers (OR = approximately 0.5).¹⁰⁸ Finally, a multicenter study of subjects drawn from numerous registries observed a protective effect of oral contraceptives 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 or more years of use).^107,

As noted under oral contraceptives in the Breast Cancer Risk Modification section of this summary, there are conflicting data regarding their effect on breast cancer risk, with some retrospective case-control studies suggesting that oral contraceptive use increases the risk of breast cancer in women at inherited risk of breast cancer,^41,¹⁰⁹ including BRCA1 mutation carriers,⁴² while a population-based study found a reduced risk among BRCA1 mutation carriers.^44,

Level of evidence: 3

Risk-Reducing Salpingo-Oophorectomy

Numerous studies have found that women at inherited risk of breast and ovarian cancer have a decreased risk of ovarian cancer following risk-reducing oophorectomy. 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.⁸³ A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend.⁸⁴ 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). 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).^105,

Recent studies have shown not only a significant reduction in risk of ovarian and breast cancer but also a significant improvement in overall survival, as well as in breast and ovarian cancer specific survival. A prospective cohort study of 666 women with germline mutations in BRCA1 and BRCA2 found a hazard ratio for overall mortality of 0.24 (95% CI, 0.08–0.71) in women who had risk-reducing salpingo-oophorectomy (RRSO) compared with women who did not.¹¹⁰ 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 to be in the range of 2.3% to 33%, with a median age of the affected women in the range of 42 to 48 years.^111,^112,^113,¹¹⁴ The wide variation in prevalence is likely due to differences in surgical technique and pathologic handling of the tissues. In addition to occult cancers, premalignant lesions have also been described in fallopian tube tissue removed for prophylaxis. In 1 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.¹¹⁵ These surgical findings in prophylactic specimens are consistent with the identification of germline BRCA1 and BRCA2 mutations in women affected with both tubal and primary peritoneal cancers.^116,^117,^118,^119,^120,^121,

These findings support the inclusion of fallopian tube cancers, which account for <1% of all gynecologic cancers in the general population, as a component of hereditary ovarian cancer, and underscore the need for the routine collection of peritoneal washings and careful pathologic evaluation of all tissue obtained at the time of prophylactic surgery. They also raise questions about the optimal surgical approach to provide maximal cancer risk reduction. Some surgeons have recommended hysterectomy in addition to RRSO to remove the remnant of fallopian tube tissue embedded in the uterus, but there is no consensus on this issue. There is also the suggestion that uterine serous papillary carcinoma may be a BRCA1-related cancer,¹²² which might support a role for risk-reducing hysterectomy, but further studies are needed to establish this association.

The peritoneum, however, appears to remain at low risk for the development of a Mullerian-type adenocarcinoma, even after oophorectomy.^123,^124,^125,^126,¹²⁷ Of the 324 women from the Gilda Radner Familial Ovarian Cancer Registry who underwent risk-reducing oophorectomy, 6 (1.8%) subsequently developed primary peritoneal carcinoma. No period of follow-up was specified.¹²⁸ Among 238 individuals in the Creighton Registry with BRCA1/2 mutations who underwent risk-reducing oophorectomy, 5 subsequently developed intra-abdominal carcinomatosis (2.1%). Of note, all 5 of these women had BRCA1 mutations.¹²⁹ A recent 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.^130,

Given the current limitations of screening for ovarian cancer and the high risk for the disease in BRCA1 and BRCA2 mutation carriers, NCCN Guidelines recommend RRSO as an effective prevention option. Given that the average age of ovarian cancer in BRCA1 mutation carriers is 48, optimal timing of the procedure is age 35 or when childbearing is complete.

Levels of evidence: 3, 5

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. The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 mutation has only been studied in the context of risk-reducing oophorectomy, a procedure known to reduce the risk of breast cancer. In a prospective study of 462 women with BRCA1 or BRCA2 mutations, 155 who had undergone bilateral oophorectomy (139 before age 50), the breast cancer risk reduction of 37% was essentially the same among the 93 women who took HRT compared to the reduction of 38% among those without HRT.⁵⁶ This finding needs to be confirmed in a larger study but suggests that HRT in this particular setting does not negate the protective effect of oophorectomy on breast cancer risk.

Recent studies have examined the effect of RRSO on quality of life. One study examined 846 high-risk women of whom 44% underwent RRSO and 56% had periodic screening.¹³¹ Of the 368 BRCA1/2 mutation carriers, 72% underwent RRSO. No significant differences were observed in quality of life (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 peri-menopausal or postmenopausal.¹³¹ 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<0.05), although 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 < 0.01). Therefore, while such symptoms are improved via HRT use, HRT is not completely effective and additional work needs to be done.

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Psychosocial Issues in Inherited Breast Cancer Syndromes

Introduction

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 surveillance 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.¹ ^2,^3,^4,^5,^6,^7,^8,⁹ 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.^10,

Interest in and Uptake of Genetic Testing

Decisions about whether or not to pursue breast cancer genetic testing involve complex biologic, behavioral and social elements.¹¹ 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 2002,¹² 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%) (OR 1.27 [95% CI],1.16–1.39). In multivariate analysis, personal and family history of cancer, study recruitment and setting were all associated with testing uptake.

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.¹³ Factors that may influence uptake of testing include:

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.^14,

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.¹⁵ 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 1 reason for nontesting in most of these women.¹⁶ Other reasons for declining included having no children and becoming acquainted with breast/ovarian cancer in the family relatively early in their lives.^15,¹⁶ A third study evaluated characteristics of 34 individuals who declined BRCA1/2 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 BRCA1/2 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 BRCA1/2 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.¹⁷ 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.^18,

Participation in breast cancer risk counseling among family 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.^19,²⁰ 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.^21,

Women recruited from high-risk clinics, i.e., women 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.^22,²³ Genetic testing uptake was influenced by eligibility for free testing, history of breast or ovarian cancer, and Ashkenazi Jewish heritage.¹⁴ Interest in testing declines sharply if it is not immediately available.²² Knowledge about the details of cancer genetic testing is not associated with the decision to be tested,²⁴ 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.^20,

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.²³ 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 for 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 BRCA1/2 mutation, and more relatives affected with breast or ovarian cancer were more likely to consider undergoing BRCA1/2 testing.²⁵ 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 BRCA1/2 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.^26,

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.²⁷ 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.^22,^28,²⁹ An additional motivation for testing is to receive information that would benefit other family members.³⁰ Lastly, other motivators for testing may include 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.^31,

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 BRCA1/2 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.³² Most mean scores of psychological functioning at baseline for subjects in genetic counseling studies were within normal limits.³³ 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.

A general tendency to overestimate inherited risk of breast and ovarian cancer has been noted in at-risk populations,^34,³⁵ in cancer patients,^35,^36,³⁷ in spouses of breast and ovarian cancer patients,³⁸ and among women in the general population.^39,^40,⁴¹ This tendency may encourage a belief that BRCA1/2 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.²³ Overestimation of both breast and ovarian cancer risk has been associated with nonadherence to physician-recommended screening practices.^42,⁴³ A meta-analysis of 12 studies of outcomes of genetic counseling for breast/ovarian cancer showed that counseling improved the accuracy of risk perception.^44,

Women appear to be the prime communicators within families about the family history of breast cancer.⁴⁵ 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. Physicians and counselors taking a family history are encouraged to elicit paternal as well as maternal family histories of breast, ovarian, or other associated cancers.⁴⁵

The accuracy of reported family history of breast or ovarian cancer varies; some studies found levels of accuracy above 90%,^46,⁴⁷ with others finding more errors in the reporting of cancer in second-degree or more distant relatives.⁴⁸ 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.⁴⁹ Providers should be aware that there are a few published cases of Munchausen syndrome in reporting of false family breast cancer history.⁵⁰ 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.^45, (Refer to the Taking a Family History section of the Elements of Cancer Genetics Risk Assessment and Counseling summary.)

Targeted written,^51,⁵² video, CD-ROM, interactive computer program,^53,^54,^55,⁵⁶ and culturally targeted educational materials ⁵⁷ 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 ineligible individuals from seeking genetic testing.⁵¹

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.⁵⁸ (See the Major Genes section of this summary.)

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. The utilization of breast conservation and radiation as cancer therapy for women who are carriers may be influenced by knowledge of mutation status. (See the Interventions section of this summary.)

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.^59,⁶⁰ 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 as well as adherence to screening.^28,^29,⁶¹ 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.⁶² Formal, objective evaluation of these outcomes are now emerging. (Refer to the sections below on Emotional Outcomes and Behavioral Outcomes.)

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.^3,^63,^64,^65,^66,^67,^68,⁶⁹ 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.⁷⁰

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 and risk-reducing oophorectomy, and the complexity of existing psychosocial risks.³ 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.³³ These prospective studies, however, were characterized by a heterogeneity of measures of cancer-specific worry and inconsistent findings in effects of change from baseline.^33,

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 BRCA1/2 penetrance estimates derived from these dramatically affected families are substantial overestimates and do not apply to most families presenting for counseling and possible testing.^71,

Emotional Outcomes of Individuals

The few 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.^51,^72,^73,⁷⁴ 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.⁷⁵ 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 under age 50 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 risk-reducing mastectomy and/or prophylactic salpingo-oophorectomy within the same time period.⁷⁶ 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 as well as on a measure of general distress, did not change among BRCA1/2 carriers.⁷⁷ One long-term study of 65 female participants explored the psychosocial consequences of carrying a BRCA1/2 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 one year postdisclosure, these scores remained within normal limits for the general population.⁷⁸ 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 BRCA1/2 testing, psychological assessment, and even, occasionally, exclusion of a few individuals who appeared highly distressed.³ Intrusive thoughts (measured by the Impact of Event Scale [IES]) ⁷⁹ about cancer diminished after results disclosure for both mutation-positive and mutation-negative individuals in 1 Dutch study.⁸⁰

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 (10 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.⁸¹ 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 BRCA1/2 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.⁵⁹ Another study found that spousal anxiety about genetic testing and supportiveness differentiated the impact of BRCA1/2 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.⁶⁰

In another study, depression rates postdisclosure were unchanged for mutation carriers and markedly decreased for noncarriers.¹⁵ 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.⁵⁹ Early optimistic findings may not sufficiently reflect the true complexity of response to disclosure of BRCA1/2 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.⁵⁹ One pilot study suggested that women diagnosed more recently were more distressed after counseling.⁸² 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 for cancer than with the genetic testing process itself. Obtaining genetic testing may be less stressful than living with the awareness of familial risk for cancer.⁸³ (Note: For more detailed information about depression and anxiety associated with a cancer diagnosis, refer to the PDQ Supportive Care summaries on Anxiety Disorder; Depression; and Normal Adjustment and the Adjustment Disorders.) Case descriptions have supported the importance of family relationships and test outcomes in shaping the distress of tested individuals.^84,⁸⁵

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 ^86,⁸⁷ and are less able themselves to anticipate the intensity of their reactions following result disclosure.⁸⁸ Female mutation carriers who have had breast cancer are often surprised by their high level of risk for 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.⁸⁷ 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.^86,^89,

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 for cancer. In a study of 735 women at all levels of risk for hereditary breast/ovarian cancer, 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.⁹⁰ 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 2 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.⁹¹ 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 2 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.^92,

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.^93,⁹⁴ One study indicated that most women wanted information given both ways.³⁶ 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.⁹⁵ Other studies explored the use of decision aids as an adjunct to standard genetic counseling to assist patients in decisions about cancer risk management (mastectomy vs. surveillance). One study showed that the use of a decision aid consisting of individualized value assessment and cancer risk management information after receiving positive BRCA1/2 test results was associated with fewer intrusive thoughts and lower levels of depression at the 6-month follow-up in unaffected women. The usage 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.^96,

Preferences for delivery of breast cancer genetic testing are reported in 1 study ⁹⁴ to include 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 Effects

Family communication about genetic testing and hereditary risk

Family communication about genetic testing for cancer susceptibility, and specifically about the results of BRCA1/2 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.⁹⁷ Among males, noncarriers were more likely than carriers to tell their sisters and children the results of their tests. BRCA1/2 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).^45,^98,

Family communication of BRCA1/2 test results to relatives is another factor affecting participation in testing. There have been more studies of communication with first-degree and second-degree relatives than with more distant family members. One study investigated the process and content of communication among sisters about BRCA1/2 test results.⁹⁹ 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. Other studies found that women with a BRCA mutation more often shared their results with their adult sisters and daughters than with their adult brothers and sons;¹⁰⁰ and another study found that disclosure was limited mainly to first-degree relatives, and dissemination of information to distant relatives was problematic.¹⁰¹ Age was a significant factor in informing distant relatives with younger patients being more willing to communicate their genetic test result.^99,^100,^101,

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.¹⁰² 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.¹⁰² 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.⁹⁸ 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.¹⁰³ 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.⁹⁸ A study of 31 mothers with a documented BRCA mutation explored patterns of dissemination to children.¹⁰⁴ 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 between 20 and 29 years of age and slightly more than 25% of the children were 19 years of age or younger. Sons and daughters were notified in equal numbers. Over 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.

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.¹⁰⁵ 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.^105,

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.¹⁰⁶ In contrast, a study of 59 men testing positive for a BRCA1/2 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.¹⁰⁷ Men in both studies expressed fears of developing cancer themselves. Irish men especially reported fear of cancer in sexual organs.

Family functioning

In a study of 212 individuals from 13 hereditary breast and ovarian cancer families who received genetic counseling and were offered BRCA1/2 testing for documented mutation in the family, individuals who were not tested were found 6-9 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.^18,

Men

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.¹⁰⁸ 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 BRCA1/2 mutation) participated. The study purpose was to analyze distress in males at risk of carrying a BRCA1/2 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.¹⁰⁹ In one study,¹⁰⁷ 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 BRCA1/2 mutations.^107,^110,

Children

Testing for BRCA1/2 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.^111,^112,¹¹³ 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.^114,¹¹⁵ 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.¹¹⁴ To date, no data exist on the testing of children for BRCA1/2, 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.^116,^117,¹¹⁸ In one study, 20 children (aged 11 to 17 years) of a selected group of mothers undergoing genetic testing (80% of whom previously had breast cancer and all of whom had discussed BRCA1/2 testing with their children) completed self-report questionnaires on their health beliefs and attitudes toward cancer, feelings related to cancer, and behavioral problems.¹¹⁹ 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 ¹²⁰ found that 1 month after disclosure of BRCA1/2 genetic test results, 53% of 42 enrolled mothers of children aged 8 to 17 years had discussed their result with 1 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.^120,

Reproductive issues

Prenatal diagnosis of breast/ovarian cancer predisposition is generally discouraged.¹²¹ Adult age at onset, good prognosis for many breast cancer patients, and the expectation of greater medical progress by the time disease onset might be expected decades into the future make the prospect of prenatal diagnosis an uncomfortable one for many geneticists, leading potentially to charges of eugenics.^114,¹²² Limited data on the use of this technology are available. In a small series, 26 mutation carriers indicated that pregnancy termination based on mutation status would not be acceptable. Interestingly, a small percentage of nonmutation carriers felt that termination of a pregnancy, where the fetus was a mutation carrier was acceptable.¹²³ Historically, in Huntington’s disease, the uptake of prenatal diagnosis and termination is low.¹²⁴ ¹²⁵

Cultural/Community Effects

The recognition that BRCA1/2 mutations are prevalent, not only in breast/ovarian cancer families but also in some ethnic groups,¹²⁶ 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 ^127, 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.¹²⁸

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.^57,^129,^130,^131,^132,

Ethical Concerns

The human implications of the ethical issues raised by the advent of genetic testing for breast/ovarian cancer susceptibility are described in case studies,¹³³ essays,^62,¹³⁴ 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 .¹³⁵ Only half of surveyed first-degree relatives of women with breast or ovarian cancer felt that written permission should be required to disclose BRCA1/2 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.²² Many professional groups have made recommendations regarding informed consent.^20,^22,^66,^136,¹³⁷ There is some evidence that not all practitioners are aware of or follow these guidelines.²⁷ Research shows that many BRCA1/2 genetic testing consent forms do not fulfill recommendations by professional groups about the 11 areas that should be addressed,¹³⁶ and they omit highly relevant points of information.²⁷ 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.¹³⁸ 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.

Psychological Aspects of Medical Interventions

Risk-reducing mastectomy is 1 of the options for risk reduction recommended for discussion with women who have an increased risk of developing breast cancer due to inherited cancer predisposition.¹³⁷ It is also offered to some women with a strong family history of breast cancer who have had, or who are contemplating, removal of 1 breast because of the presence of tumor,¹³⁹ and to women with premalignant breast disease or extreme cancer fear.¹⁴⁰ Recommendation for risk-reducing mastectomy has been controversial because of the lack of clarity in criteria for its appropriate use ¹⁴¹ and limited data on the emotional and social ramifications.¹⁴² Reports of >90% risk reduction for women at high and moderate risk for breast cancer strengthen the likelihood that providers will discuss risk-reducing mastectomy with women at increased hereditary risk.^143,¹⁴⁴

Caution is advised in interpreting the value and advisability of risk-reducing mastectomy among women at increased genetic risk because of the need to consider the psychological and other costs of surgery.¹⁴⁵

On the other hand, many women found to be mutation carriers express interest in risk-reducing mastectomy in hopes of minimizing their risk of breast cancer. In 1 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 (2/12) intended to have mastectomies and 33% (4/12) intended to have oophorectomies.⁷² In a later study of the same population, risk-reducing mastectomy was considered an important option by 35% of women who tested positive, whereas risk-reducing oophorectomy was considered an important option by 76%. Initial interest does not always translate into the decision for surgery. Two different studies found low rates of prophylactic mastectomy among mutation carriers in the year following result disclosure, one showing 3% (1 of 29) of carriers and the other 9% (3/34) of carriers having had this surgery.^110,¹⁴⁶ 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 risk-reducing mastectomy, 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% (12/26) had obtained an oophorectomy by 2 years after testing. Of those carriers aged 25 to 39 years, 29% (5/17) underwent oophorectomy, while 78% (7/9) of the carriers aged 40 years and older had this procedure.¹⁴⁷ 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.¹⁴⁸ 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 9 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:

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.^148,

A number of women choose to undergo risk-reducing mastectomy and risk-reducing salpingo-oophorectomy (RRSO) without genetic testing because:

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.^149,^150,

Among first-degree relatives of breast cancer patients attending a surveillance clinic, women who expressed an interest in prophylactic mastectomy 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 prophylactic mastectomy. Cancer worry at the time of entry into the clinic was highest among women who subsequently underwent prophylactic mastectomy compared with women who expressed interest but had not yet had surgery, as well as women who did not intend to have surgery (P <.001).¹⁵¹

Discussion of risk-reducing surgical options may not consistently occur during pre-test genetic counseling. In one multi-institutional study, only one half of genetics specialists discussed risk-reducing mastectomy and salpingo-oophorectomy in consultations with women from high-risk breast cancer families,^152,¹⁵³ 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.^154,

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 (134) or family history (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. 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 breast self-examination.^155,

Psychosocial Outcome Studies

A prospective study conducted in the Netherlands found that among 26 BRCA1/2 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.¹⁵⁶ 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 BRCA1/2 mutations. Of the women who had a prophylactic mastectomy, all but 1 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.¹⁵⁶ At 5-year follow-up, women who had undergone risk-reducing mastectomy had less favorable body image and changes in sexual relationships, but also had a significant reduction in the fear of developing cancer.^78,

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.^157,

A study of 60 healthy women who underwent risk-reducing mastectomy 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 risk-reducing mastectomy, 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.^158,

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 BRCA1/2 genetic testing at the time of breast cancer diagnosis.^159,¹⁶⁰ 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 prophylactic mastectomy was chosen by 48% of mutation-positive women ¹⁵⁹ and by 100% of mutation-positive women in a smaller series ¹⁶⁰ of women undergoing testing at the time of diagnosis. Of women in whom no mutation was found, 24% also opted for bilateral mastectomy. Four percent of the test decliners also underwent bilateral mastectomy. Among mutation carriers, predictors of bilateral mastectomy included whether patients reported their physicians had recommended BRCA1/2 testing and bilateral mastectomy prior to testing, and whether they received a positive test result.¹⁵⁹ Data are lacking on quality-of-life outcomes for women undergoing prophylactic mastectomy following genetic testing performed at the time of diagnosis.

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.¹⁶¹ 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).^161,¹⁶² None of these women had genetic testing for mutations in the BRCA1/2 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.

Quality of life in 59 women who underwent RRSO was assessed at 24 months postprocedure.¹⁶³ 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 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.¹⁶⁴ 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.

Interventions: Psychological

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, as well as 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 1 report.¹⁶⁵ Another recommends rehearsal of affective state in the context of all potential outcomes of cancer genetic testing for BRCA1/2.¹⁶⁶ 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 BRCA1/2 mutation carriers evaluated whether psychological and behavioral outcomes of BRCA1/2 testing are improved among mutation carriers by providing a psychosocial telephone counseling intervention in addition to standard genetic counseling.¹⁶⁷ 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 BRCA1/2 result. The final telephone session focused on integration and closure on the issues raised as well as implementing 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 6-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.^168,

Women who called the NCI'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).^169,

Behavioral Outcomes

A study ¹⁷⁰ of screening behaviors of 216 self-referred, high-risk (>10% risk of carrying a BRCA1/2 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 transvaginal ultrasound. Further analysis of this study population ¹⁷⁰ 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.¹⁷¹ 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.¹⁷²

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,^19,^21,^170,¹⁷³ 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 4 cancer genetics clinics.¹⁷⁴ Breast self-exam, clinical breast examination, 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. Breast self-exam was not done at the recommended time and frequency by most women.

This is a critical issue not only for women testing positive, but also for adherence to screening for those testing negative as well as 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 breast self-exam, for which compliance is negatively associated with procedure-specific anxiety.⁴² 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, breast self-examination, 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.

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Disclaimer

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Changes to This Summary (3/15/2007)

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.

Linked genes and hereditary syndromes to Online Mendelian Inheritance in Man (OMIM) throughout the summary.

Introduction

Added text about the new NCI Dictionary of Genetics Terms.

Updated incidence and mortality estimates for 2007 (cited American Cancer Society as reference 1).

Added Hankinson et al. as reference 12.

Added McTiernan as reference 41.

Major Genes

Added STK11 as a susceptibility gene associated with breast cancer.

Added Variants of uncertain significance as a new subsection.

Added Gronwald et al. as reference 74.

Added text to state that a large prospective study also found an increased risk of breast cancer associated with CHEK2 mutations (cited Weischer as reference 190). Also added text about the results of a study that found CHEK2 mutations contributed to 8% of early onset breast cancer in Polish women (cited Cybulski et al. as reference 197).

Added text about the incidence and risk of cancer in the Peutz-Jeghers Syndrome (cited Hearle et al. as reference 227 and Giardiello as reference 228).

Genetic Polymorphisms and Breast Cancer Risk

Added text about the definitions of low- and high-penetrance. Also added text about the incidence of breast cancer in a susceptible population (cited Pharoah et al. as reference 2) and a large combined analysis that did not find low-penetrance variants in BRCA1/BRCA2 (cited the Breast Cancer Association Consortium as reference 3).

Interventions

Added text about the results of a prospective cohort study that showed a survival advantage among women who have undergone risk-reducing salpingo-oophorectomy (RRSO) (cited Domchek et al. as reference 110).

Added text about the results of a study of women with a BRCA1 or BRCA2 mutation and the risk of peritoneal cancers, 20 years after RRSO (cited Finch et al. as reference 130).

Psychosocial Issues in Inherited Breast Cancer Syndromes

Added Mancini et al. as reference 52.

Added Cancer screening and risk-reducing behaviors as a new subsection.

Added text about the results of a study that facilitated informed decision making about breast cancer risk and genetic counseling among women who called the NCI's Cancer Information Service (cited Miller et al. as reference 169).

More Information

About PDQ

PDQ® - NCI's Comprehensive Cancer Database.
Full description of the NCI PDQ database.

Additional PDQ Summaries

PDQ® Cancer Information Summaries: Adult Treatment
Treatment options for adult cancers.

PDQ® Cancer Information Summaries: Pediatric Treatment
Treatment options for childhood cancers.

PDQ® Cancer Information Summaries: Supportive Care
Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)
Tests or procedures that detect specific types of cancer.

PDQ® Cancer Information Summaries: Prevention
Risk factors and methods to increase chances of preventing specific types of cancer.

PDQ® Cancer Information Summaries: Genetics
Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

PDQ® Cancer Information Summaries: Complementary and Alternative Medicine
Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) .

2007-03-15

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