Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Recommendation Statement

Summary of Recommendations The U.S. Preventive Services Task Force (USPSTF) recommends against routine referral for genetic counseling or routine breast cancer susceptibility gene ( BRCA ) testing for women whose family history is not associated with an increased risk for deleterious mutations in breast cancer susceptibility gene 1 ( BRCA1 ) or breast cancer susceptibility gene 2 ( BRCA2 ). This is a grade D recommendation. (See Appendix Table 1 for a description of the USPSTF classification of recommendations.) Appendix Table 1. U.S. Preventive Services Task Force Recommendations and Ratings The USPSTF found fair evidence that women without certain specific family history patterns, termed here increased-risk family history (see Clinical Considerations for a definition), have a low risk for developing breast or ovarian cancer associated with BRCA1 or BRCA2 mutations. Thus, any benefit to routine screening of these women for BRCA1 or BRCA2 mutations, or routine referral for genetic counseling, would be small or zero. The USPSTF found fair evidence regarding important adverse ethical, legal, and social consequences that could result from routine referral and testing of these women. Interventions such as prophylactic surgery, chemoprevention, or intensive screening have known harms. The USPSTF estimated that the magnitude of these potential harms is small or greater. The USPSTF concluded that the potential harms of routine referral for genetic counseling or BRCA testing in these women outweigh the benefits. (See Appendix Table 2 for a description of the USPSTF classification of levels of evidence.) Appendix Table 2. U.S. Preventive Services Task Force Grades for Strength of Overall Evidence The USPSTF recommends that women whose family history is associated with an increased risk for deleterious mutations in BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing. This is a grade B recommendation. The USPSTF found fair evidence that women with certain specific family history patterns (increased-risk family history) have an increased risk for developing breast or ovarian cancer associated with BRCA1 or BRCA2 mutations. The USPSTF determined that these women would benefit from genetic counseling that allows informed decision making about testing and further prophylactic treatment. This counseling should be done by suitably trained health care providers. There is insufficient evidence to determine the benefits of chemoprevention or intensive screening in improving health outcomes in these women if they test positive for deleterious BRCA1 or BRCA2 mutations. However, there is fair evidence that prophylactic surgery for these women significantly decreases breast and ovarian cancer incidence. Thus, the potential benefits of referral and discussion of testing and prophylactic treatment for these women may be substantial. The USPSTF also found insufficient evidence regarding important adverse ethical, legal, and social consequences that could result from referral and testing of high-risk women. Prophylactic surgery is associated with known harms. The USPSTF estimated that the magnitude of these potential harms is small. The USPSTF concluded that the benefits of referring women with an increased-risk family history to suitably trained health care providers outweigh the harms. Clinical Considerations These recommendations apply to women who have not received a diagnosis of breast or ovarian cancer. They do not apply to women with a family history of breast or ovarian cancer that includes a relative with a known deleterious mutation in BRCA1 or BRCA2 genes; these women should be referred for genetic counseling. These recommendations do not apply to men. Although there currently are no standardized referral criteria, women with an increased-risk family history should be considered for genetic counseling to further evaluate their potential risks. Certain specific family history patterns are associated with an increased risk for deleterious mutations in the BRCA1 or BRCA2 gene. Both maternal and paternal family histories are important. For nonAshkenazi Jewish women, these patterns include 2 first-degree relatives with breast cancer, 1 of whom received the diagnosis at age 50 years or younger; a combination of 3 or more first- or second-degree relatives with breast cancer regardless of age at diagnosis; a combination of both breast and ovarian cancer among first- and second- degree relatives; a first-degree relative with bilateral breast cancer; a combination of 2 or more first- or second-degree relatives with ovarian cancer regardless of age at diagnosis; a first- or second-degree relative with both breast and ovarian cancer at any age; and a history of breast cancer in a male relative. For women of Ashkenazi Jewish heritage, an increased-risk family history includes any first-degree relative (or 2 second-degree relatives on the same side of the family) with breast or ovarian cancer. About 2% of adult women in the general population have an increased-risk family history as defined here. Women with none of these family history patterns have a low probability of having a deleterious mutation in BRCA1 or BRCA2 genes. Computational tools are available to predict the risk for clinically important BRCA mutations (that is, BRCA mutations associated with the presence of breast cancer, ovarian cancer, or both), but these tools have not been verified in the general population. There is no empirical evidence concerning the level of risk for a BRCA mutation that merits referral for genetic counseling. Not all women with a potentially deleterious BRCA mutation will develop breast or ovarian cancer. In a woman who has a clinically important BRCA mutation, the probability of developing breast or ovarian cancer by age 70 years is estimated to be 35% to 84% for breast cancer and 10% to 50% for ovarian cancer. Appropriate genetic counseling helps women make informed decisions, can improve their knowledge and perception of absolute risk for breast and ovarian cancer, and can often reduce anxiety. Genetic counseling includes elements of counseling; risk assessment; pedigree analysis; and, in some cases, recommendations for testing for BRCA mutations in affected family members, the presenting patient, or both. It is best delivered by a suitably trained health care provider. A BRCA test is typically ordered by a physician. When done in concert with genetic counseling, the test assures the linkage of testing with appropriate management decisions. Genetic testing may lead to potential adverse ethical, legal, and social consequences, such as insurance and employment discrimination; these issues should be discussed in the context of genetic counseling and evaluation for testing. Among women with BRCA1 or BRCA2 mutations, prophylactic mastectomy or oophorectomy decreases the incidence of breast and ovarian cancer; there is inadequate evidence for mortality benefits. Chemoprevention with selective estrogen receptor modulators may decrease incidence of estrogen receptor-positive breast cancer; however, it is also associated with adverse effects, such as pulmonary embolism, deep venous thrombosis, and endometrial cancer. Most breast cancer associated with BRCA1 mutations is estrogen receptor-negative and thus is not prevented by tamoxifen. Intensive screening with mammography has poor sensitivity, and there is no evidence of benefit of intensive screening for women with BRCA1 or BRCA2 gene mutations. Magnetic resonance imaging (MRI) may detect more cases of cancer, but the effect on mortality is not clear. Women with an increased-risk family history are at risk not only for deleterious BRCA1 or BRCA2 mutations but potentially for other unknown mutations as well. Women with an increased-risk family history who have negative results on tests for BRCA1 and BRCA2 mutations may also benefit from surgical prophylaxis. The USPSTF has made recommendations on mammography screening for breast cancer, screening for ovarian cancer, and chemoprevention of breast cancer, which can be accessed at www.preventiveservices.ahrq.gov. Discussion Breast and ovarian cancer are associated with a family history of these conditions. Approximately 5% to 10% of women with breast cancer have a mother or sister with breast cancer, and up to 20% have a first-degree or a second-degree relative with breast cancer (1-6). Germline mutations in 2 genes, BRCA1 and BRCA2, have been associated with an increased risk for breast cancer and ovarian cancer (7, 8). Specific BRCA mutations (founder mutations) are clustered among certain ethnic groups, such as Ashkenazi Jews, and among families in the Netherlands, Iceland, and Sweden (1). Several characteristics are associated with an increased likelihood of BRCA mutations (1, 9-12). These include breast cancer diagnosed at an early age, bilateral breast cancer, history of both breast and ovarian cancer, presence of breast cancer in 1 or more male family members, multiple cases of breast cancer in the family, both breast and ovarian cancer in the family, 1 or more family members with 2 primary cases of cancer, and Ashkenazi Jewish background. No direct measures of the prevalence of clinically important BRCA1 or BRCA2 mutations in the general, non-Jewish U.S. population have been published; however, models have estimated it to be about 1 in 300 to 500 (13-16). Prevalence estimates in a large study of individuals from referral populations with various levels of family history ranged from 3.9% (no breast cancer diagnosed in relatives <50 years of age and no ovarian cancer) to 16.4% (breast cancer diagnosed in a relative <50 years of age and ovarian cancer diagnosed at any age) (17). Penetrance is the probability of developing breast or ovarian cancer in women who have a BRCA1 or BRCA2 mutation. Published reports of penetrance describe estimates of BRCA1 and BRCA2 mutations ranging from 35% to 84% for breast cancer and 10%