SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. About 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Breast cancer is the second leading cause of cancer death in the US. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. These mutations can be inherited from either of the parents in an autosomal dominant pattern and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.
It is estimated that BRCA1/2 gene mutations occur in approximately 1 in 400 women in the general population and account for 5-10% of breast cancer cases and 15% of ovarian cancer cases. The estimated prevalence of potentially harmful BRCA1/2 mutations is 6% in women with cancer onset before age 40 years, and 2.1% among Ashkenazi Jewish women. Among individuals with a family history of breast or ovarian cancer, BRCA1 mutation prevalence is approximately 13%, BRCA2 mutation prevalence is about 8%, and prevalence of either mutation is about 20%. Mutations in the BRCA1/2 genes increase breast cancer risk by 45-65% by age 70 years. The risk of ovarian, fallopian tube, or peritoneal cancer, increases to 39% for BRCA1 mutations, and 10-17% for BRCA2 mutations.
The US Preventive Services Task Force (USPSTF) in this publication updated the 2013 recommendations on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. These recommendations are based on the evidence of both the benefits and harms of the service and this assessment does not consider the costs of providing a service.
The USPSTF reviewed the evidence on risk assessment, genetic counseling, and genetic testing for potentially harmful BRCA1/2 mutations in asymptomatic women who have never been diagnosed with BRCA-related cancer, as well as those with a previous diagnosis of breast, ovarian, tubal, or peritoneal cancer who have completed treatment and are considered cancer free. In addition, the USPSTF reviewed interventions to reduce the risk for breast, ovarian, tubal, or peritoneal cancer in women with potentially harmful BRCA1/2 mutations, including intensive cancer screening, medications, and risk-reducing surgery.
1) The USPSTF recommended that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations, with an appropriate brief familial risk assessment tool. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing.
2) The USPSTF recommends against routine risk assessment, genetic counseling, or genetic testing for women whose personal or family history or ancestry is not associated with potentially harmful BRCA1/2 gene mutations.
Clinicians should obtain medical and family history specifically inquiring patients about specific types of cancer, primary cancer sites, which family members were affected, whether relatives had multiple types of primary cancer, the age at diagnosis, age at death, and sex of affected family members, both immediate (parents and siblings) as well as more distant (aunts, uncles, grandparents, and cousins). Women who have a family or personal history of breast, ovarian, tubal, or peritoneal cancer should be evaluated by clinicians, to determine the need for in-depth genetic counseling, using appropriate familial risk assessment tools, recognized by the USPSTF. Familial risk assessment factors include breast cancer diagnosis before age 50 years, bilateral breast cancer, presence of both breast and ovarian cancer in one individual, male family members with breast cancer, multiple cases of breast cancer in the family, one or more family members with 2 primary types of BRCA-related cancer (such as ovarian cancer), and Ashkenazi Jewish ancestry. Breast cancer risk assessment models such as the National Cancer Institute Breast Cancer Risk Assessment Tool, which is based on the Gail model are not designed to identify BRCA-related cancer risk and should not be used for this purpose.
Genetic counseling includes detailed kindred analysis and risk assessment for potentially harmful BRCA1/2mutations, identification of individuals for testing, discussion of the benefits and harms of genetic testing, interpretation of results after testing, and discussion of management options. Genetic counseling should be performed by trained health professionals, including suitably trained primary care clinicians.
Testing for BRCA1/2 mutations should be performed only when an individual with history suggesting inherited cancer susceptibility, is willing to talk with a qualified health professional, trained to provide genetic counseling and interpret test results, and when test results will aid in decision-making. BRCA mutation testing should begin with a relative with known BRCA-related cancer, including male relatives, to determine if a clinically significant mutation is detected in the family, before testing individuals without cancer. If an affected family member with a BRCA-related cancer is not available, then the relative with the highest probability of mutation should be tested. Reporting BRCA1/2 mutations identified by genetic tests should include a 5-tier terminology system, using the terms “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign.
Treatment and Interventions for women with harmful BRCA1/2 mutations
The USPSTF recommends that clinicians offer intensive screening and risk-reducing medications such as Tamoxifen, Raloxifene, or Aromatase Inhibitors to women at increased risk for breast cancer and at low risk for adverse medication effects. General care for these individuals may include risk-reducing mastectomy and salpingo-oophorectomy.
US Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322:652-665.