Grade: B The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.
The USPSTF recommends 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 breast cancer susceptibility 1 and 2 (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.
Frequency of Service
Consideration of screening for potentially harmful BRCA mutations should begin once women have reached the age of consent (18 years). Primary care providers should periodically assess all patients for changes in family history (for example, comprehensive review at least every 5 to 10 years)
Risk Factor Information
Patients with family or personal histories of breast, ovarian, tubal, or peritoneal cancer or ancestry associated with harmful < i>BRCA1/2 mutations should be assessed using a familial risk assessment tool. The USPSTF found adequate evidence that these tools are accurate in identifying women with increased likelihood of < i>BRCA1/2mutations. Tools evaluated by the USPSTF include the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, 7-Question Family History Screening Tool, International Breast Cancer Intervention Study instrument (Tyrer-Cuzick), and brief versions of BRCAPRO. These tools should be used to guide referrals to genetic counseling. Persons should consider their sex at birth to determine which recommendation best applies to them.
Patient Population Under Consideration
This recommendation applies to women who are asymptomatic for BRCA-related cancer and have unknown BRCA mutation status. It includes women who have never been diagnosed with BRCA-related cancer, as well as those with a previous breast, ovarian, tubal, or peritoneal cancer diagnosis who have completed treatment and are considered cancer free but have not been previously tested. While this recommendation applies to women, the net benefit estimates are driven by biological sex (ie, male/female) rather than gender identity. Persons should consider their sex at birth to determine which recommendation best applies to them.
Assessment of Risk
Mutations in the BRCA1/2 genes cluster in families, showing an autosomal dominant pattern of inheritance in either the mother’s or father’s family. When taking medical and family history information from patients, primary care clinicians should ask about specific types of cancer, primary cancer sites, which family members were affected, and whether relatives had multiple types of primary cancer. Clinicians should also inquire about the age at diagnosis, age at death, and sex of affected family members, both immediate (ie, parents and siblings) as well as more distant (ie, aunts, uncles, grandparents, and cousins).
For women who have family members with breast, ovarian, tubal, or peritoneal cancer or have a personal history of these types of cancer, primary care clinicians may use appropriate brief familial risk assessment tools to determine the need for in-depth genetic counseling. Tools evaluated by the USPSTF include the Ontario Family History Assessment Tool (Table 1), Manchester Scoring System (Table 2), Referral Screening Tool (Table 3), Pedigree Assessment Tool (Table 4), 7-Question Family History Screening Tool (Table 5), International Breast Cancer Intervention Study instrument (Tyrer-Cuzick) (Table 6), and brief versions of BRCAPRO. Each of these tools has been validated and accurately estimate the likelihood of carrying a harmful BRCA1/2 mutation. They can be used to guide referrals to genetic counseling for more definitive risk assessment.28 General breast cancer risk assessment models (eg, 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.
In general, these brief familial risk assessment tools include factors associated with increased likelihood of potentially harmful BRCA1/2 mutations. These 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, 1 or more family members with 2 primary types of BRCA-related cancer (such as ovarian cancer), and Ashkenazi Jewish ancestry. The USPSTF recognizes that each risk assessment tool has advantages and limitations and found insufficient evidence to recommend one over another.
The process of genetic counseling includes detailed kindred analysis and risk assessment for potentially harmful BRCA1/2 mutations. It also includes identification of candidates for testing, patient education, discussion of the benefits and harms of genetic testing, interpretation of results after testing, and discussion of management options. Genetic counseling about BRCA1/2 mutation testing should be performed by trained health professionals, including suitably trained primary care clinicians. Several professional organizations describe the skills and training necessary to provide comprehensive genetic counseling.
Testing for BRCA1/2 mutations should be performed only when an individual has personal or family history that suggests an inherited cancer susceptibility, when an individual is willing to talk with a health professional who is suitably trained to provide genetic counseling and interpret test results, and when test results will aid in decision-making. Clinical practice guidelines recommend that BRCA1/2 mutation testing 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.29 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. The type of mutation analysis required depends on family history. Individuals from families with known mutations or from ancestry groups in which certain mutations are more common (eg, Ashkenazi Jewish founder mutations) can be tested for these specific mutations. Because risk assessment is primarily based on family history, it is unclear how women with a limited or unknown family history should be assessed for BRCA1/2 mutation risk and potential referral to counseling or genetic testing.
Tests for BRCA1/2 mutations are highly sensitive and specific for known mutations. The availability of testing options has changed since the 2013 US Supreme Court ruling that determined human genes are not patentable (Association for Molecular Pathology et al v Myriad Genetics Inc et al).30 Previously, BRCA1/2 mutation testing in the United States was mainly conducted by 1 laboratory. Since the ruling, the number of testing options has significantly increased, with more than 80 multigene panels that include BRCA1/2, as well as tests marketed directly to consumers.31
Guidelines from the American College of Medical Genetics and Genomics, which were updated in 2015, recommend new standard terminology for reporting BRCA1/2 mutations identified by genetic tests. These include a 5-tier terminology system using the terms “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign.”32
Treatment and Interventions
Management of increased cancer risk related to BRCA1/2 mutations is beyond the scope of this Recommendation Statement. In general, care for women with harmful BRCA1/2 mutations consists of a variety of interventions to lower future cancer risk. This includes intensive screening, risk-reducing medications, and risk-reducing mastectomy and salpingo-oophorectomy.
Additional Tools and Resources
The National Cancer Institute Cancer Genetics Services Directory provides a list of professionals who offer services related to cancer genetics, including cancer risk assessment, genetic counseling, and genetic testing.33
Research Needs and Gaps
Research on risk assessment and testing for BRCA1/2 mutations has focused on short-term outcomes for highly selected women in referral centers. To determine the best approaches for population-based risk assessment and testing, more research is needed about mutation prevalence and effects on the general population as well as ethnicities or ancestries associated with BRCA1/2 mutations. Because risk assessment is primarily based on family history, more research is needed to better understand how women with an unknown family history should be assessed for BRCA1/2 mutation risk. Additional studies are needed, including comparative effectiveness trials, of approaches to risk screening and strategies to improve access to genetic counseling, as well as BRCA1/2 testing for high-risk individuals.
It would be helpful to understand which methods of delivery of genetic counseling are most effective, including those that can increase access to genetic counseling in rural or other settings with limited access. Trials comparing types of clinicians and protocols could address these questions. The consequences of genetic testing for individuals and their relatives require more study. Well-designed investigations using standardized measures and diverse study populations are needed.
An expanded database or registry of patients receiving genetic counseling for inherited breast and ovarian cancer susceptibility or who are tested for BRCA1/2 mutations would provide useful information about predictors of cancer and response to interventions. Additional data are needed from women of varying socioeconomic and racial/ethnic groups.
For women who are BRCA1/2 mutation carriers, studies about the effectiveness of intensive cancer screening and risk-reducing medications and the effects of age at intervention on improving long-term outcomes are needed. This research would increase knowledge of the relative benefits and harms of interventions that are provided on the basis of genetic risk information.
Update of Previous USPSTF Recommendation
In 2005 and 2013, the USPSTF recommended that women whose family history is associated with an increased risk for potentially harmful mutations in the BRCA1/2 genes be referred for genetic counseling and evaluation for BRCA1/2 testing. It also recommended against routine referral for genetic counseling or routine BRCA1/2 mutation testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1/2 genes.14,147 This Recommendation Statement is consistent with the USPSTF’s previous recommendation.
Since 2013, the validity of genetic testing for BRCA1/2 mutations has been established and the potential benefits and harms of previously reviewed interventions, such as risk-reducing medications and surgery, have been studied for longer follow-up periods. In addition, there have been more studies of newer imaging techniques (breast MRI), surgical procedures (salpingo-oophorectomy rather than oophorectomy alone), and medications (aromatase inhibitors). The updated recommendation expands the population eligible for screening to include women with a previous breast, ovarian, tubal, or peritoneal cancer diagnosis who have completed treatment and are considered cancer free and more explicitly includes ancestry associated with BRCA1/2 mutations (ie, founder mutations) as a risk factor.
Potentially harmful mutations of the BRCA1/2 genes are associated with increased risk for breast, ovarian, fallopian tube, and peritoneal cancer.1-6 For women in the United States, breast cancer is the most common cancer after nonmelanoma skin cancer and the second leading cause of cancer death.7 In the general population, BRCA1/2 mutations occur in an estimated 1 in 300 to 500 women and account for 5% to 10% of breast cancer cases and 15% of ovarian cancer cases.8-11 A woman’s risk for breast cancer increases if she has clinically significant mutations in the BRCA1/2 genes.12,13 Mutations in the BRCA1/2 genes increase breast cancer risk to 45% to 65% by age 70 years. Risk of ovarian, fallopian tube, or peritoneal cancer increases to 39% for BRCA1 mutations and 10% to 17% for BRCA2 mutations.12,13
Genetic risk assessment and BRCA1/2 mutation testing is a multistep process that begins with identifying patients with family or personal histories of breast, ovarian, tubal, or peritoneal cancer; family members with known harmful BRCA1/2 mutations; or ancestry associated with harmful BRCA1/2 mutations. Risk for clinically significant BRCA1/2 mutations can be further evaluated with genetic counseling by suitably trained health care clinicians, followed by genetic testing of selected high-risk individuals and posttest counseling about results. The USPSTF found adequate evidence that familial risk assessment tools are accurate in identifying women with increased likelihood of BRCA1/2 mutations. These tools can be used by primary care clinicians to guide referrals to genetic counseling.
The USPSTF has previously established that there is adequate evidence that current genetic tests can accurately detect known BRCA1/2 mutations.14
Benefits of Screening, Genetic Counseling, and Genetic Testing
The USPSTF found adequate evidence that the benefits of risk assessment, genetic counseling, and genetic testing are moderate in women whose family history is associated with an increased risk for harmful mutations in the BRCA1/2 genes.
The USPSTF found adequate evidence that the benefits of risk assessment, genetic counseling, and genetic testing are small to none in women whose family history is not associated with an increased risk for harmful mutations in the BRCA1/2 genes.
Harms of Screening, Genetic Counseling, and Genetic Testing
The USPSTF found adequate evidence that the harms associated with risk assessment, genetic counseling, genetic testing, and interventions are small to moderate.
The USPSTF concludes with moderate certainty that the net benefit of risk assessment for increased risk of BRCA1/2 mutations, testing for BRCA1/2 mutations, and use of risk-reducing interventions outweighs the harms in women whose family or personal history is associated with an increased risk for potentially harmful mutations in the BRCA1/2 genes.
The USPSTF concludes with moderate certainty that the harms of risk assessment for increased risk of BRCA1/2 mutations, testing for BRCA1/2 mutations, and use of risk-reducing interventions outweigh the benefits in women whose family or personal history is not associated with an increased risk for potentially harmful mutations in the BRCA1/2 genes.
Other Related USPSTF RecommendationsThe USPSTF recommends that clinicians offer to prescribe 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 (B recommendation). It recommends against the routine use of medications for risk reduction of primary breast cancer in women not at increased risk for breast cancer (D recommendation).34 The USPSTF recommends against screening for ovarian cancer in women (D recommendation). This recommendation does not apply to women with known genetic mutations that increase their risk for ovarian cancer (eg, BRCA1/2 mutations).35 The USPSTF found insufficient evidence to assess the balance of benefits and harms of performing screening pelvic examinations in asymptomatic women for the early detection and treatment of a range of gynecologic conditions (I statement).36Recommendations of OthersThe National Comprehensive Cancer Network provides specific criteria for genetic counseling and testing.29 The American College of Medical Genetics and the American Society of Clinical Oncology recommend testing for BRCA1/2 mutations only when an individual has personal or family cancer history suggestive of inherited cancer susceptibility, the test can be adequately interpreted, and the results will aid in management.148,149 The American College of Obstetricians and Gynecologists recommends performing a hereditary cancer risk assessment and subsequent referral to a specialist in cancer genetics if necessary.150 The Society for Gynecologic Oncology recommends that individuals with a likelihood of inherited predisposition to cancer based on personal or family history should be offered genetic counseling.151 The American Society of Breast Surgeons recommends that genetic testing be made available to all patients with a personal history of breast cancer.152 The National Institute for Health and Care Excellence recommends that health care professionals respond to a patient who presents with concerns but should not, in most instances, actively seek to identify persons with a family history of breast cancer.153 It recommends that in some circumstances, including when a patient has concerns about relatives with breast cancer, a first- and second-degree family history be taken in primary care to assess risk. Referral to secondary care is recommended if risk factors are identified in family history taking.153 The European Society for Medical Oncology follows the recommendations of the National Institute for Health and Care Excellence for initial risk assessment and the decision when to perform genetic counseling and testing.154
- JAMA Patient Page: Should I Be Tested for BRCA Mutations?
- Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: AFP's Putting Prevention Into PracticeThe journal American Family Physician (AFP) provides a series of short case studies and quizzes based on recommendations issued by the U.S. Preventive Services Task Force.