BRCA-Related Cancer: Risk Assessment, Genetic Counseling, & Genetic Testing -- Women Not at Increased Risk


General

Grade: D The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Discourage the use of this service.

Specific Recommendations

The USPSTF recommends against routine genetic counseling or BRCA testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes.

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

Mutations in the BRCA genes cluster in families, exhibiting an autosomal dominant pattern of transmission in maternal or paternal lineage. During standard elicitation of family history information from patients, primary care providers should ask about specific types of cancer, primary cancer sites, which family members were affected, relatives with multiple types of primary cancer, and the age at diagnosis and sex of affected family members.For women who have at least 1 family member with breast, ovarian, or other types of BRCA-related cancer, primary care providers may use 1 of several brief familial risk stratification tools to determine the need for in-depth genetic counseling. Although several risk tools are available, the 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), and FHS-7 (Table 5). The Referral Screening Tool (available at www.breastcancergenescreen.org) and FHS-7 are the simplest and quickest to administer. All of these tools seem to be clinically useful predictors of which women should be referred for genetic counseling due to increased risk for potentially harmful BRCA mutations (most sensitivity estimates were >85%), although some models have been evaluated in only 1 study. To determine which patients would benefit from BRCA risk assessment, primary care providers should not use general breast cancer risk assessment models (for example, the National Cancer Institute Breast Cancer Risk Assessment Tool, which is based on the Gail model) because they are not designed to determine which women should receive genetic counseling or BRCA testing. In general, these tools elicit information about factors that are associated with increased likelihood of BRCA mutations. Family history factors associated with increased likelihood of potentially harmful BRCA mutations include breast cancer diagnosis before age 50 years, bilateral breast cancer, presence of breast and ovarian cancer, presence of breast cancer in 1 or more male family members, multiple cases of breast cancer in the family, 1 or more family members with 2 primary types of BRCA-related cancer, and Ashkenazi Jewish ethnicity. The USPSTF recognizes that each risk assessment tool has limitations and found insufficient comparative evidence to recommend one tool over another. The USPSTF also found insufficient evidence to support a specific risk threshold for referral for testing.


Clinical

Patient Population Under Consideration

This recommendation applies to asymptomatic women who have not been diagnosed with BRCA-related cancer.

Women who have 1 or more family members with a known potentially harmful mutation in the BRCA1 or BRCA2genes should be offered genetic counseling and testing.

The USPSTF recognizes the potential importance of further evaluating women who have a diagnosis of breast or ovarian cancer. Some women receive genetic testing as part of a cancer evaluation at the time of diagnosis of breast cancer. The USPSTF did not review the appropriate use of BRCA testing in the evaluation of women who are newly diagnosed with breast cancer. That assessment is part of disease management and is beyond the scope of this recommendation. Women who have been diagnosed with breast cancer in the past and who did not receive BRCA testing as part of their cancer care but have a family history of breast or ovarian cancer should be encouraged to discuss further evaluation with their clinician.

These recommendations do not apply to men, although male family members may be identified for testing during evaluation.

Family History Screening and Risk Assessment

Mutations in the BRCA genes cluster in families, exhibiting an autosomal dominant pattern of transmission in maternal or paternal lineage. During standard elicitation of family history information from patients, primary care providers should ask about specific types of cancer, primary cancer sites, which family members were affected, relatives with multiple types of primary cancer, and the age at diagnosis and sex of affected family members.

For women who have at least 1 family member with breast, ovarian, or other types of BRCA-related cancer, primary care providers may use 1 of several brief familial risk stratification tools to determine the need for in-depth genetic counseling.

Although several risk tools are available, the 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), and FHS-7 (Table 5). The Referral Screening Tool (available at www.breastcancergenescreen.org) and FHS-7 are the simplest and quickest to administer. All of these tools seem to be clinically useful predictors of which women should be referred for genetic counseling due to increased risk for potentially harmful BRCA mutations (most sensitivity estimates were >85%), although some models have been evaluated in only 1 study. To determine which patients would benefit from BRCA risk assessment, primary care providers should not use general breast cancer risk assessment models (for example, the National Cancer Institute Breast Cancer Risk Assessment Tool, which is based on the Gail model) because they are not designed to determine which women should receive genetic counseling or BRCA testing.

In general, these tools elicit information about factors that are associated with increased likelihood of BRCA mutations. Family history factors associated with increased likelihood of potentially harmful BRCA mutations include breast cancer diagnosis before age 50 years, bilateral breast cancer, presence of breast and ovarian cancer, presence of breast cancer in 1 or more male family members, multiple cases of breast cancer in the family, 1 or more family members with 2 primary types of BRCA-related cancer, and Ashkenazi Jewish ethnicity. The USPSTF recognizes that each risk assessment tool has limitations and found insufficient comparative evidence to recommend one tool over another. The USPSTF also found insufficient evidence to support a specific risk threshold for referral for testing.

Genetic Counseling

Genetic counseling about BRCA mutation testing may be done by trained health professionals, including trained primary care providers. Several professional organizations describe the skills and training necessary to provide comprehensive genetic counseling. The process of genetic counseling includes detailed kindred analysis and risk assessment for potentially harmful BRCA mutations; education about the possible results of testing and their implications; identification of affected family members who may be preferred candidates for testing; outlining options for screening, risk-reducing medications, or surgery for eligible patients; and follow-up counseling for interpretation of test results.

BRCA Mutation Testing

Adequate evidence suggests that current genetic sequencing tests can accurately detect BRCA mutations. Testing for BRCA mutations should be done only when an individual has personal or family history that suggests an inherited cancer susceptibility, when an individual has access to a health professional who is trained to provide genetic counseling and interpret test results, and when test results will aid in decision making. Initial testing of a family member who has breast or ovarian cancer is the preferred strategy in most cases, but it is reasonable to test if no affected relative is available. It is essential that before testing, the individual is fully informed about the implications of testing and has expressed a desire for it.

The type of mutation analysis required depends on family history. Individuals from families with known mutations or from ethnic groups in which certain mutations are more common (for example, Ashkenazi Jewish women) can be tested for these specific mutations.

Individuals without linkages to families or groups with known mutations receive more comprehensive testing. In these cases, when possible, testing should begin with a relative who has breast or ovarian cancer to determine whether affected family members have a clinically significant mutation.

Tests for BRCA mutations are highly sensitive and specific for known mutations, but interpretation of results is complex and generally requires posttest counseling. Test results for genetic mutations are reported as positive (that is, potentially harmful mutation detected), variants of uncertain clinical significance, uninformative-negative, or true-negative. Women who have relatives with known BRCA mutations can be reassured about their inherited risk for a potentially harmful mutation if the results are negative (that is, a true negative). Some studies suggest increased breast cancer risk in some women with true-negative results. However, a comprehensive meta-analysis conducted for the USPSTF that included these studies found that breast cancer risk is generally not increased in women with true-negative results. An uninformative-negative result occurs when a woman's test does not detect a potentially harmful mutation but no relatives have been tested or no mutations have been detected in tested relatives. Available tests may not be able to identify mutations in these families. Risk for breast cancer is increased in women with uninformative-negative results.

Timing of Screening

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.

Interventions for Women Who Are BRCA Mutation Carriers

Interventions that may reduce risk for cancer or cancer-related death in women who are BRCA mutation carriers include earlier, more frequent, or intensive cancer screening; risk-reducing medications (for example, tamoxifen or raloxifene); and risk-reducing surgery (for example, mastectomy or salpingo-oophorectomy). However, the strength of evidence varies across the types of interventions.

Evidence is lacking on the effect of intensive screening for BRCA-related cancer on clinical outcomes in women who are BRCA mutation carriers. Medications, such as tamoxifen and raloxifene, have been shown to reduce the incidence of invasive breast cancer in high-risk women in the general population, but they have not been studied specifically in women who are BRCA mutation carriers.

In high-risk women and those who are BRCA mutation carriers, cohort studies of risk-reducing surgery (mastectomy and salpingo-oophorectomy) showed substantially reduced risk for breast or ovarian cancer. Breast cancer risk was reduced by 85% to 100% with mastectomy and by 37% to 100% with oophorectomy, and ovarian cancer risk was reduced by 69% to 100% with oophorectomy or salpingo-oophorectomy. Salpingo-oophorectomy was also associated with a 55% relative reduction in all-cause mortality (as measured during the course of the study) in women with BRCA1 or BRCA2mutations and without a history of breast cancer.

Other Approaches to Prevention

The USPSTF recommendations on medications for breast cancer risk reduction are available on the USPSTF Web site (www.uspreventiveservicestaskforce.org).

The USPSTF recommends against screening for ovarian cancer in women. This recommendation does not apply to women with known genetic mutations that increase their risk for ovarian cancer (for example, BRCA mutations).

Useful 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 susceptibility testing (available at http://www.cancer.gov/cancertopics/genetics/directory).  

Other Considerations

Although some studies have reported that women prefer in-person genetic counseling, telephone- or computer-based counseling may be considered for women who would not otherwise have access to these services.

Research Needs and Gaps

Research on risk assessment and testing for BRCA mutations has focused on short-term outcomes for highly selected women in referral centers. Additional studies are needed, including comparative effectiveness trials of approaches to risk screening and strategies to improve access to genetic counseling and BRCA testing for high-risk individuals.

Another unresolved question is what specific training is needed (for persons other than trained genetic counselors) to provide genetic counseling. 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. Trials comparing types of providers and protocols could address these questions.

What happens after patients are identified as high-risk in clinical settings is unknown. 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 BRCA mutations would provide useful information about predictors of cancer and response to interventions. Additional data are needed from women of varying socioeconomic, racial, and ethnic groups.

For women who are 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.

Rationale

No information available.


Others

The National Comprehensive Cancer Network provides specific criteria for genetic counseling and testing. The American Congress of Obstetricians and Gynecologists recommends genetic risk assessment for women who have more than a 20% to 25% risk for an inherited predisposition to breast and ovarian cancer and states that it may be helpful for patients with more than a 5% to 10% risk. The American Society of Clinical Oncology recommends genetic testing when there is personal or family history suggestive of genetic cancer susceptibility, the test can be adequately interpreted, and the results will aid in diagnosis or medical management of the patient or family member who has hereditary risk for cancer. It also recommends genetic testing only when pretest and posttest counseling are included. The National Society of Genetic Counselors has issued practice guidelines for risk assessment and genetic counseling for hereditary breast and ovarian cancer. It recommends that genetic testing should be offered to individuals with a personal or family history suggestive of an inherited cancer syndrome, when the test can be adequately interpreted, if testing will influence medical management of the patient or relative, when potential benefits outweigh potential risks, if testing is voluntary, and when the individual seeking testing or a legal proxy can provide informed consent. The European Society for Medical Oncology recommends that all patients who may be referred for BRCA testing should first complete informed consent and genetic counseling and patients who are mutation carriers should be encouraged to advise close family members to obtain genetic counseling. The Society of Gynecologic Oncologists recommends genetic risk assessment for individuals with a personal risk of more than approximately 20% to 25% for an inherited predisposition to cancer and states that it may be helpful for patients with more than approximately 5% to 10% risk. Genetic testing for cancer predisposition requires informed consent that should encompass pretest education and counseling about the risks, benefits, and limitations of testing, including the implications of both positive and negative genetic test results.


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