Note: This draft Recommendation Statement is not the final recommendation of the U.S. Preventive Services Task Force. This draft is distributed solely for the purpose of pre-release review. It has not been disseminated otherwise by the USPSTF. It does not represent and should not be interpreted to represent a USPSTF determination or policy.
This draft Recommendation Statement is based on an Evidence Report that was also available for public comment. To read the accompanying draft Evidence Report on Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer, go to http://www.uspreventiveservicestaskforce.org/uspstf12/brcatest/brcatestdraftrep.htm.
The USPSTF makes recommendations about the effectiveness of specific clinical preventive services for patients without related signs or symptoms.
It bases its recommendations on the evidence of both the benefits and harms of the service, and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.
The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decisionmaking to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.
This draft Recommendation Statement was available for comment from April 2 until April 29, 2013, at 5:00 PM ET. A fact sheet that explains the draft recommendations in plain language is available here.
Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: U.S. Preventive Services Task Force Recommendation Statement
Summary of Recommendations and Evidence
The U.S. Preventive Services Task Force (USPSTF) recommends that primary care providers screen women who have family members with breast or ovarian cancer with one of several screening tools (see the Clinical Considerations) designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2). Women with a positive screen should receive genetic counseling and, if indicated after counseling, BRCA testing.
This is a B recommendation.
The USPSTF recommends against routine genetic counseling or routine BRCA testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes.
This is a D recommendation.
Cancer types related to potentially harmful mutations of the BRCA genes are predominantly breast, ovarian, and fallopian tube cancer, although other types are also associated. In the general population, 12.3% of women will develop breast cancer over their lifetime and 2.8% will die, while 1.4% will develop ovarian cancer and 1.0% will die. A woman's risk of breast cancer by age 70 years increases to 34% to 70% if there are clinically significant mutations in either of the BRCA genes (1). BRCA1 mutations increase ovarian cancer risk to 41% to 46% by age 70 years, and BRCA2 mutations increase risk to 17% to 23% (1). In the general population, these mutations are estimated to occur in 1 in 300 to 500 women (0.2% to 0.3%).
Genetic risk assessment and BRCA mutation testing is generally a multi-step process involving identification of individuals who may be at elevated risk for potentially harmful mutations, followed by genetic counseling by suitably trained health care providers and genetic testing of selected high-risk individuals when indicated. Several familial risk stratification tools can accurately identify patients for referral to genetic counseling to further determine their candidacy for possible BRCA mutation status testing.
Benefits of Testing for Potentially Harmful Mutations in the BRCA1 or BRCA2 Genes
For women whose family history is associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes, there is adequate evidence that the benefits of testing for harmful mutations in the BRCA1 or BRCA2 genes are moderate.
For women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes, there is adequate evidence that the benefits of testing for potentially harmful mutations in the BRCA1 or BRCA2 genes are few to none.
Harms of Detection and Early Intervention/Treatment
There is adequate evidence that the overall harms of detection and early intervention for potentially harmful BRCA mutations are small to moderate.
For women whose family history is associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes, there is moderate certainty that the net benefit of testing for potentially harmful mutations in the BRCA1 or BRCA2 genes and early intervention is moderate.
For women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes, there is moderate certainty that the net benefit of testing for potentially harmful mutations in the BRCA1 or BRCA2 genes and early intervention ranges from minimal to potentially harmful.
Patient Population Under Consideration
These recommendations apply to women who have not received a diagnosis of breast or ovarian cancer but who have family members with breast or ovarian cancer whose BRCA status is unknown. Women presenting to their primary care providers who have a relative with a known potentially harmful mutation in the BRCA1 or BRCA2 genes should receive genetic counseling and consideration for testing. These recommendations do not apply to men, although male family members may be identified for testing during the course of the evaluation.
Screening, Risk Assessment, and Testing
In the course of standard elicitation of family history information from patients, primary care providers should ask about specific types of cancer, which family members were affected, and the age and sex of affected family members.
For women who have positive family histories of breast or ovarian cancer, primary care providers may use one of several brief familial risk stratification tools to determine the need for in-depth genetic counseling. Although several risk tools are available, tools evaluated in published studies include: the Ontario Family History Assessment Tool (FHAT), Manchester scoring system, Referral Screening Tool (RST), Pedigree Assessment Tool (PAT), and FHS-7 (2-10). These tools are clinically useful predictors of which women should be referred for genetic counseling because of increased risk of potentially harmful BRCA mutations (c-statistics >0.80), though some models have only been evaluated in single studies (1). Primary care providers should not use general breast cancer risk assessment models (e.g., National Cancer Institute Breast Cancer Risk Assessment tool, based on the Gail model), because these are not designed to determine which women should receive genetic counseling or BRCA testing.
The RST and FHS-7 are particularly simple and quick to administer. In general, these tools elicit information about factors that are associated with increased likelihood of BRCA mutations. Some examples of family history factors associated with increased likelihood of potentially harmful BRCA mutations include: breast cancer diagnosis before age 50 years, bilateral breast cancer, history of both breast and ovarian cancer in the family and/or in the same person, presence of breast cancer in one or more male family members, multiple cases of breast cancer in the family, one or more family members with two primary BRCA-related cancers, and Ashkenazi Jewish background.
Genetic counseling regarding BRCA mutation testing may be performed by trained health professionals, including trained primary care providers. 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 surgeries for eligible patients; and followup counseling for interpretation of test results.
BRCA Mutation Testing
Testing for BRCA mutations should be done only when an individual has personal or family history features suggestive of inherited cancer susceptibility, access to a health professional trained to provide genetic counseling and interpret test results, and test results that will aid in decisionmaking. Initial testing of a family member diagnosed with breast or ovarian cancer is the preferred strategy in most cases. It is essential that prior to testing, the individual has been fully informed about the implications of testing and expressed a desire for testing. There is adequate evidence that current genetic sequencing tests can accurately detect BRCA mutations.
The type of mutation analysis required depends on family history. Individuals from families with known mutations or from ethnic groups in which certain mutations may be more common can be tested for these mutations specifically.
Individuals without linkages to families or groups with known mutations undergo direct deoxyribonucleic acid (DNA) sequencing. In these cases, when possible, testing should begin with a relative affected by breast or ovarian cancer to determine if affected family members may have a clinically significant mutation.
Tests for BRCA mutations are highly sensitive and specific for known mutations, but interpretation of results is complex. Tests for genetic mutations may result in positive (i.e., potentially harmful mutation detected), variants of uncertain clinical significance, uninformative negative, or true negative results. A woman who has relatives with cancer who have known potentially harmful mutations can be reassured about her inherited risk if her result is negative (i.e., a true negative). An uninformative negative result occurs if no potentially harmful mutations have been detected, but no relatives have identified mutations or no relatives have been tested.
Timing of Screening
Consideration of screening for potentially harmful BRCA1 and BRCA2 mutations should begin once women have reached the age of consent (age 18 years). Primary care providers should periodically assess all patients for changes in family history.
Interventions for BRCA1 and BRCA2 Mutation Carriers
Interventions that may reduce risk for cancer in BRCA mutation carriers include earlier, more frequent, or intensive cancer screening; use of risk-reducing medications (e.g., tamoxifen and raloxifene); and risk-reducing surgery (e.g., mastectomy and salpingo-oophorectomy). However, the strength of evidence varies across the types of interventions.
No trials of the effectiveness of intensive screening for BRCA-related cancers on clinical outcomes for women who are BRCA mutation carriers have been published. 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 have not been studied specifically in BRCA mutation carriers (11).
In high-risk women and mutation carriers, cohort studies of risk-reducing surgeries (mastectomy and salpingo-oophorectomy) showed substantially reduced risks for breast or ovarian cancer, with breast cancer reduced by 85% to 100% with mastectomy (12-14) and by 37% to 100% with oophorectomy, and ovarian cancer reduced by 69% to 100% with oophorectomy or salpingo-oophorectomy (1).
Other Approaches to Prevention
The USPSTF's recommendation on medications for breast cancer risk reduction is being updated.
The USPSTF recommends against screening for ovarian cancer in women.
The National Institutes of Health offers information about genetic testing and counseling (available at http://health.nih.gov/topic/GeneticTestingCounseling).
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. Issues requiring additional study include comparative effectiveness trials of screening approaches and access to genetic counseling and BRCA testing for individuals with high risk.
Another unresolved question is what specific training is needed (for persons other than trained genetic counselors) to provide genetic counseling. It would also be helpful to understand which methods for delivery of genetic counseling are most effective, including delivery methods that can increase access to genetic counseling from 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 not known; similarly, 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.
Regarding potential interventions for mutation carriers, comparative effectiveness studies of outcomes of more intensive screening strategies, the effectiveness of risk-reducing medications in mutation carriers, and the effects of age at intervention on long-term outcomes require further evaluation. This research would increase knowledge of the relative benefits and harms of interventions that are undertaken based on genetic risk information.
Burden of Disease
Breast cancer is the second most common cancer in women in the United States and is the second leading cause of cancer death (15, 16). In 2013, an estimated 232,340 women in the United States will be diagnosed with breast cancer and 39,620 women will die (17). According to lifetime risk estimates for the general population, 12.3% of women will develop breast cancer at some point during their lives and 2.8% will die from breast cancer (18).
Ovarian cancer is the fifth leading cause of cancer death among women in the United States (16), accounting for an estimated 22,240 new cases and 14,030 deaths in 2013 (19). According to lifetime risk estimates for the general population, 1.4% of women will develop ovarian cancer at some point during their lives and 1.0% will die from ovarian cancer (18).
Estimates of the prevalence of potentially harmful BRCA1 or BRCA2 mutations vary by population. Among women in general, the estimated prevalence is 0.2% to 0.3% (20-23); it is 6.0% among women with cancer onset prior to age 40 years (1) and 2.1% among a general population of Ashkenazi Jewish women (1). In a meta-analysis of studies in which recruitment was based on family history of breast or ovarian cancer, BRCA1 prevalence was 13.6%, BRCA2 prevalence was 7.9%, and prevalence of either mutation was 19.8% (1).
Scope of the Review
For this updated review, the USPSTF considered risk assessment, genetic counseling, and genetic testing for potentially harmful BRCA1 or BRCA2 mutations in asymptomatic adult women with a family history of breast and/or ovarian cancer but no personal history of cancer or known potentially harmful BRCA mutations in their families. The USPSTF also reviewed interventions aimed at reducing the risk of BRCA-related cancer among women with potentially harmful mutations, including intensive screening (e.g., earlier and more frequent mammography, breast magnetic resonance imaging [MRI]), use of medications (e.g., tamoxifen, raloxifene), and risk-reducing surgery (e.g., mastectomy, oophorectomy). Studies about patients with current or past breast or ovarian cancer were excluded unless they were designed to address screening issues in women without cancer (e.g., retrospective or case-control studies).
Accuracy of Risk Assessment
The USPSTF reviewed several tools that could be used in primary care settings to predict individual risk for breast cancer and potentially harmful BRCA mutations.
A recent systematic review included 19 studies of 13 general risk stratification tools to identify women at increased risk for breast cancer (24). Most of these tools are based on the Breast Cancer Risk Assessment Tool, also known as the Gail model. Most models are only modestly accurate predictors of breast cancer risk for individual women (concordance statistics of 0.55 to 0.65). This level of accuracy is usually considered inadequate for clinical purposes.
Familial risk stratification tools for BRCA-related cancer are primarily intended for use by nongeneticists to guide referrals to genetic counselors for more definitive evaluations. Models that have been validated in studies include the FHAT, Manchester scoring system, RST, PAT, and FHS-7 (2-10). In general, these tools elicit information about factors that are associated with increased likelihood of BRCA mutations. They are accurate predictors of which women should be referred for genetic counseling because of increased risk of potentially harmful BRCA mutations (c-statistics >0.80), though some models have only been evaluated in single studies (1).
Accuracy of Screening Tests
The type of mutation analysis performed depends on family history. Individuals from families with known mutations or from ethnic groups with common mutations (e.g., Ashkenazi Jewish heritage) can be tested specifically for these mutations. The sensitivity and specificity of analytic techniques are determined by the individual clinical laboratories and are not publicly available. Individuals without linkages to families or groups with known mutations undergo direct DNA sequencing. In these cases, guidelines recommend initial testing of a relative with known breast or ovarian cancer to check for the presence of clinically significant mutations. Most direct DNA sequencing in the United States is performed by one commercial laboratory, Myriad Genetic Laboratories, which reports analytic sensitivity and specificity both greater than 99% (25).
Effectiveness of Testing for Potentially Harmful BRCA Mutations and Early Detection and/or Treatment
To understand the potential benefits and harms of genetic counseling, the USPSTF reviewed 16 studies (26-38) published since its previous review. Studies generally reported positive (or no negative) psychological effects, increased accuracy of risk perception, and/or decreased intention to undergo genetic testing.
Genetic counseling significantly decreased breast cancer worry in seven studies (30-32, 34, 36). Three studies (27, 30, 35) reported significant decreases in anxiety and depression after genetic counseling, while other studies found no significant differences in anxiety scores (34, 36). Eight studies published since 2004 reported improved accuracy of risk perception after genetic counseling (27, 28, 30-33, 35, 36, 38). Two studies reported decreased intention to undergo genetic testing after genetic counseling (31, 32).
Interventions that may reduce risk for cancer in BRCA mutation carriers include:
- Earlier, more frequent, or intensive cancer screening
- Use of selective estrogen receptor modulators (SERMs) as risk-reducing medications (e.g., tamoxifen and raloxifene)
- Risk-reducing surgery (e.g., mastectomy and salpingo-oophorectomy)
No trials of the effectiveness of intensive screening for BRCA-related cancers on clinical outcomes for women who are BRCA mutation carriers have been published. However, the test performance characteristics of various screening modalities in this high-risk population have been reported. For breast cancer, MRI was more sensitive than mammography (71%–77% vs. 40%–41%), with comparable specificity (81%–90% vs. 93%–95%) (39, 40). For ovarian cancer, transvaginal ultrasonography was less sensitive than serum cancer antigen (CA)-125 measurement (43% vs. 71%), with similarly high specificity (99%) (41).
SERMs have reduced the incidence of invasive breast cancer in several randomized, controlled trials (42-48). In a meta-analysis (49) of trials published to date, both tamoxifen and raloxifene reduced the incidence of estrogen receptor (ER)-positive invasive breast cancer, with 7 fewer events per 1,000 women for tamoxifen (four trials) and 9 fewer events per 1,000 women for raloxifene (two trials), assuming 5 years of treatment. Compared to placebo, raloxifene also reduced the incidence of vertebral fractures by 7 events per 1,000 women (two trials), while tamoxifen reduced the incidence of nonvertebral fractures by 3 events per 1,000 women (one trial) (48). However, clinical studies of tamoxifen and raloxifene have not been conducted specifically in BRCA mutation carriers. SERMs would not reduce risks for ER-negative breast cancer, which includes 78% of breast cancers associated with BRCA1 mutations and 23% associated with BRCA2 mutations (50).
In cohort studies of high-risk women and BRCA mutation carriers, risk-reducing surgeries (e.g., mastectomy and salpingo-oophorectomy) substantially reduced risks for breast or ovarian cancer. Mastectomy reduced breast cancer risks by 85% to 100%, and oophorectomy or salpingo-oophorectomy reduced ovarian cancer risks by 69% to 100% and breast cancer risks by 37% to 100% (1).
Potential Harms of Screening and Treatment
Intensive screening for breast and ovarian cancer is associated with false-positive results, unnecessary imaging, and unneeded surgeries. In two studies comparing MRI to mammography for breast cancer screening in which 18% to 100% of study participants were BRCA mutation carriers, mammography was associated with higher false-positive rates (14% vs. 5.5% in first round of screening [p<0.001] ; 15% vs. 11% in another study ) and more false-negative results [12 vs. 1 case in first round of screening; 12 vs. 4 cases in subsequent rounds ). In a retrospective analysis of a cohort of women with potentially harmful BRCA mutations or their first-degree relatives, women who were screened with mammography were more likely to undergo unneeded imaging; however, rates of unneeded biopsies were similar (52). Compared to mammography, however, MRI was associated with higher rates of unneeded breast biopsies (53) and recalls for further evaluation (11% vs. 3.9% per woman-year) (40). In the latter study, 245 of 279 recalls were for benign findings, amounting to 8.5 recalls per cancer detected (40). In one fair-quality prospective cohort study, discomfort, pain, and anxiety were similar among women undergoing intensive screening with annual mammography, MRI, or biannual clinical breast examinations (54).
Risk-reducing medications (e.g., tamoxifen and raloxifene) can increase risks for thromboembolic events (4–7 events per 1,000 women over 5 years). Tamoxifen increased endometrial cancer (4 to 5 cancer cases per 1,000 women) compared to placebo or raloxifene, as well as cataracts (15/1,000 compared to raloxifene) (23, 48).
Data are limited about the long-term physical harms of risk-reducing mastectomy. Among high-risk women undergoing risk-reducing mastectomy with immediate reconstruction, 21% in one series had complications (e.g., hematomas, contractures, or implant ruptures) (55); in another series, 64% reported post-surgical symptoms (e.g., numbness, pain, tingling, infection, swelling, breast hardness, bleeding, organizing hematoma, failed reconstruction, breathing problems, thrombosis, and pulmonary embolism) (56). After risk-reducing oophorectomy, 5% of women in one study experienced post-surgical complications (e.g., wound infection, bladder or uterine perforation, small bowel obstruction) (57).
Five observational studies provided data on psychological distress due to risk-reducing mastectomy (56, 58-61) or oophorectomy (62). In one study of 90 women who had risk-reducing bilateral mastectomy (58, 59), there were significant reductions in scores for both anxiety and sexual pleasure; there were no significant differences in depression scores, body image concerns, or other measures. In another study, there were no significant differences in psychological or sexual activity measures among women who were undergoing versus considering risk-reducing mastectomy (60). Ten years after risk-reducing mastectomy, the majority of women in another study reported that their family lives were unchanged, but 39% reported negative effects on spousal relationships due to decreased sensation and changed body appearance (61). After risk-reducing salpingo-oophorectomy, most women reported significant worsening of vasomotor symptoms and decreased sexual function (62).
Estimate of Magnitude of Net Benefit
For women whose family history is associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes, the USPSTF found adequate evidence that the benefits of testing for potentially harmful mutations in BRCA genes, detection, and early intervention are moderate. For women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes, the USPSTF found adequate evidence that the benefits of testing for potentially harmful mutations in BRCA genes, detection, and early intervention are few to none. The USPSTF found adequate evidence that the overall harms of testing, detection, and early intervention for potentially harmful BRCA mutations are small to moderate.
For women whose family history is associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes, the USPSTF concludes with moderate certainty that the net benefit of testing for potentially harmful mutations in BRCA genes, detection, and early intervention is moderate. For women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes, the USPSTF concludes with moderate certainty that the net benefit of testing, detection, and early intervention ranges from minimal to potentially harmful.
How Does Evidence Fit With Biological Understanding?
BRCA1 and BRCA2 are tumor suppressor genes. Mutations of these genes have been linked to hereditary breast and ovarian cancer. Risks for developing breast, ovarian, and other BRCA-related cancers are greatly increased in patients who have inherited potentially harmful BRCA1 or BRCA2 mutations. Genetic testing may identify potentially harmful BRCA1 and BRCA2 mutations. Several options are available to manage cancer risks in patients who are found to be mutation carriers.
Update of Previous USPSTF Recommendation
In 2005, the USPSTF recommended that women whose family history is associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing. The USPSTF also recommended against routine referral for genetic counseling or routine BRCA testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes (63).
This recommendation statement reaffirms the USPSTF's previous recommendation. Since 2005, family history risk stratification tools have been developed and validated for use in primary care practice to guide referrals for BRCA genetic counseling. The potential benefits and harms of medications for breast cancer risk reduction have been studied for longer followup periods. More information is available about the potential psychological impact of genetic counseling and risk-reducing surgeries.
Recommendations of Other Groups
The National Comprehensive Cancer Network provides specific criteria for genetic counseling and testing (64). The American Congress of Obstetricians and Gynecologists recommends genetic risk assessment for women who have more than a 20% to 25% chance of having an inherited predisposition to breast or ovarian cancer (65). The American Society of Clinical Oncology (ASCO) 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 members at hereditary risk of cancer. ASCO recommends genetic testing only when pre- and post-test counseling are included (66). The Evaluation of Genomic Applications in Practice and Prevention Working Group concluded in 2009 that there was insufficient evidence to support a recommendation for or against the use of genetic testing (67).
Table 1: What the Grades Mean and Suggestions for Practice
Table 2: Levels of Certainty Regarding Net Benefit
|Level of Certainty*||Description|
|High||The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies.|
|Moderate||The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by factors such as:
As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion.
|Low||The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of:
More information may allow an estimation of effects on health outcomes.
*The U.S. Preventive Services Task Force defines certainty as "likelihood that the USPSTF assessment of the net benefit of a preventive service is correct." The net benefit is defined as benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature of the overall evidence available to assess the net benefit of a preventive service.
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AHRQ Publication No. 12-05164-EF-2
Current as of April 2013
U.S. Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: Draft Recommendation Statement. AHRQ Publication No. 12-05164-EF-2. http://www.uspreventiveservicestaskforce.org/uspstf12/brcatest/draftrecbrcatest.htm