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Annals of Internal Medicine
Risk Assessment, Genetic Counseling, and Genetic Testing for
BRCA-Related Cancer in Women: U.S. Preventive Services Task
Force Recommendation Statement
Virginia A. Moyer, MD, MPH, on behalf of the U.S. Preventive Services Task Force*
Description: Update of the 2005 U.S. Preventive Services Task
ovarian, tubal, or peritoneal cancer with 1 of several screening tools Force (USPSTF) recommendation on genetic risk assessment and designed to identify a family history that may be associated with an BRCA mutation testing for breast and ovarian cancer susceptibility.
increased risk for potentially harmful mutations in breast cancersusceptibility genes (BRCA1 or BRCA2). Women with positive Methods: The USPSTF reviewed the evidence on risk assessment,
screening results should receive genetic counseling and, if indicated genetic counseling, and genetic testing for potentially harmful after counseling, BRCA testing. (B recommendation) BRCA mutations in asymptomatic women with a family history of The USPSTF recommends against routine genetic counseling or breast or ovarian cancer but no personal history of cancer or known BRCA testing for women whose family history is not associated potentially harmful BRCA mutations in their family. The USPSTF with an increased risk for potentially harmful mutations in the also reviewed interventions aimed at reducing the risk for BRCA- BRCA1 or BRCA2 genes. (D recommendation) related cancer in women with potentially harmful BRCA mutations,including intensive cancer screening, medications, and risk-reducingsurgery.
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Population: This recommendation applies to asymptomatic women
For author affiliation, see end of text.
who have not been diagnosed with BRCA-related cancer.
* For a list of the members of the USPSTF, see the Appendix (available at Recommendation: The USPSTF recommends that primary care
This article was published online first at on 24 December providers screen women who have family members with breast, The U.S. Preventive Services Task Force (USPSTF) makes BRCA2). Women with positive screening results should recommendations about the effectiveness of specific preventive receive genetic counseling and, if indicated after counsel- care services for patients without related signs or symptoms. It bases its recommendations on the evidence of both the The USPSTF recommends against routine genetic benefits and harms of the service and an assessment of the counseling or BRCA testing for women whose family his- balance. The USPSTF does not consider the costs of providing tory is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes. (D The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should See the Clinical Considerations section for additional understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes See the Figure for a summary of the recommendation
that policy and coverage decisions involve considerations in and suggestions for clinical practice.
addition to the evidence of clinical benefits and harms. SUMMARY OF RECOMMENDATIONS AND EVIDENCE
The USPSTF recommends that primary care providers screen women who have family members with breast, ovar- ian, tubal, or peritoneal cancer with 1 of several screening Related article. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Summary for Patients . . . . . . . . . . . . . . . . . . . . . . . . . 2 tools designed to identify a family history that may beassociated with an increased risk for potentially harmful Web-Only
mutations in breast cancer susceptibility genes (BRCA1 or Annals of Internal Medicine
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Clinical Guideline Risk Assessment and Genetic Testing for BRCA-Related Cancer in Women Figure. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: clincal summary of U.S.
Preventive Services Task Force recommendation.
RISK ASSESSMENT, GENETIC COUNSELING, AND GENETIC TESTING
FOR BRCA-RELATED CANCER IN WOMEN
CLINICAL SUMMARY OF U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATION
Population
Women who have not been diagnosed with BRCA-related cancer and who have no signs or symptoms of the disease Screen women whose family history may be associated with an increased risk for potentially harmful BRCA mutations. Do not routinely recommend genetic counseling or BRCA Women with positive screening results should testing to women whose family history is not associated with Recommendation
receive genetic counseling and, if indicated after an increased risk for potentially harmful 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, family history of breast and ovarian cancer, presence of breast cancer in ≥1 male family member, multiple cases of breast cancer in the family, ≥1 family member with 2 primary Risk Assessment
types of BRCA-related cancer, and Ashkenazi Jewish ethnicity.
Several familial risk stratification tools are available to determine the need for in-depth genetic counseling, such as the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Genetic risk assessment and BRCA mutation testing are generally multistep processes involving identification of women who may be at increased risk for potentially harmful mutations, followed by genetic counseling by suitably trained health care Screening Tests
providers and genetic testing of selected high-risk women when indicated.
Tests for BRCA mutations are highly sensitive and specific for known mutations, but interpretation of results is complex and generally requires posttest counseling.
Interventions in women who are BRCA mutation carriers include earlier, more frequent, or intensive cancer screening; Treatment
risk-reducing medications (e.g., tamoxifen or raloxifene); and risk-reducing surgery (e.g., mastectomy or In women whose family history is associated with an In women whose family history is not associated with an Balance of Benefits and
increased risk for potentially harmful BRCA mutations, increased risk for potentially harmful BRCA mutations, the the net benefit of genetic testing and early net benefit of genetic testing and early intervention ranges Other Relevant USPSTF
The USPSTF has made recommendations on medications for the reduction of breast cancer risk and screening for ovarian Recommendations
cancer. These recommendations are available at www.uspreventiveservicestaskforce.org.
For a summary of the evidence systematically reviewed in making this recommendation, the full recommendation statement, and supporting documents, please go to www.uspreventiveservicestaskforce.org.
Appendix Table 1 describes the USPSTF grades, and
will develop breast cancer during their lifetime and 2.74% Appendix Table 2 describes the USPSTF classification of
will die of the disease, whereas 1.4% of women will de- levels of certainty about net benefit (both tables are avail- velop ovarian cancer and 1.0% will die of the disease (2). A woman’s risk for breast cancer increases to 45% to 65% byage 70 years if there are clinically significant mutations in RATIONALE
either BRCA gene (3, 4). Mutations in the BRCA1 gene Importance
increase ovarian cancer risk to 39% by age 70 years, and The cancer types related to potentially harmful muta- BRCA2 mutations increase ovarian cancer risk to 10% to tions of the BRCA genes are predominantly breast, ovar- 17% by age 70 years (3, 4). In the general population, ian, and fallopian tube cancer, although other types are also these mutations occur in an estimated 1 in 300 to 500 associated (1). In the general population, 12.3% of women women (0.2% to 0.3%) (5– 8). In a meta-analysis con- www.annals.org
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Risk Assessment and Genetic Testing for BRCA-Related Cancer in Women Clinical Guideline ducted for the USPSTF, the combined prevalence of or ovarian cancer. Some women receive genetic testing as BRCA1 and BRCA2 mutations was 2.1% in a general pop- part of a cancer evaluation at the time of diagnosis of breast ulation of Ashkenazi Jewish women (9).
cancer. The USPSTF did not review the appropriate use of Detection of Potentially Harmful BRCA Mutations
BRCA testing in the evaluation of women who are newly Genetic risk assessment and BRCA mutation testing diagnosed with breast cancer. That assessment is part of is generally a multistep process involving identification of disease management and is beyond the scope of this individuals who may be at increased risk for potentially recommendation. Women who have been diagnosed with harmful mutations, followed by genetic counseling from breast cancer in the past and who did not receive BRCA suitably trained health care providers and genetic testing of testing as part of their cancer care but have a family history selected high-risk individuals when indicated. Several fa- of breast or ovarian cancer should be encouraged to discuss milial risk stratification tools are clinically useful for select- further evaluation with their clinician.
ing patients who should be offered genetic counseling to These recommendations do not apply to men, al- further determine their candidacy for possible BRCA mu- though male family members may be identified for testing Benefits of Testing for Potentially Harmful
Family History Screening and Risk Assessment
BRCA Mutations
Mutations in the BRCA genes cluster in families, ex- For women whose family history is associated with an hibiting an autosomal dominant pattern of transmission in increased risk for potentially harmful mutations in the maternal or paternal lineage. During standard elicitation of BRCA1 or BRCA2 genes, adequate evidence suggests that family history information from patients, primary care pro- the benefits of testing for potentially harmful BRCA mu- viders should ask about specific types of cancer, primary cancer sites, which family members were affected, relatives For women whose family history is not associated with with multiple types of primary cancer, and the age at di- an increased risk for potentially harmful mutations in the agnosis and sex of affected family members.
BRCA1 or BRCA2 genes, there is adequate evidence that For women who have at least 1 family member with the benefits of testing for potentially harmful BRCA mu- breast, ovarian, or other types of BRCA-related cancer, pri- mary care providers may use 1 of several brief familial risk Harms of Detection of Potentially Harmful BRCA
stratification tools to determine the need for in-depth ge- Mutations and Early Intervention and Treatment
Adequate evidence suggests that the overall harms of Although several risk tools are available, the tools eval- detection of and early intervention for potentially harmful uated by the USPSTF include the Ontario Family History BRCA mutations are small to moderate.
Assessment Tool (Table 1), Manchester Scoring System
(Table 2), Referral Screening Tool (Table 3), Pedigree As-
USPSTF Assessment
sessment Tool (Table 4), and FHS-7 (Table 5) (10 –19).
For women whose family history is associated with an The Referral Screening Tool (available at increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes, there is moderate certainty that est to administer. All of these tools seem to be clinically the net benefit of testing for potentially harmful BRCA useful predictors of which women should be referred for mutations and early intervention is moderate.
genetic counseling due to increased risk for potentially For women whose family history is not associated with harmful BRCA mutations (most sensitivity estimates were an increased risk for potentially harmful mutations in the Ͼ85%), although some models have been evaluated in BRCA1 or BRCA2 genes, there is moderate certainty that only 1 study (9, 20). To determine which patients would the net benefit of testing for potentially harmful BRCA benefit from BRCA risk assessment, primary care providers mutations and early intervention ranges from minimal to should not use general breast cancer risk assessment models (for example, the National Cancer Institute Breast CancerRisk Assessment Tool, which is based on the Gail model) CLINICAL CONSIDERATIONS
because they are not designed to determine which women Patient Population Under Consideration
should receive genetic counseling or BRCA testing.
This recommendation applies to asymptomatic women In general, these tools elicit information about factors who have not been diagnosed with BRCA-related cancer.
that are associated with increased likelihood of BRCA mu- Women who have 1 or more family members with a tations. Family history factors associated with increased known potentially harmful mutation in the BRCA1 or likelihood of potentially harmful BRCA mutations include BRCA2 genes should be offered genetic counseling and breast cancer diagnosis before age 50 years, bilateral breast cancer, presence of breast and ovarian cancer, presence of The USPSTF recognizes the potential importance of breast cancer in 1 or more male family members, multiple further evaluating women who have a diagnosis of breast cases of breast cancer in the family, 1 or more family mem- www.annals.org
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Clinical Guideline Risk Assessment and Genetic Testing for BRCA-Related Cancer in Women Table 1. Ontario Family History Assessment Tool*
Table 2. Manchester Scoring System*
Risk Factor
Risk Factor
BRCA1 Score
BRCA2 Score
Breast and ovarian cancer
Age at onset of female breast cancer†
Breast cancer relative
Age at onset of male breast cancer†
Breast cancer characteristics
Age at onset of ovarian cancer†
Pancreatic cancer
Age at onset of prostate cancer†
Ovarian cancer relative
* From reference 13. Developed so that a score of 10 in either column or acombined score of 15 for both columns would be equivalent to a 10% chance of Age at ovarian cancer onset
identifying a BRCA1 or BRCA2 mutation.
† For relatives in direct lineage.
Age at prostate cancer onset
BRCA Mutation Testing
Adequate evidence suggests that current genetic se- Age at colon cancer onset
quencing tests can accurately detect BRCA mutations.
Testing for BRCA mutations should be done only when an Family total
individual has personal or family history that suggests an inherited cancer susceptibility, when an individual has ac- cess to a health professional who is trained to provide ge- † Referral with a score of Ն10 corresponds to doubling of lifetime risk for breast netic counseling and interpret test results, and when test results will aid in decision making. Initial testing of a fam-ily member who has breast or ovarian cancer is the pre- bers with 2 primary types of BRCA-related cancer, and ferred strategy in most cases, but it is reasonable to test if Ashkenazi Jewish ethnicity. The USPSTF recognizes thateach risk assessment tool has limitations and found insuf-ficient comparative evidence to recommend one tool over Table 3. Referral Screening Tool*
another. The USPSTF also found insufficient evidence tosupport a specific risk threshold for referral for testing.
Risk Factor
Breast Cancer
Ovarian Cancer
at Age <50 y
at Any Age
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 com- prehensive genetic counseling. The process of genetic counseling includes detailed kindred analysis and risk as- sessment for potentially harmful BRCA mutations; educa- tion about the possible results of testing and their implica- Ն2 cases of breast cancer after age 50 y tions; 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 * From reference 16. A patient completes the checklist if she has a family history of breast or ovarian cancer and receives a referral if she checks Ն2 items.
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Risk Assessment and Genetic Testing for BRCA-Related Cancer in Women Clinical Guideline identify mutations in these families. Risk for breast cancer Table 4. Pedigree Assessment Tool*
is increased in women with uninformative-negativeresults (9).
Risk Factor
Score†
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 providersshould periodically assess all patients for changes in family * From reference 17. A score of Ն8 is the optimum referral threshold.
history (for example, comprehensive review at least every 5 For every family member with a breast or ovarian cancer diagnosis, including Interventions for Women Who Are BRCA
no affected relative is available. It is essential that before Mutation Carriers
testing, the individual is fully informed about the implica- Interventions that may reduce risk for cancer or tions of testing and has expressed a desire for it.
cancer-related death in women who are BRCA mutation The type of mutation analysis required depends on carriers include earlier, more frequent, or intensive cancer family history. Individuals from families with known mu- screening; risk-reducing medications (for example, tamox- tations or from ethnic groups in which certain mutations ifen or raloxifene); and risk-reducing surgery (for example, are more common (for example, Ashkenazi Jewish women) mastectomy or salpingo-oophorectomy). However, the can be tested for these specific mutations.
strength of evidence varies across the types of interventions.
Individuals without linkages to families or groups with Evidence is lacking on the effect of intensive screening known mutations receive more comprehensive testing. In for BRCA-related cancer on clinical outcomes in women these cases, when possible, testing should begin with a rel- who are BRCA mutation carriers. Medications, such as ative who has breast or ovarian cancer to determine tamoxifen and raloxifene, have been shown to reduce the whether affected family members have a clinically signifi- incidence of invasive breast cancer in high-risk women in the general population, but they have not been studied Tests for BRCA mutations are highly sensitive and specifically in women who are BRCA mutation carriers specific for known mutations, but interpretation of results is complex and generally requires posttest counseling. Test In high-risk women and those who are BRCA muta- results for genetic mutations are reported as positive (that tion carriers, cohort studies of risk-reducing surgery is, potentially harmful mutation detected), variants of un- (mastectomy and salpingo-oophorectomy) showed sub- certain clinical significance, uninformative-negative, or stantially reduced risk for breast or ovarian cancer. Breast true-negative. Women who have relatives with known cancer risk was reduced by 85% to 100% with mastectomy BRCA mutations can be reassured about their inherited (27–29) and by 37% to 100% with oophorectomy, and risk for a potentially harmful mutation if the results are ovarian cancer risk was reduced by 69% to 100% with negative (that is, a true negative). Some studies suggest oophorectomy or salpingo-oophorectomy (26). Salpingo- increased breast cancer risk in some women with true- oophorectomy was also associated with a 55% relative re- negative results (21–24). However, a comprehensive meta- duction in all-cause mortality (as measured during the analysis conducted for the USPSTF that included these course of the study) in women with BRCA1 or BRCA2 studies found that breast cancer risk is generally not in- mutations and without a history of breast cancer (27).
creased in women with true-negative results (9). Anuninformative-negative result occurs when a woman’s test Other Approaches to Prevention
does not detect a potentially harmful mutation but no rel- The USPSTF recommendations on medications for atives have been tested or no mutations have been detected breast cancer risk reduction are available on the USPSTF in tested relatives. Available tests may not be able to The USPSTF recommends against screening for ovarian cancer in women. This recommendation does not Table 5. FHS-7*
apply to women with known genetic mutations that in-crease their risk for ovarian cancer (for example, BRCA Did any of your first-degree relatives have breast or ovarian cancer? Did any of your relatives have bilateral breast cancer?Did any man in your family have breast cancer? Useful Resources
Did any woman in your family have breast and ovarian cancer?Did any woman in your family have breast cancer before age 50 y? The National Cancer Institute Cancer Genetics Do you have 2 or more relatives with breast and/or ovarian cancer? Services Directory provides a list of professionals who Do you have 2 or more relatives with breast and/or bowel cancer? offer services related to cancer genetics, including cancer * From reference 18. One positive response initiates referral.
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Clinical Guideline Risk Assessment and Genetic Testing for BRCA-Related Cancer in Women Ovarian cancer is the fifth leading cause of cancer death in women in the United States (31), accounting foran estimated 22 240 new cases and 14 030 deaths in 2013(33). According to lifetime risk estimates for the general OTHER CONSIDERATIONS
population, 1.4% of women will develop ovarian cancer Although some studies have reported that women pre- during their lives and 1.0% will die of it (2).
fer in-person genetic counseling, telephone- or computer- Estimates of the prevalence of potentially harmful based counseling may be considered for women who BRCA mutations vary by population. The estimated prev- would not otherwise have access to these services.
alence is 0.2% to 0.3% in the general population of Research Needs and Gaps
women (5– 8), 6.0% in women with cancer onset before Research on risk assessment and testing for BRCA mu- age 40 years (8, 34, 35), and 2.1% in the general popula- tations has focused on short-term outcomes for highly se- tion of Ashkenazi Jewish women (36 –39). In a meta- lected women in referral centers. Additional studies are analysis of studies in which recruitment was based on fam- needed, including comparative effectiveness trials of ap- ily history of breast or ovarian cancer, BRCA1 mutation proaches to risk screening and strategies to improve access prevalence was 13.6%, BRCA2 mutation prevalence was to genetic counseling and BRCA testing for high-risk 7.9%, and prevalence of either mutation was 19.8% (9).
Scope of Review
Another unresolved question is what specific training This recommendation applies to women who have is needed (for persons other than trained genetic counsel- no signs or symptoms of BRCA-related cancer. For its ors) to provide genetic counseling. It would be helpful to updated evidence review, the USPSTF considered risk understand which methods of delivery of genetic counsel- assessment, genetic counseling, and genetic testing for po- ing are most effective, including those that can increase tentially harmful BRCA1 or BRCA2 mutations in asymp- access to genetic counseling in rural or other settings. Trials tomatic women with a family history of breast or ovarian comparing types of providers and protocols could address cancer but no personal history of cancer or known poten- tially harmful BRCA mutations in their family. The What happens after patients are identified as high-risk USPSTF also reviewed interventions aimed at reducing the in clinical settings is unknown. The consequences of ge- risk for BRCA-related cancer in women with potentially netic testing for individuals and their relatives require more harmful BRCA mutations, including intensive cancer study. Well-designed investigations using standardized screening (for example, earlier and more frequent mam- measures and diverse study populations are needed.
mography or magnetic resonance imaging of the breast), An expanded database or registry of patients receiving medications (for example, tamoxifen or raloxifene), and genetic counseling for inherited breast and ovarian cancer risk-reducing surgery (for example, mastectomy or oopho- susceptibility or who are tested for BRCA mutations would rectomy). Studies about patients with current or past breast provide useful information about predictors of cancer or ovarian cancer were excluded unless they were designed and response to interventions. Additional data are needed to address screening issues in women without cancer (for from women of varying socioeconomic, racial, and ethnic example, retrospective or case– control studies).
For women who are mutation carriers, studies about Accuracy of Familial Risk Assessment
the effectiveness of intensive cancer screening and risk- The USPSTF reviewed several tools that could be used reducing medications and the effects of age at intervention in primary care settings to predict individual risk for breast on improving long-term outcomes are needed. This re- cancer and potentially harmful BRCA mutations.
search would increase knowledge of the relative benefits Tools specifically designed to determine risk for and harms of interventions that are provided on the basis BRCA-related cancer are primarily intended for use by nongeneticist health care providers to guide referral to ge-netic counselors for more definitive evaluation. Modelsthat have been validated in studies include the Ontario DISCUSSION
Family History Assessment Tool (Table 1), Manchester
Burden of Disease
Scoring System (Table 2), Referral Screening Tool (Table
Breast cancer is the second most common cancer in 3), Pedigree Assessment Tool (Table 4), and FHS-7 (Table
women in the United States and is the second leading 5) (10 –19). In general, these tools elicit information about
cause of cancer death (30, 31). In 2013, an estimated factors associated with increased likelihood of BRCA mu- 232 340 women in the United States will be diagnosed tations. They are clinically useful predictors of which with breast cancer and 39 620 women will die of the dis- women should be referred for genetic counseling because ease (32). According to lifetime risk estimates for the gen- of increased risk for potentially harmful BRCA mutations eral population, 12.3% of women will develop breast can- (most sensitivity estimates were Ͼ85%), although some cer during their lives and 2.74% will die of it (2).
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Risk Assessment and Genetic Testing for BRCA-Related Cancer in Women Clinical Guideline USPSTF recognizes that each risk assessment tool has lim- per 1000 women for raloxifene (2 trials), assuming 5 years itations and found insufficient evidence to recommend one of treatment. Selective estrogen receptor modulators do not reduce risk for estrogen receptor–negative breast cancer,which includes 69% of breast cancer cases associated with Accuracy of BRCA Mutation Testing
BRCA1 mutations and 16% associated with BRCA2 The type of mutation analysis done depends on family history. Individuals from families with known mutations In cohort studies of high-risk women and those who or from ethnic groups with common mutations (for exam- are BRCA mutation carriers, risk-reducing surgery (for ex- ple, Ashkenazi Jewish women) can be tested specifically for ample, mastectomy or salpingo-oophorectomy) substan- these mutations. The sensitivity and specificity of analysis tially reduced risk for breast or ovarian cancer. Mastectomy techniques are measured by individual clinical laboratories reduced breast cancer risk by 85% to 100%, and oopho- and are not publicly available. Individuals without linkages rectomy or salpingo-oophorectomy reduced ovarian cancer to families or groups with known mutations receive more risk by 69% to 100% and breast cancer risk by 37% to comprehensive testing. In these cases, guidelines recom- 100% (9). In 1 fair-quality prospective cohort study (27), mend initial testing of a relative with known breast or salpingo-oophorectomy was also associated with a 55% rel- ovarian cancer, when possible, to check for the presence of ative reduction in all-cause mortality (as measured during the course of the study) in women with BRCA1 and Effectiveness of BRCA Mutation Testing and Early
BRCA2 mutations without a history of breast cancer.
Detection and Treatment
Breast cancer risk reduction associated with oophorectomy To understand the potential benefits and harms of was more pronounced in women who were premenopausal genetic counseling, the USPSTF reviewed 18 studies (40 – 57) published since its previous review. Studies generallyreported positive (or no negative) psychological effects, in- Potential Harms of Cancer Screening and Treatment
creased accuracy of risk perception, or decreased intention Intensive screening for breast and ovarian cancer is associated with false-positive results, unnecessary imaging, Genetic counseling significantly decreased breast can- and unneeded surgery. In 2 studies comparing mammog- cer worry in 8 studies (44 – 46, 48, 50, 53–55). Three raphy with magnetic resonance imaging for breast cancer studies (41, 44, 49) reported decreased or no changes in screening in which 18% to 100% of study participants general anxiety and depression after genetic counseling, were BRCA mutation carriers, mammography was associ- whereas other studies found no significant differences in ated with higher false-positive rates (14% vs. 5.5% in the anxiety scores (48, 50). However, 1 of these studies noted first round of screening; P Ͻ 0.001 [68]; 15% vs. 11% in an increase in state anxiety scores after genetic counseling another study [69]) and more false-negative results (12 vs.
(44). Eight studies published since 2004 reported im- 1 case in the first round of screening; 12 vs. 4 cases in proved accuracy of risk perception after genetic counseling subsequent rounds [68]). In a retrospective analysis of a (41, 42, 44 – 47, 49, 50, 52). Two studies reported de- cohort of women with potentially harmful BRCA muta- creased intention to have genetic testing after genetic coun- tions or first-degree relatives with BRCA mutations, those who were screened with mammography were more likely Interventions that may reduce risk for cancer in to have unneeded imaging than those who were screened women who are BRCA mutation carriers include: earlier, with magnetic resonance imaging; however, rates of un- more frequent, or intensive cancer screening; use of selective estrogen receptor modulators as risk-reducing Risk-reducing medications (for example, tamoxifen or medications (for example, tamoxifen or raloxifene); and raloxifene) can increase risk for thromboembolic events (4 risk-reducing surgery (for example, mastectomy or to 7 events per 1000 women over 5 years). Tamoxifen increased the risk for endometrial cancer (4 to 5 cases per Evidence is lacking on the effect of intensive screening 1000 women) compared with placebo or raloxifene, and it for BRCA-related cancer on clinical outcomes in women also increased risk for cataracts (15 per 1000 women) com- Selective estrogen receptor modulators reduced the in- Data on the long-term physical harms of risk-reducing cidence of invasive breast cancer in several randomized, mastectomy are limited. In high-risk women having risk- controlled trials (58 – 64), although clinical trials of tamox- reducing mastectomy with immediate reconstruction, 21% ifen and raloxifene have not been conducted specifically in in 1 series had complications (for example, hematoma, women who are BRCA mutation carriers. In a meta- contracture, or implant rupture) (70). In another series, analysis of trials published to date (26, 65), tamoxifen and 64% reported postsurgical symptoms (for example, numb- raloxifene reduced the incidence of estrogen receptor– ness, pain, tingling, infection, swelling, breast hardness, positive invasive breast cancer, with 7 fewer events per bleeding, organizing hematoma, failed reconstruction, 1000 women for tamoxifen (4 trials) and 9 fewer events breathing problems, thrombosis, and pulmonary embo- www.annals.org
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Clinical Guideline Risk Assessment and Genetic Testing for BRCA-Related Cancer in Women lism) (71). After risk-reducing oophorectomy, 5% of Response to Public Comments
women in 1 study had postsurgical complications (for ex- A draft version of this recommendation statement was ample, wound infection, bladder or uterine perforation, or posted for public comment on the USPSTF Web site from 2 April through 29 April 2013. In response to comments, Seven observational studies provided data on psycho- the USPSTF clarified that this recommendation statement logical distress due to risk-reducing mastectomy (71, 73– applies to women. It also expanded the recommendation to 76) or oophorectomy (25, 77). In 1 study of 90 women include women who have family members with tubal or who had risk-reducing bilateral mastectomy (73, 74), there peritoneal (in addition to breast or ovarian) cancer. The were significant reductions in scores for anxiety and sexual USPSTF clarified that it recognizes the potential impor- pleasure and no significant differences in depression scores, tance of further evaluating women who have a diagnosis of body image concerns, or other measures. In another study breast or ovarian cancer; however, that assessment is part (75), there were no significant differences in psychological of disease management and is beyond the scope of this measures between women who had risk-reducing mastec- tomy and a reference sample that did not have the proce- The USPSTF added that it found insufficient evidence dure. Ten years after risk-reducing mastectomy, most to recommend one risk assessment tool over another or to women in another study reported that their family lives support a specific risk threshold for referral for genetic were unchanged, but 39% reported negative effects on counseling and BRCA testing. It also added a compilation spousal relationships because of decreased sensation and of risk assessment tools (Tables 1 to 5). Although the pre-
changed body appearance (76). After risk-reducing ferred BRCA testing strategy is initial testing of a family salpingo-oophorectomy, premenopausal women reported member with breast or ovarian cancer, the USPSTF clari- significant worsening of vasomotor symptoms and de- fied that it is reasonable to start testing in an unaffected individual if no affected relative is available. Because of thecomplexity of BRCA test results, the USPSTF also suggests Estimate of Magnitude of Net Benefit
posttest counseling. It also clarified and updated informa- For women whose family history is associated with an tion on BRCA testing, other resources, and recommenda- increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes, the USPSTF found adequate ev-idence that the benefits of testing, detection, and early in-tervention are moderate. For women whose family history UPDATE OF PREVIOUS USPSTF RECOMMENDATION
is not associated with an increased risk for potentially In 2005, the USPSTF recommended that women harmful mutations in the BRCA1 or BRCA2 genes, the whose family history is associated with an increased risk for USPSTF found adequate evidence that the benefits of test- potentially harmful mutations in the BRCA1 or BRCA2 ing, detection, and early intervention are few to none. The genes be referred for genetic counseling and evaluation for USPSTF found adequate evidence that the overall harms BRCA testing. It also recommended against routine refer- of testing, detection, and early intervention are small to ral for genetic counseling or routine BRCA testing for women whose family history is not associated with an in- For women whose family history is associated with an creased risk for potentially harmful mutations in the increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes (78).
BRCA1 or BRCA2 genes, the USPSTF concludes with moderate certainty that the net benefit of testing, detec- USPSTF’s previous recommendation. Since 2005, family tion, and early intervention is moderate. For women whose history risk stratification tools have been developed and family history is not associated with an increased risk for validated for use in primary care practice to guide referral potentially harmful mutations in the BRCA1 or BRCA2 for BRCA genetic counseling (Tables 1 to 5). In addition,
genes, the USPSTF concludes with moderate certainty that the potential benefits and harms of medications for breast the net benefit of testing, detection, and early intervention cancer risk reduction have been studied for longer ranges from minimal to potentially harmful.
follow-up periods, and more information is available aboutthe potential psychological effects of genetic counseling How Does Evidence Fit With Biological Understanding?
The BRCA1 and BRCA2 genes are tumor suppressor genes. Mutations of these genes have been linked to hered-itary breast and ovarian cancer. Risks for breast, ovarian, RECOMMENDATIONS OF OTHER GROUPS
and other types of BRCA-related cancer are greatly in- The National Comprehensive Cancer Network pro- creased in patients who have inherited potentially harmful vides specific criteria for genetic counseling and testing (1).
BRCA1 or BRCA2 mutations. Genetic testing may identify The American Congress of Obstetricians and Gynecolo- such mutations. Several options are available to manage gists recommends genetic risk assessment for women who cancer risk in patients who are found to be mutation have more than a 20% to 25% risk for an inherited pre- disposition to breast and ovarian cancer and states that it www.annals.org
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Risk Assessment and Genetic Testing for BRCA-Related Cancer in Women Clinical Guideline may be helpful for patients with more than a 5% to 10% syndromes - second edition. J Natl Cancer Inst Monogr. 2008:1-93. [PMID: risk (79). The American Society of Clinical Oncology rec- 18559331]
2. Howlader N, Noone AM, Krapcho M, Garshell J, Neyman N, Altekruse SF,
ommends genetic testing when there is personal or family et al, eds. SEER Cancer Statistics Review, 1975–2010. Bethesda, MD: National
history suggestive of genetic cancer susceptibility, the test Cancer Institute; 2013. Accessed at on 14 can be adequately interpreted, and the results will aid in diagnosis or medical management of the patient or family 3. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al.
Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2
member who has hereditary risk for cancer. It also recom- mutations detected in case series unselected for family history: a combined anal- mends genetic testing only when pretest and posttest coun- ysis of 22 studies. Am J Hum Genet. 2003;72:1117-30. [PMID: 12677558] seling are included (80). The National Society of Genetic 4. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance.
Counselors has issued practice guidelines for risk assess- J Clin Oncol. 2007;25:1329-33. [PMID: 17416853] ment and genetic counseling for hereditary breast and 5. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J ovarian cancer. It recommends that genetic testing should be offered to individuals with a personal or family history 6. Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF. Risk models
suggestive of an inherited cancer syndrome, when the test for familial ovarian and breast cancer. Genet Epidemiol. 2000;18:173-90.
can be adequately interpreted, if testing will influence med- [PMID: 10642429]
7. Antoniou AC, Pharoah PD, McMullan G, Day NE, Stratton MR, Peto J,
ical management of the patient or relative, when potential et al. A comprehensive model for familial breast cancer incorporating BRCA1,
benefits outweigh potential risks, if testing is voluntary, BRCA2 and other genes. Br J Cancer. 2002;86:76-83. [PMID: 11857015] and when the individual seeking testing or a legal proxy 8. Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, et al. Prevalence
can provide informed consent (81). The European Society of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.
J Natl Cancer Inst. 1999;91:943-9. [PMID: 10359546] for Medical Oncology recommends that all patients who 9. Nelson HD, Fu R, Goddard K, Priest Mitchell J, Okinaka-Hu L, Pappas M,
may be referred for BRCA testing should first complete et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-
informed consent and genetic counseling and patients who Related Cancer: Systematic Review to Update the U.S. Preventive Services Task are mutation carriers should be encouraged to advise close Force Recommendation. Evidence synthesis no. 101. AHRQ publication no.
family members to obtain genetic counseling (82). The 12-05164-EF-1. Rockville, MD: Agency for Healthcare Research and Quality;2013.
Society of Gynecologic Oncologists recommends genetic 10. Panchal SM, Ennis M, Canon S, Bordeleau LJ. Selecting a BRCA risk
risk assessment for individuals with a personal risk of more assessment model for use in a familial cancer clinic. BMC Med Genet. 2008;9: than approximately 20% to 25% for an inherited predis- position to cancer and states that it may be helpful for 11. Parmigiani G, Chen S, Iversen ES Jr, Friebel TM, Finkelstein DM, Anton-
Culver H, et al. Validity of models for predicting BRCA1 and BRCA2 muta-
patients with more than approximately 5% to 10% risk.
tions. Ann Intern Med. 2007;147:441-50. [PMID: 17909205] Genetic testing for cancer predisposition requires informed 12. Oros KK, Ghadirian P, Maugard CM, Perret C, Paredes Y, Mes-Masson
consent that should encompass pretest education and AM, et al. Application of BRCA1 and BRCA2 mutation carrier prediction mod-
counseling about the risks, benefits, and limitations of test- els in breast and/or ovarian cancer families of French Canadian descent. ClinGenet. 2006;70:320-9. [PMID: 16965326] ing, including the implications of both positive and nega- 13. Evans DG, Eccles DM, Rahman N, Young K, Bulman M, Amir E, et al. A
new scoring system for the chances of identifying a BRCA1/2 mutation outper-forms existing models including BRCAPRO. J Med Genet. 2004;41:474-80.
From the U.S. Preventive Services Task Force, Rockville, Maryland.
[PMID: 15173236]
14. Barcenas CH, Hosain GM, Arun B, Zong J, Zhou X, Chen J, et al.
Assessing BRCA carrier probabilities in extended families. J Clin Oncol. 2006;
Disclaimer: Recommendations made by the USPSTF are independent of
the U.S. government. They should not be construed as an official posi- 15. Antoniou AC, Hardy R, Walker L, Evans DG, Shenton A, Eeles R, et al.
tion of the Agency for Healthcare Research and Quality or the U.S.
Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of Department of Health and Human Services.
BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring systemusing data from UK genetics clinics. J Med Genet. 2008;45:425-31. [PMID: Financial Support: The USPSTF is an independent, voluntary body.
The U.S. Congress mandates that the Agency for Healthcare Research 16. Bellcross CA, Lemke AA, Pape LS, Tess AL, Meisner LT. Evaluation of a
and Quality support the operations of the USPSTF.
breast/ovarian cancer genetics referral screening tool in a mammography popula-
tion. Genet Med. 2009;11:783-9. [PMID: 19752737]
17. Hoskins KF, Zwaagstra A, Ranz M. Validation of a tool for identifying
Potential Conflicts of Interest: Disclosure forms from USPSTF
women at high risk for hereditary breast cancer in population-based screening.
Cancer. 2006;107:1769-76. [PMID: 16967460] 18. Ashton-Prolla P, Giacomazzi J, Schmidt AV, Roth FL, Palmero EI,
Kalakun L, et al. Development and validation of a simple questionnaire for the
Requests for Single Reprints: Reprints are available from the USPSTF
identification of hereditary breast cancer in primary care. BMC Cancer. 2009;9: 283. [PMID: 19682358]
19. Gilpin CA, Carson N, Hunter AG. A preliminary validation of a family
history assessment form to select women at risk for breast or ovarian cancer for
referral to a genetics center. Clin Genet. 2000;58:299-308. [PMID: 11076055]
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APPENDIX: U.S. PREVENTIVE SERVICES TASK FORCE
(Pima County Department of Health, Tucson, Arizona); Adelita Members of the U.S. Preventive Services Task Force at the Gonzales Cantu, RN, PhD (University of Texas Health Science time this recommendation was finalized† are Virginia A. Moyer, Center, San Antonio, Texas); David C. Grossman, MD, MPH MD, MPH, Chair (American Board of Pediatrics, Chapel Hill, (Group Health Cooperative, Seattle, Washington); Jessica Herz- North Carolina); Michael L. LeFevre, MD, MSPH, Co-Vice stein, MD, MPH (Air Products, Allentown, Pennsylvania); Chair (University of Missouri School of Medicine, Columbia, Wanda K. Nicholson, MD, MPH, MBA (University of North Missouri); Albert L. Siu, MD, MSPH, Co-Vice Chair (Mount Carolina School of Medicine, Chapel Hill, North Carolina); Sinai School of Medicine, New York, and James J. Peters Veter- Douglas K. Owens, MD, MS (Veterans Affairs Palo Alto Health ans Affairs Medical Center, Bronx, New York); Linda Ciofu Bau- Care System, Palo Alto, and Stanford University, Stanford, Cal- mann, PhD, RN (University of Wisconsin, Madison, Wiscon- ifornia); William R. Phillips, MD, MPH (University of Wash- sin); Kirsten Bibbins-Domingo, PhD, MD (University of ington, Seattle, Washington); and Michael P. Pignone, MD, California, San Francisco, San Francisco, California); Susan J.
MPH (University of North Carolina, Chapel Hill, North Curry, PhD (University of Iowa College of Public Health, Iowa City, Iowa); Mark Ebell, MD, MS (University of Georgia, Ath- † For a list of current Task Force members, go to ens, Georgia); Glenn Flores, MD (University of Texas South- western, Dallas, Texas); Francisco A.R. Garcı´a, MD, MPH Appendix Table 1. What the USPSTF Grades Mean and Suggestions for Practice
Definition
Suggestions for Practice
The USPSTF recommends the service. There is high certainty that the The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the netbenefit is moderate to substantial.
The USPSTF recommends selectively offering or providing this service Offer/provide this service for selected patients depending on individual to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the netbenefit is small.
The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harmsoutweigh the benefits.
The USPSTF concludes that the current evidence is insufficient to Read the Clinical Considerations section of the USPSTF Recommendation assess the balance of benefits and harms of the service. Evidence is Statement. If the service is offered, patients should understand the lacking, of poor quality, or conflicting, and the balance of benefits uncertainty about the balance of benefits and harms.
Appendix Table 2. USPSTF Levels of Certainty Regarding Net Benefit
Level of Certainty*
Description
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. Thisconclusion is therefore unlikely to be strongly affected by the results of future studies.
The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by such factors as: the number, size, or quality of individual studies;inconsistency of findings across individual studies;limited generalizability of findings to routine primary care practice; andlack of coherence in the chain of evidence.
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.
The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of: the limited number or size of studies;important flaws in study design or methods;inconsistency of findings across individual studies;gaps in the chain of evidence;findings that are not generalizable to routine primary care practice; anda lack of information on important health outcomes.
More information may allow an estimation of effects on health outcomes.
* The USPSTF 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 minusharm of the preventive service as implemented in a general primary care population. The USPSTF assigns a certainty level on the basis of the nature of the overall evidenceavailable to assess the net benefit of a preventive service.
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