Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display key questions addressed by the review to allow the USPSTF to evaluate the effectiveness and harms of a preventive service. The questions are depicted by linkages that relate interventions to outcomes; a dashed line indicates a linkage that is known and not addressed by the evidence review. Refer to the USPSTF procedure manual for further details.36BRCA indicates breast cancer susceptibility gene.
aClinically significant pathogenic mutations in the BRCA1 and BRCA2 genes associated with increased risk for breast cancer, ovarian cancer, or both. bIncludes women who may have a previous diagnosis of breast or ovarian cancer but have completed treatment and are considered cancer-free. cDescriptions of genetic counseling, scope of services, and appropriate clinicians are described in the full report. dTesting may be conducted on the index patient, her relative with cancer, or her relative with highest risk, as appropriate. eIncludes interpretation of results, determination of eligibility for risk-reducing interventions, and patient decision-making. fInterventions include early detection through intensive screening, use of risk-reducing medications, and risk-reducing surgery when performed for prevention purposes.
BRCA indicates breast cancer susceptibility gene; KQ, key question.
aIncludes reference lists of relevant articles, studies, and systematic reviews; suggestions from reviewers.
bOne hundred three studies in 110 publications provided data; some addressed more than 1 KQ.
eMethods 1. Search Strategies
eMethods 2. Criteria for Assessing Internal Validity of Individual Studies
eTable 1. Inclusion and Exclusion Criteria
eTable 2. Studies of Distress After Genetic Testing
eTable 3. Studies of Test Characteristics of Mammography vs MRI for Breast Cancer Screening
eTable 4. Meta-analysis of Results of Placebo-controlled Trials of Risk-Reducing Medications—Benefits
eTable 5. Distress due to Intensive Screening for Breast Cancer among Mutation Carriers
eTable 6. Meta-Analysis of Results of Placebo-controlled Trials of Risk-Reducing Medications—Harms
eTable 7. Distress Related to Risk-Reducing Surgery
eTable 8. Quality Assessment of Diagnostic Accuracy Studies
eTable 9. Quality Assessment of Randomized Controlled Trials
eTable 10. Quality Assessment of Cohort Studies
eTable 11. Quality Assessment of Single Arm Cohort Studies
eTable 12. Quality Assessment of Case-Control Studies
eTable 13. Quality Assessment of Systematic Review
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Nelson HD, Pappas M, Cantor A, Haney E, Holmes R. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2019;322(7):666–685. doi:10.1001/jama.2019.8430
Pathogenic mutations in breast cancer susceptibility genes BRCA1 and BRCA2 increase risks for breast, ovarian, fallopian tube, and peritoneal cancer in women; interventions reduce risk in mutation carriers.
To update the 2013 US Preventive Services Task Force review on benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA1/2-related cancer in women.
Cochrane libraries; MEDLINE, PsycINFO, EMBASE (January 1, 2013, to March 6, 2019, for updates; January 1, 1994, to March 6, 2019, for new key questions and populations); reference lists.
Discriminatory accuracy studies, randomized clinical trials (RCTs), and observational studies of women without recently diagnosed BRCA1/2-related cancer.
Data Extraction and Synthesis
Data on study methods, setting, population characteristics, eligibility criteria, interventions, numbers enrolled and lost to follow-up, outcome ascertainment, and results were abstracted. Two reviewers independently assessed study quality.
Main Outcomes and Measures
Cancer incidence and mortality; discriminatory accuracy of risk assessment tools for BRCA1/2 mutations; benefits and harms of risk assessment, genetic counseling, genetic testing, and risk-reducing interventions.
For this review, 103 studies (110 articles; N = 92 712) were included. No studies evaluated the effectiveness of risk assessment, genetic counseling, and genetic testing in reducing incidence and mortality of BRCA1/2-related cancer. Fourteen studies (n = 43 813) of 8 risk assessment tools to guide referrals to genetic counseling demonstrated moderate to high accuracy (area under the receiver operating characteristic curve, 0.68-0.96). Twenty-eight studies (n = 8060) indicated that genetic counseling was associated with reduced breast cancer worry, anxiety, and depression; increased understanding of risk; and decreased intention for testing. Twenty studies (n = 4322) showed that breast cancer worry and anxiety were higher after testing for women with positive results and lower for others; understanding of risk was higher after testing. In 8 RCTs (n = 54 651), tamoxifen (relative risk [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials), and aromatase inhibitors (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials) were associated with lower risks of invasive breast cancer compared with placebo; results were not specific to mutation carriers. Mastectomy was associated with 90% to 100% reduction in breast cancer incidence (6 studies; n = 2546) and 81% to 100% reduction in breast cancer mortality (1 study; n = 639); oophorectomy was associated with 69% to 100% reduction in ovarian cancer (2 studies; n = 2108); complications were common with mastectomy.
Conclusions and Relevance
Among women without recently diagnosed BRCA1/2-related cancer, the benefits and harms of risk assessment, genetic counseling, and genetic testing to reduce cancer incidence and mortality have not been directly evaluated by current research.
Pathogenic mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are associated with increased risks for breast, ovarian, fallopian tube, and peritoneal cancer in women, breast cancer in men, and, to a lesser degree, pancreatic and early-onset prostate cancer1-6; BRCA2 is also associated with melanoma.3,4BRCA1/2 mutations cluster in families, exhibiting an autosomal dominant pattern of transmission in either the maternal or paternal lineage. Penetrance, the probability of developing cancer in BRCA1/2 mutation carriers, is variable, and many carriers never develop cancer.
BRCA1/2 mutations occur in 1 in 300 to 500 individuals in the general population7-10 and account for 5% to 10% of breast and 15% of ovarian cancer.7,11 Specific BRCA1/2 mutations, known as founder mutations, are clustered among certain groups, such as Ashkenazi Jews,12-14 among others. In general, breast cancer risk increases to 45% to 65% by age 70 years for pathogenic mutations in either the BRCA1 or the BRCA2 gene15,16; ovarian, fallopian tube, or peritoneal cancer risk increases to 39% for mutations in BRCA1 and 10% to 17% in BRCA2.15-23 Genetic counseling involves identifying and advising individuals at risk for inherited cancer susceptibility and is recommended before and after BRCA1/2 mutation testing.24-26 Accreditation standards outline essential training and skills for genetics professionals.27 Interventions to reduce risk for cancer in mutation carriers include earlier, more frequent, or intensive cancer screening; risk-reducing medications; and risk-reducing surgery, including mastectomy and salpingo-oophorectomy.
This report was used by the US Preventive Services Task Force (USPSTF) to update the 2013 recommendation on risk assessment, genetic counseling, and genetic testing for BRCA1/2-related cancer in women with clinically relevant family cancer histories (B recommendation) but not for women without family histories (D recommendation).28,29 This report focuses on BRCA1/2 mutations because they are more prevalent and penetrant than other types,4,30-32 estimates of associated cancer risk are available, and interventions to reduce risk for carriers have been studied.32-34
Detailed methods are available in the full evidence report at https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/brca-related-cancer-risk-assessment-genetic-counseling-and-genetic-testing1.35Figure 1 shows the analytic framework and key questions (KQs) that guided this review. Studies of male breast cancer, pancreatic cancer, prostate cancer, and melanoma are outside the scope of this review, although all types of cancer are considered during familial risk assessment. Ovarian, fallopian tube, and peritoneal carcinomas are overlapping epithelial malignancies in which the designation of the 3 primary sites is often arbitrary. For the purpose of this review, the 3 disease sites are collectively referred to as ovarian carcinoma. The screening population was expanded for this update to include women with unknown mutation status and either no previous diagnosis of BRCA1/2-related cancer or previous diagnosis but completion of cancer treatment.
The Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, Ovid EMBASE, and MEDLINE (January 1, 2013, to March 6, 2019, for updates; January 1, 1994, to March 6, 2019, for new KQs and populations) were searched for relevant English-language articles (eMethods 1 in the Supplement); reference lists were manually reviewed. Studies published before 2013 were identified from prior systematic reviews for the USPSTF.29,37
Investigators reviewed abstracts and full-text articles using prespecified eligibility criteria (eTable 1 in the Supplement).35,36 A second reviewer independently confirmed results of the initial review, and discrepancies were resolved by consensus with a third reviewer if needed.
Randomized clinical trials (RCTs), systematic reviews, prospective and retrospective cohort studies, case-control studies, and diagnostic accuracy evaluations that addressed KQs were eligible. These included studies of the accuracy of risk assessment tools (KQ2a), outcomes of genetic counseling and testing (KQ1, KQ2b, KQ2c, KQ2d), and effectiveness studies of interventions to reduce risk of BRCA1/2-related cancer among mutation carriers (KQ4). Interventions included intensive screening (earlier and more frequent mammography, breast magnetic resonance imaging [MRI], transvaginal ultrasound [TVUS], cancer antigen 125 [CA-125] levels), risk-reducing medications (tamoxifen, raloxifene, aromatase inhibitors), and risk-reducing surgery (mastectomy, salpingo-oophorectomy). Risk assessment tools were included only if they were intended for use by nonspecialists in genetics to guide referrals, such as the Pedigree Assessment Tool (PAT), and were applicable to US clinical settings. Evaluation of complex models used in genetic counseling was outside the scope of this review. Studies of any design were included to describe potential harms of risk assessment, genetic counseling, genetic testing, and risk-reducing interventions (KQ3, KQ5).
Studies that included women with histories of breast or ovarian cancer were excluded from the 2013 review. For this update, studies that included women who were diagnosed with breast or ovarian cancer at least 5 years before enrollment and completed cancer treatment were included to ensure that genetic testing was intended for risk reduction rather than treatment purposes. Studies that did not report the time since breast or ovarian cancer diagnosis were excluded.
For the included RCTs and observational studies, investigators abstracted data on study design; setting; population characteristics (including age, ethnicity, and diagnosis); eligibility criteria; interventions; numbers enrolled and lost to follow-up; method of outcome ascertainment; and results for each outcome. For studies of risk assessment tools, investigators abstracted data on study design; population characteristics; eligibility criteria; reference standards; risk factors included in the models; and performance measures of the models. A second investigator reviewed accuracy of abstracted data.
Two investigators independently applied criteria developed by the USPSTF36 to rate the quality of each study as good, fair, or poor (eMethods 2 and eTables in the Supplement). Discrepancies were resolved through a consensus process.
For all KQs, the overall quality of evidence was rated good, fair, or poor based on study quality, consistency of results, precision of estimates, study limitations, risk of reporting bias, and applicability, and summarized in a table.36 No statistical meta-analysis was performed.
For this review, 103 studies (110 articles; N = 92 712) were included (Figure 2)38-147: 14 discriminatory accuracy studies (n = 43 813), 15 RCTs (n = 4132), 59 cohort studies (n = 41 300), 2 case-control studies (n = 481), 12 before-and-after studies (n = 1372), and 1 systematic review (n = 1614).
Key Question 1. In women with unknown BRCA1/2 mutation status, does risk assessment, genetic counseling, and genetic testing result in reduced incidence of BRCA1/2-related cancer and cause-specific and all-cause mortality?
No studies were identified for KQ1.
Key Question 2a. What is the accuracy of familial risk assessment for BRCA1/2-related cancer when performed by a nonspecialist in genetics in a clinical setting? What are the optimal ages and intervals for risk assessment?
Fourteen discriminatory accuracy studies (n = 43 813) of 8 risk assessment tools met inclusion criteria (Table 1),38-51 including 4 new studies that evaluated existing tools.42,44,47,51 No studies evaluated optimal ages and intervals for risk assessment. Most studies used results of BRCA1/2 mutation testing as the reference standard, although 2 studies used clinical criteria that involved risk estimates from more complex risk assessment models.39,41
Risk assessment tools were developed to predict the likelihood of BRCA1/2 mutations in individuals and generally include variations of familial risk factors. These include BRCA1/2 mutations previously detected in relatives; Ashkenazi Jewish ancestry; numbers, ages, and types of relatives affected with breast or ovarian cancer; and presentations of cancer that are highly suggestive of BRCA1/2 mutations, such as male or bilateral breast cancer, breast and ovarian cancer in the same person, and young age (<50 years) at cancer onset. Risk assessment tools included initial and revised versions of the Ontario Family History Assessment Tool (FHAT), 7-question Family History Screening (FHS-7), Manchester Scoring System (MSS), PAT, Referral Screening Tool (RST), International Breast Cancer Intervention Study (IBIS) risk model, and brief versions of BRCAPRO, a complex statistical model typically used by genetic counselors.
Results of the 4 new studies42,44,47,51 were consistent with the 10 previous studies38-41,43,45,46,48-50 indicating moderate to high diagnostic accuracy of risk assessment tools in predicting BRCA1/2 mutations in individuals (area under the receiver operating characteristic curve [AUC], 0.68-0.96). A new study of a revised version of the MSS that integrated pathology data of the family member diagnosed with cancer47 reported a higher AUC than the previous version43,45,50,51 (0.80 [95% CI, 0.78-0.82] for revised MSS vs 0.77 [95% CI, 0.75-0.79] for previous MSS). In new validation studies, the discriminatory accuracy of referral tools was comparable to that of more complex tools for the PAT (AUC, 0.71 for PAT; 0.68 for Myriad II; 0.72 for Penn II)51 and IBIS (AUC, 0.75 [95% CI, 0.74-0.76] for IBIS; 0.79 [95% CI, 0.78-0.80] for the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA]; 0.80 [95% CI, 0.78-0.81] for BRCAPRO; 0.75 [95% CI, 0.73-0.76] for eClaus).44 In another new study, the accuracy of 3 brief versions of BRCAPRO followed by the full BRCAPRO if indicated was similar to using BRCAPRO alone (AUC, 0.78-0.79 for brief versions followed by full BRCAPRO; AUC, 0.78 [95% CI, 0.76-0.81] for full BRCAPRO alone).42
Key Question 2b. What are the benefits of pretest genetic counseling in determining eligibility for genetic testing for BRCA1/2-related cancer?
Twenty-eight studies (30 articles; n = 8060) were included (Table 2),52-81 including 1 new before-and-after study.52 The new study showed that agreement between a woman’s understanding of her breast cancer risk and her genetic counselor’s appraisal decreased 1 year after counseling compared with immediately after (49% agreement vs 35%) among 89 women in the Netherlands.52
Studies included in the previous review reported additional outcomes. Of 17 studies evaluating breast cancer worry, 1 reported increased measures after genetic counseling but only in women at high risk60; 8 reported decreases54,57,61,62,65,67,69,76; and 8 reported no associations.56,58,63,68,71,72,80,81 Some studies showed mixed results that varied by subgroup or type of counseling.55,60,61,71
Thirteen studies evaluated anxiety associated with genetic counseling; none reported increases, 5 reported decreases,58,60,62,77,78 and 8 reported no associations.54,64,68,69,73,76,80,81 Seven studies of depression also showed no increases in measures of depression, while 1 study indicated decreases78 and 6 reported no associations.54,58,64,73,76,80
Of 22 studies evaluating the association of genetic counseling with women’s understanding of their cancer risk, 14 reported increased understanding,57,58,60,62,63,65-68,72,74,77,78,80 1 reported decreased understanding,70 6 (including the new study) reported no associations,52,56,69,73,75,81 and 1 reported mixed results.64 Five studies evaluated the association of genetic counseling with intention for genetic testing; 1 study reported increased intention,71 4 reported decreased intention,57,60,63,67 and none reported no associations.
Key Question 2c. What are optimal testing approaches to determine the presence of pathogenic BRCA1/2 mutations in women at increased risk for BRCA1/2-related cancer?
A new good-quality RCT randomized 691 women and 343 men of Ashkenazi Jewish ancestry (4 grandparents) to population-based BRCA1/2 mutation testing vs family history–based testing in the United Kingdom.96 The detected prevalence of BRCA1/2 mutations among participants was 2.45% overall, with 13 BRCA1/2 carriers identified by population testing and 9 by family history. Over 3 years of follow-up, 210 of the 438 family history–negative participants opted to complete testing that identified an additional 5 carriers among family history–negative participants.96 Health outcomes related to increased detection, such as cancer incidence, mortality, and potential harms, were not determined. Short-term measures of anxiety, health anxiety, depression, distress, uncertainty, and quality of life were similar between testing groups.
Key Question 2d. What are optimal posttest counseling approaches to interpret results and determine eligibility for interventions to reduce risk of BRCA1/2-related cancer?
No studies were identified that specifically addressed posttest counseling.
Key Question 3a. What are adverse effects of risk assessment?
No studies were identified for KQ3a.
Key Question 3b. What are adverse effects of pretest genetic counseling?
Twenty-eight studies (30 articles; n = 8060) of pretest genetic counseling included for KQ2b (Table 2)52-81 were also included for KQ3b because the outcome measures were designed to indicate benefits or harms. Results indicated that counseling was not associated with increased breast cancer worry, anxiety, or depression as described above. Two studies indicated women have less understanding of their risks after genetic counseling,64,70 while 14 studies indicated increased understanding.57,58,60,62,63,65-68,72,74,77,78,80
Key Question 3c. What are adverse effects of genetic testing?
Twenty observational studies (22 articles; n = 4322), including 6 new studies82,89,93,95,96,102 and 14 (in 16 articles) from the 2013 review,83-88,90-92,94,97-101,103 met inclusion criteria (eTable 2 in the Supplement).82-95,97-104 Studies determined psychological effects of genetic testing for BRCA1/2-related cancer, measured as changes in worry, anxiety, depression, and understanding of risk. Two studies were not included in the 2013 review because they enrolled women previously treated for breast or ovarian cancer.82,102
Studies included cohort, case-control, and before-and-after designs that were small; lacked comparison groups; varied in methodology, enrollment criteria, and outcomes; and had high loss to follow-up. Results indicate that breast cancer worry and anxiety generally increased for women with positive results and decreased for others, although measures varied across studies. Understanding of risk improved after receiving test results.
Key Question 3d. What are adverse effects of posttest genetic counseling?
Key Question 4. Do interventions reduce the incidence of BRCA1/2-related cancer and mortality in women at increased risk?
No effectiveness trials of intensive screening for breast or ovarian cancer in BRCA1/2 mutation carriers that report cancer or mortality outcomes have been published. Studies of performance characteristics of intensive screening may be useful in clinical decision-making, but these studies do not directly address this key question. In 2 studies including 1364 BRCA1/2 mutation carriers, sensitivity of screening for breast cancer was 63% to 69% for MRI, 25% to 62% for mammography, and 66% to 70% for combined modalities; specificity was 91% or higher for either modality alone or combined (eTable 3 in the Supplement).148,149 In a study of 459 BRCA1/2 mutation carriers, sensitivity of screening for ovarian cancer was 43% for TVUS, 71% for CA-125, and 71% for combined modalities; specificity was 99% for either modality alone or combined.132
No trials of risk-reducing medications reported results specifically for BRCA1/2 mutation carriers. A systematic review and meta-analysis150 of 8 placebo-controlled RCTs (n = 54 651) of tamoxifen,151-154 raloxifene,155,156 and the aromatase inhibitors anastrozole157-159 and exemestane160,161 and a head-to-head trial of tamoxifen vs raloxifene (n = 19 747)162 provide efficacy outcomes for women at various risk levels. Trials were clinically heterogeneous and data were not available to compare doses, duration, and timing of use. Tamoxifen (risk ratio [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials; n = 28 421), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials; n = 17 806), and aromatase inhibitors (RR, 0.45 [95% CI, 0.26- 0.70]; 2 trials; n = 8424) were associated with lower risk of invasive breast cancer after 3 to 5 years of use compared with placebo (eTable 4 in the Supplement); tamoxifen had a greater effect than raloxifene in the head-to-head trial (RR, 1.24 [95% CI, 1.05-1.47]; n = 19 747).162 Risks for invasive breast cancer were lower in all subgroups evaluated based on family history of breast cancer. Reduction was significant for estrogen receptor (ER)–positive, but not ER-negative, breast cancer, noninvasive breast cancer, and mortality.
Six observational studies (7 articles; n = 2546) of risk-reducing mastectomy,105-110,118 2 of risk-reducing salpingo-oophorectomy (n = 2379),105,111 and 7 of oophorectomy alone (n = 6807)112-117,119 were included (Table 3). Risk-reducing bilateral mastectomy was associated with 90% to 100% reduction in breast cancer incidence for high-risk women and BRCA1/2 mutation carriers.105-110 Breast cancer–specific mortality was lower by 81% to 100% after risk-reducing mastectomy in 1 study of 639 women.108
Newer studies of oophorectomy or salpingo-oophorectomy that control for biases did not show associations between surgery and breast cancer risk,111,112,114 although some studies showed reduced risk specifically among younger women after surgery.112-115 Oophorectomy was associated with 69% to 100% reduction in ovarian cancer risk among 2108 women in 2 studies105,113,116 but with no differences in cancer-specific mortality.105
Key Question 5. What are adverse effects of interventions to reduce risk for BRCA1/2-related cancer?
For breast cancer screening, 3 studies (4 articles; n = 2631) of false-positive and false-negative results, recall rates, and diagnostic procedures136-139 and 3 studies (4 articles; n = 513) of discomfort, pain, breast cancer worry, anxiety, and depression128,143-145 were included (eTable 5 in the Supplement). In these studies, false-positive rates,137 recall,138 additional imaging,136and benign biopsy results136 were higher with MRI than with mammography. In most studies, women experienced no anxiety or depression after screening with MRI, mammography, or clinical breast examination, and breast cancer worry decreased over time.128,143-145 For ovarian cancer screening, studies indicated a false-positive rate of 3.4% (55/1595) for TVUS123 and a diagnostic surgery rate of 55% (6/11), with benign results for combined TVUS and CA-125.133
No studies evaluated the adverse effects of risk-reducing medications specifically in BRCA1/2 mutation carriers, although adverse effects were reported in 9 RCTs of women at various levels of risk,150 including placebo-controlled trials of tamoxifen,151-154 raloxifene,155,156 and the aromatase inhibitors anastrozole157-159 and exemestane160,161 and a head-to-head RCT of tamoxifen vs raloxifene.162 Data on long-term effects were incomplete, particularly for aromatase inhibitors. Tamoxifen (RR, 1.93 [95% CI, 1.33-2.68]; 4 trials; n = 28 421) and raloxifene (RR, 1.56 [95% CI, 1.11-2.60]; 2 trials; n = 17 806) were associated with increased thromboembolic events compared with placebo (eTable 6 in the Supplement),150 and numbers of events were higher for tamoxifen than for raloxifene in the head-to-head trial (RR, 0.75 [95% CI, 0.60-0.93]; n = 19 747).162 Tamoxifen was also associated with increased endometrial cancer (RR, 2.25 [95% CI, 1.17-4.41]; 3 trials; n = 11 721)150 and cataracts.151 All medications were associated with undesirable adverse effects for some women, such as vasomotor and musculoskeletal symptoms.
Twelve observational studies (13 articles; n = 2684), including 8 new studies (n = 750), of surgical complications, physical symptoms, or psychological outcomes related to risk-reducing mastectomy120,121,124,125,127,130-132,134,140,142,146,147 and 5 studies (n = 530), including 4 new studies (n = 449), related to risk-reducing salpingo-oophorectomy or oophorectomy122,126,129,135,141 were included (eTable 7 in the Supplement). In studies of mastectomy, 50% or more of women experienced surgical complications including necrosis, pain, infection, hematoma, and implant problems.121,130-132,140,142 While body image and psychological symptoms worsened after surgery for some women, most measures returned to baseline later.127,131,134,146 Rates of surgical complications with salpingo-oophorectomy were approximately 4% (7/159) in a single study,135 although women had worsening of vasomotor symptoms, sexual functioning, and fatigue.129,141
This evidence report reviewed current research on benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA1/2-related cancer in women. Table 4 summarizes the evidence reviewed.
This review expands the scope of previous reports for the USPSTF29,37 by including studies of untested women with previous diagnoses of BRCA1/2-related cancer who completed treatment and are considered cancer-free. These women may have missed earlier opportunities for risk assessment, genetic counseling, genetic testing, and risk-reducing interventions because these services may not have been available previously. Despite a comprehensive literature search, only 2 relevant studies that included this population were identified for this review, and they provided very limited information addressing key questions.
Four new studies evaluated the discriminatory accuracy of existing risk-assessment tools intended to guide referrals from primary care settings to genetic counseling. Studies indicated moderate to high predictive accuracy of revised versions of the MSS and brief versions of BRCAPRO and additional validation of the PAT and IBIS.
An RCT was the only study addressing a new KQ (KQ2c) regarding optimal testing approaches to determine the presence of pathogenic BRCA1/2 mutations in women at increased risk for BRCA1/2-related cancer. Results indicated that population-based testing of Ashkenazi Jews detected more BRCA1/2 mutations than family history–based testing. The study also found that potential harms, such as anxiety, depression, distress, uncertainty, and quality of life, were similar between groups. However, that study did not evaluate clinical outcomes central to decisions about screening, such as reduction in cancer incidence and mortality.
Only 1 new small study evaluated the benefits and harms of genetic counseling and indicated no association between a woman’s understanding of her breast cancer risk and the genetic counselor’s assessment, contrary to most studies that show improved understanding. Six new studies of benefits and harms of genetic testing were generally consistent with previous studies showing that breast cancer worry and anxiety increased after testing for those with positive results and decreased for others.
Two new RCTs of aromatase inhibitors indicated reductions in invasive breast cancer compared with placebo, although results were not specifically reported in BRCA1/2 mutation carriers. Similar to tamoxifen and raloxifene, aromatase inhibitors were associated with reduced ER-positive but not ER-negative breast cancer, noninvasive breast cancer, or breast cancer–specific or all-cause mortality. Unlike tamoxifen and raloxifene, adverse effects of aromatase inhibitors in risk reduction trials are unclear because of short follow-up times. All medications were associated with symptomatic adverse effects, such as vasomotor and musculoskeletal symptoms.
New observational studies are consistent with previous studies showing that risk-reducing mastectomy was associated with reduced breast cancer and breast cancer mortality. Risk-reducing salpingo-oophorectomy was associated with reduced ovarian cancer incidence.
Despite the inclusion of 103 studies in this report, current research is limited or lacking for most KQs. Risk assessment, genetic counseling, and genetic testing to reduce BRCA1/2-related cancer incidence and mortality as a prevention service for women has not been directly addressed by current research that focuses on specific issues in highly selected populations. To determine the appropriateness of risk assessment and genetic testing for BRCA1/2 mutations as a preventive service in primary care, more information is needed about mutation prevalence and the effect of testing in the general population. Research has focused on highly selected women in referral centers and generally reported short-term outcomes. Issues such as access to genetic testing and follow-up, effectiveness of screening approaches including risk stratification and multigene panels, effects of direct-to-consumer marketing, use of system supports, and patient acceptance and education require additional study.
Identification of appropriate candidates for genetic testing is essential to effective BRCA1/2 mutation testing. Who should perform risk assessment and genetic counseling services, necessary skills, how it should be done, effectiveness of different methods to deliver services, and its effect on patient choices and outcomes are unresolved questions. Trials comparing types of clinicians and protocols could address these issues. What happens after patients are identified as high-risk in clinical settings is also not known. The consequences of genetic testing on individuals and their relatives need to be further understood. Well-designed investigations using standardized measures and enrolling participants that reflect the general population, including minority women, are needed. Additional research on effective interventions is also needed. Without effectiveness trials of intensive screening, practice standards have preceded supporting evidence. This information could improve patient decision-making and lead to better health outcomes.
Current research to identify women with pathogenic BRCA1/2 mutations indicates that familial risk tools for primary care settings that evaluate individual risks can accurately guide referrals for genetic counseling. Comprehensive evaluations by genetic counselors provide estimates of individual risks for BRCA1/2 mutations and identify candidates for genetic testing. Genetic counseling reduces breast cancer worry, anxiety, and depression; increases women’s understanding of risk; and reduces intention for inappropriate mutation testing. Results of genetic testing improve a woman’s understanding of her risk of developing BRCA1/2-related cancer depending on the type of mutation and specific test results.
Once a pathogenic mutation is identified, how to choose the best options for clinical management is currently unclear. Subjecting otherwise healthy women to clinical interventions requires careful consideration of benefits and harms. Although intensive screening for breast and ovarian cancer in BRCA1/2 mutation carriers using MRI, TVUS, and CA-125 is supported by experts, its effectiveness in reducing cancer incidence and mortality has not been evaluated. Use of risk-reducing medications in mutation carriers has also not been studied. Tamoxifen and raloxifene increase thromboembolic events, tamoxifen increases endometrial cancer and cataracts, and all medications cause symptomatic adverse effects. While risk-reducing mastectomy and salpingo-oophorectomy are associated with reduced breast and ovarian cancer in BRCA1/2 mutation carriers, they are invasive procedures with potential complications.
The process of familial risk assessment in primary care, referral and evaluation by genetic counselors, genetic testing, and use of intensive screening and risk-reducing medications and surgical procedures is complex. Each step of the pathway requires careful interpretation of information, consideration of future risks, and shared decision-making before moving on to the next step. Services must be well integrated and highly individualized to optimize benefits and minimize harms for patients as well as their families. Several evidence gaps relevant to prevention remain, and additional studies are necessary to fill them.
This review has several limitations. First, it included only English-language articles and studies applicable to the United States, although this focus improves its relevance to the USPSTF recommendation. Second, the number, quality, and applicability of studies evaluated in the evidence review varied widely. Third, most studies in this review included highly selected samples of women, some with preexisting breast or ovarian cancer or from high-risk groups that were defined in various ways, or from previously identified cancer kindreds. It is not known how the results of studies based on highly selected women in research settings, particularly in non-US settings, translate to general screening populations in US clinical practice.
Among women without recently diagnosed BRCA1/2-related cancer, the benefits and harms of risk assessment, genetic counseling, and genetic testing to reduce cancer incidence and mortality have not been directly evaluated by current research.
Corresponding Author: Heidi D. Nelson, MD, MPH, MACP, FRCP, Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code BICC, Portland, OR 97239 (firstname.lastname@example.org).
Accepted for Publication: May 29, 2019.
Author Contributions: Dr Nelson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Nelson, Cantor, Haney.
Acquisition, analysis, or interpretation of data: Nelson, Pappas, Cantor, Haney, Holmes.
Drafting of the manuscript: Nelson, Pappas, Haney, Holmes.
Critical revision of the manuscript for important intellectual content: Nelson, Cantor, Holmes.
Obtained funding: Nelson.
Administrative, technical, or material support: Pappas, Cantor, Holmes.
Conflict of Interest Disclosures: None reported.
Funding/Support: This research was funded under contract HHSA290201500009I, Task Order 7, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF).
Role of the Funder/Sponsor: Investigators worked with the USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.
Additional Contributions: We gratefully acknowledge the following individuals for their contributions to this project: AHRQ Medical Officer Justin Mills, MD, and Pacific Northwest Evidence-based Practice Center expert consultant Elizabeth Swisher, MD, research librarian Andrew Hamilton, MLS, MS, and research assistant Lucy Stillman, BS. We also acknowledge past and current USPSTF members who contributed to topic deliberations. USPSTF members, external reviewers, and federal partner reviewers did not receive financial compensation for their contributions.
Additional Information: A draft version of this evidence report underwent external peer review from 5 federal partners at the Centers for Disease Control and Prevention, National Institutes of Health, and National Cancer Institute and 3 content experts (Mary Daly, MD, Risk Assessment Program, Department of Clinical Genetics, Fox Chase Cancer Center, Temple University; Kelly Metcalfe, PhD, University of Toronto and Familial Breast Cancer Research Institute at the Women’s College Research Institute, Toronto, Onatario, Canada; and Robert Pilarski, MS, Clinical Cancer Genetics Program, Division of Human Genetics, The Ohio State University). Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.
Editorial Disclaimer: This evidence report is presented as a document in support of the accompanying the USPSTF Recommendation Statement. It did not undergo additional peer review after submission to JAMA.