BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing
August 20, 2019
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
By Heidi D. Nelson, MD, MPH, MACP, FRCP; Miranda Pappas, MA; Amy Cantor,MD, MPH; Elizabeth Haney, MD; and Rebecca Holmes, MD
The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.
This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.
This article was published in JAMA on August 20, 2019 (JAMA. 2019;322(7):666-685. doi:10.1001/jama.2019.8430).
Importance: 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.
Objective: 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.
Data Sources: 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.
Study Selection: 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.
Results: 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 cancer;1-6 BRCA2 is also associated with melanoma.3,4 BRCA1/2 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 gene;15,16 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
Scope of Review
Detailed methods are available in the full evidence report at https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/brca-related-cancer-riskassessment-genetic-counseling-and-genetic-testing1, 35 Figure 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.
Data Sources and Searches
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; 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.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, salpingooophorectomy). 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.
Data Extraction and Quality Assessment
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. Discrepancies were resolved through a consensus process.
Data Synthesis and Analysis
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).
Effectiveness of Risk Assessment, Genetic Counseling, and Genetic Testing in Reducing Incidence and Mortality of BRCA1/2-Related Cancer
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.
Accuracy of Risk Assessment and Pretest Genetic Counseling
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 risk;60 8 reported decreases;54, 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.
BRCA1/2 Mutation Testing and Posttest Genetic Counseling
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.
Harms of Risk Assessment and Pretest Genetic 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.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?
No studies were identified that specifically addressed posttest counseling.
Effectiveness and Harms of Interventions to Reduce BRCA1/2- Related Cancer and Mortality in BRCA1/2 Mutation Carriers
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.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; 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 salpingooophorectomy (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. In these studies, false-positive rates,137 recall,138 additional imaging,136 and 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,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. 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.
Source: This article was first published in the Journal of the American Medical Association on August 20, 2019 (JAMA, 2019;322(7):666-685. doi:10.1001/jama.2019.8430)
Conflict of Interest Disclosures: None reported.
Funding/Support: This research was funded under contract HHSA-290-2015-00009-I, Task Order No.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 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, Ontario, 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.
1. Brody LC, Biesecker BB. Breast cancer susceptibility genes. BRCA1 and BRCA2. Medicine (Baltimore). 1998;77(3):208-226.
2. Mersch J, Jackson MA, Park M, et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer. 2015;121(2):269-275.
3. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66-71.
4. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med. 2003;348(23):2339-2347.
5. Sherman ME, Piedmonte M, Mai PL, et al. Pathologic findings at risk-reducing salpingo-oophorectomy: primary results from Gynecologic Oncology Group Trial GOG-0199. N Engl J Med. 2014;32(29):3275-3283.
6. Norquist BM, Garcia RL, Allison KH, et al. The molecular pathogenesis of hereditary ovarian carcinoma: alterations in the tubal epithelium of women with BRCA1 and BRCA2 mutations. Cancer. 2010;116(22):5261-5271.
7. Anglian Breast Cancer Study Group. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer. 2000;83(10):1301-1308.
8. Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF. Risk models for familial ovarian and breast cancer. Genet Epidemiol. 2000;18(2):173-190.
9. Antoniou AC, Pharoah PD, McMullan G, et al. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer. 2002;86(1):76-83.
10. Peto J, Collins N, Barfoot R, et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999;91(11):943-949.
11. Whittemore AS, Gong G, John EM, et al. Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic whites. Cancer Epidemiol Biomarkers Prev. 2004;13(12):2078-2083.
12. Neuhausen S, Gilewski T, Norton L, et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet. 1996;13(1):126-128.
13. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336(20):1401.
14. Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996;14(2):185-187.
15. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130.
16. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. N Engl J Med. 2007;25(11):1329-1333.
17. Lakhani SR, Manek S, Penault-Llorca F, et al. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res. 2004;10(7):2473-2481.
18. Evans DG, Young K, Bulman M, Shenton A, Wallace A, Lalloo F. Probability of BRCA1/2 mutation varies with ovarian histology: results from screening 442 ovarian cancer families. Clin Genet. 2008;73(4):338-345.
19. Tonin PN, Maugard CM, Perret C, Mes-Masson AM, Provencher DM. A review of histopathological subtypes of ovarian cancer in BRCA-related French Canadian cancer families. Fam Cancer. 2007;6(4):491-497.
20. Crum CP, Drapkin R, Kindelberger D, Medeiros F, Miron A, Lee Y. Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer. Clin Med Res. 2007;5(1):35-44.
21. Bolton KL, Chenevix-Trench G, Goh C, et al; EMBRACE; kConFab Investigators; Cancer Genome Atlas Research Network. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA. 2012; 307(4):382-390.
22. Levine DA, Argenta PA, Yee CJ, et al. Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J Clin Oncol. 2003;21(22):4222-4227.
23. Mavaddat N, Barrowdale D, Andrulis IL, et al; HEBON; EMBRACE; GEMO Study Collaborators; kConFab Investigators; SWE-BRCA Collaborators; Consortium of Investigators of Modifiers of BRCA1/2. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev. 2012;21(1):134-147.
24. National Comprehensive Cancer Network (NCCN). Genetic/familial high-risk assessment: breast and ovarian. NCCN website. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Published 2019. Accessed April 16, 2019.
25. Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17(1):70-87.
26. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: breast cancer screening and diagnosis. NCCN website. https://www.nccn.org. Published 2018. Accessed May 1, 2019.
27. American College of Surgeons (ACS). Cancer Program Standards 2016. ACS website. https://www.facs.org/cancer/coc/programstandards2012.html. Published 2016. Accessed May 1, 2019.
28. Moyer V; U.S. Preventive Services Task Force. Risk assessement, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160(4):271-281.
29. Nelson HD, Fu R, Goddard K, et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
30. Lindor NM, Greene MH. The concise handbook of family cancer syndromes: Mayo Familial Cancer Program. J Natl Cancer Inst. 1998;90(14):1039-1071.
31. National Cancer Institute. PDQ® Breast Cancer Treatment. 2013. https://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional. Accessed May 1, 2019.
32. Daly MB, Pilarski R, Berry M, et al. NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017. J Natl Compr Canc Netw. 2017;15(1):9-20.
33. Stuckey AR, Onstad MA. Hereditary breast cancer: an update on risk assessment and genetic testing in 2015. Am J Obstet Gynecol. 2015;213(2):161-165.
34. Easton DF, Pharoah PD, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med. 2015;372(23):2243-2257.
35. Nelson HD, Pappas M, Cantor A, Haney E, Holmes R, Stillman L. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: A Systematic Review for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2019.
36. US Preventive Services Task Force (USPSTF). Methods and Processes. USPSTF website. https://www.uspreventiveservicestaskforce.org/Page/Name/methods-and-processes. Published 2018. Accessed May 1, 2019.
37. Nelson HD, Pappas M, Zakher B, Priest Mitchell J, Kinaka-Hu L, Fu R. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: a systematic review to update the U.S.Preventive Services Task Force recommendation. Ann Intern Med. 2014;160(4):255-266.
38. Antoniou AC, Hardy R, Walker L, et al. Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics. J Med Genet. 2008;45(7):425-431.
39. Ashton-Prolla P, Giacomazzi J, Schmidt AV, et al. Development and validation of a simple questionnaire for the identification of hereditary breast cancer in primary care. BMC Cancer. 2009;9:283.
40. Barcenas CH, Hosain GMM, Arun B, et al. Assessing BRCA carrier probabilities in extended families. N Engl J Med. 2006;24(3):354-360.
41. Bellcross CA, Lemke AA, Pape LS, Tess AL, Meisner LT. Evaluation of a breast/ovarian cancer genetics referral screening tool in a mammography population. Genet Med. 2009;11(11):783-789.
42. Biswas S, Atienza P, Chipman J, et al. A two-stage approach to genetic risk assessment in primary care. Breast Cancer Res Treat. 2016;155(2):375-383.
43. Evans DG, Eccles DM, Rahman N, et al. A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet. 2004;41(6):474-480.
44. Fischer C, Kuchenbacker K, Engel C, et al. Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium. J Med Genet. 2013;50(6):360-367.
45. 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(4):299-308.
46. Hoskins KF, Zwaagstra A, Ranz M. Validation of a tool for identifying women at high risk for hereditary breast cancer in population-based screening. Cancer. 2006;107(8):1769-1776.
47. Kast K, Schmutzler RK, Rhiem K, et al. Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer. Int J Cancer. 2014;135(10):2352-2361.
48. Oros KK, Ghadirian P, Maugard CM, et al. Application of BRCA1 and BRCA2 mutation carrier prediction models in breast and/or ovarian cancer families of French Canadian descent. Clin Genet. 2006;70(4):320-329.
49. Panchal SM, Ennis M, Canon S, Bordeleau LJ. Selecting a BRCA risk assessment model for use in a familial cancer clinic. BMC Med Genet. 2008;9:116.
50. Parmigiani G, Chen S, Iversen ES Jr, et al. Validity of models for predicting BRCA1 and BRCA2 mutations. Ann Intern Med. 2007;147(7):441-450.
51. Teller P, Hoskins KF, Zwaagstra A, et al. Validation of the pedigree assessment tool (PAT) in families with BRCA1 and BRCA2 mutations. Ann Surg Oncol. 2010;17(1):240-246.
52. Albada A, van Dulmen S, Dijkstra H, Wieffer I, Witkamp A, Ausems MG. Counselees' expressed level of understanding of the risk estimate and surveillance recommendation are not associated with breast cancer surveillance adherence. J Genet Couns. 2016;25(2):279-289.
53. Armstrong K, Micco E, Carney A, Stopfer J, Putt M. Racial differences in the use of BRCA1/2 testing among women with a family history of breast or ovarian cancer. JAMA. 2005;293(14):1729-1736.
54. Bennett P, Wilkinson C, Turner J, et al. Psychological factors associated with emotional responses to receiving genetic risk information. J Genet Couns. 2008;17(3):234-241.
55. Bennett P, Wilkinson C, Turner J, et al. Factors associated with intrusive cancer-related worries in women undergoing cancer genetic risk assessment. Fam Cancer. 2009;8(2):159-165.
56. Bloom JR, Stewart SL, Chang S, You M. Effects of a telephone counseling intervention on sisters of young women with breast cancer. Prev Med. 2006;43(5):379-384.
57. Bowen DJ, Burke W, Culver JO, Press N, Crystal S. Effects of counseling Ashkenazi Jewish women about breast cancer risk. Cultur Divers Ethnic Minor Psychol. 2006;12(1):45-56.
58. Bowen DJ, Burke W, McTiernan A, Yasui Y, Andersen MR. Breast cancer risk counseling improves women's functioning. Patient Educ Couns. 2004;53(1):79-86.
59. Bowen DJ, Burke W, Yasui Y, McTiernan A, McLeran D. Effects of risk counseling on interest in breast cancer genetic testing for lower risk women. Genet Med. 2002;4(5):359-365.
60. Brain K, Norman P, Gray J, Rogers C, Mansel R, Harper P. A randomized trial of specialist genetic assessment: psychological impact on women at different levels of familial breast cancer risk. Br J Cancer. 2002;86(2):233-238.
61. Brain K, Parsons E, Bennett P, Cannings-John R, Hood K. The evolution of worry after breast cancer risk assessment: 6-year follow-up of the TRACE study cohort. Psychooncology. 2011;20(9):984-991.
62. Braithwaite D, Sutton S, Mackay J, Stein J, Emery J. Development of a risk assessment tool for women with a family history of breast cancer. Cancer Detect Prev. 2005;29(5):433-439.
63. Burke W, Culver JO, Bowen D, et al. Genetic counseling for women with an intermediate family history of breast cancer. Am J Med Genet. 2000;90(5):361-368.
64. Cull A, Miller H, Porterfield T, et al. The use of videotaped information in cancer genetic counselling: a randomized evaluation study. Br J Cancer. 1998;77(5):830-837.
65. Fry A, Cull A, Appleton S, et al. A randomised controlled trial of breast cancer genetics services in South East Scotland: psychological impact. Br J Cancer. 2003;89(4):653-659.
66. Gurmankin AD, Domchek S, Stopfer J, Fels C, Armstrong K. Patients' resistance to risk information in genetic counseling for BRCA1/2. Arch Intern Med. 2005;165(5):523-529.
67. Helmes AW, Culver JO, Bowen DJ. Results of a randomized study of telephone versus in-person breast cancer risk counseling. Patient Educ Couns. 2006;64(1-3):96-103.
68. Hopwood P, Wonderling D, Watson M, et al. A randomised comparison of UK genetic risk counselling services for familial cancer: psychosocial outcomes. Br J Cancer. 2004;91(5):884-892.
69. Hopwood P, Keeling F, Long A, Pool C, Evans G, Howell A. Psychological support needs for women at high genetic risk of breast cancer: some preliminary indicators. Psychooncology. 1998;7(5):402-412.
70. Kelly KM, Senter L, Leventhal H, Ozakinci G, Porter K. Subjective and objective risk of ovarian cancer in Ashkenazi Jewish women testing for BRCA1/2 mutations. Patient Educ Couns. 2008;70(1):135-142.
71. Lerman C, Hughes C, Benkendorf JL, et al. Racial differences in testing motivation and psychological distress following pretest education for BRCA1 gene testing. Cancer Epidemiol Biomarkers Prev. 1999;8(4 Pt 2):361-367.
72. Lerman C, Schwartz MD, Miller SM, Daly M, Sands C, Rimer BK. A randomized trial of breast cancer risk counseling: interacting effects of counseling, educational level, and coping style. Health Psychol. 1996;15(2):75-83.
73. Lobb EA, Butow PN, Barratt A, et al. Communication and information-giving in high-risk breast cancer consultations: influence on patient outcomes. Br J Cancer. 2004;90(2):321-327.
74. Matloff ET, Moyer A, Shannon KM, Niendorf KB, Col NF. Healthy women with a family history of breast cancer: impact of a tailored genetic counseling intervention on risk perception, knowledge, and menopausal therapy decision making. J Womens Health (Larchmt). 2006;15(7):843-856.
75. Mikkelsen EM, Sunde L, Johansen C, Johnsen SP. Risk perception among women receiving genetic counseling: a population-based follow-up study. Cancer Detect Prev. 2007;31(6):457-464.
76. Mikkelsen EM, Sunde L, Johansen C, Johnsen SP. Psychosocial consequences of genetic counseling: a population-based follow-up study. Breast J. 2009;15(1):61-68.
77. Pieterse AH, Ausems MG, Spreeuwenberg P, van Dulmen S. Longer-term influence of breast cancer genetic counseling on cognitions and distress: smaller benefits for affected versus unaffected women. Patient Educ Couns. 2011;85(3):425-431.
78. Roshanai AH, Rosenquist R, Lampic C, Nordin K. Does enhanced information at cancer genetic counseling improve counselees' knowledge, risk perception, satisfaction and negotiation of information to at-risk relatives? A randomized study. Acta Oncol. 2009;48(7):999-1009.
79. Smerecnik CM, Mesters I, Verweij E, De Vries NK, De Vries H. A systematic review of the impact of genetic counseling on risk perception accuracy. J Genet Couns. 2009;18(3):217-228.
80. Watson M, Duvivier V, Wade Walsh M, et al. Family history of breast cancer: what do women understand and recall about their genetic risk? J Med Genet. 1998;35(9):731-738.
81. Watson M, Lloyd S, Davidson J, et al. The impact of genetic counselling on risk perception and mental health in women with a family history of breast cancer. Br J Cancer. 1999;79(5-6):868-874.
82. Andrews L, Meiser B, Apicella C, Tucker K. Psychological impact of genetic testing for breast cancer susceptibility in women of Ashkenazi Jewish background: a prospective study. Genet Test. 2004;8(3):240-247.
83. Arver B, Haegermark A, Platten U, Lindblom A, Brandberg Y. Evaluation of psychosocial effects of pre-symptomatic testing for breast/ovarian and colon cancer pre-disposing genes: a 12-month follow-up. Fam Cancer. 2004;3(2):109-116.
84. Dagan E, Shochat T. Quality of life in asymptomatic BRCA1/2 mutation carriers. Prev Med. 2009;48(2):193-196.
85. Ertmański S, Metcalfe K, Trempała J, et al. Identification of patients at high risk of psychological distress after BRCA1 genetic testing. Genet Test Mol Biomarkers. 2009;13(3):325-330.
86. Foster C,Watson M, Eeles R, et al; Psychosocial Study Collaborators. Predictive genetic testing for BRCA1/2 in a UK clinical cohort: three-year follow-up. Br J Cancer. 2007;96(5):718-724.
87. Geirdal AO, Dahl AA. The relationship between coping strategies and anxiety in women from families with familial breast-ovarian cancer in the absence of demonstrated mutations. Psychooncology. 2008;17(1):49-57.
88. Geirdal AO, Reichelt JG, Dahl AA, et al. Psychological distress in women at risk of hereditary breast/ovarian or HNPCC cancers in the absence of demonstrated mutations. Fam Cancer. 2005;4(2):121-126.
89. Godard B, Pratte A, Dumont M, Simard-Lebrun A, Simard J. Factors associated with an individual’s decision to withdraw from genetic testing for breast and ovarian cancer susceptibility: implications for counseling. Genet Test. 2007;11(1):45-54.
90. Graves KD, Vegella P, Poggi EA, et al. Long-term psychosocial outcomes of BRCA1/BRCA2 testing: differences across affected status and risk-reducing surgery choice. Cancer Epidemiol Biomarkers Prev. 2012;21(3):445-455.
91. Julian-Reynier C, Mancini J, Mouret-Fourme E, et al. Cancer risk management strategies and perceptions of unaffected women 5 years after predictive genetic testing for BRCA1/2 mutations. Eur J Hum Genet. 2011;19(5):500-506.
92. Kinney AY, Bloor LE, Mandal D, et al. The impact of receiving genetic test results on general and cancer-specific psychologic distress among members of an African-American kindred with a BRCA1 mutation. Cancer. 2005;104(11):2508-2516.
93. Lieberman S, Tomer A, Ben-Chetrit A, et al. Population screening for BRCA1/BRCA2 founder mutations in Ashkenazi Jews: proactive recruitment compared with self-referral. Genet Med. 2017;19(7):754-762.
94. Low CA, Bower JE, Kwan L, Seldon J. Benefit finding in response to BRCA1/2 testing. Ann Behav Med. 2008;35(1):61-69.
95. Lumish HS, Steinfeld H, Koval C, et al. Impact of panel gene testing for hereditary breast and ovarian cancer on patients. J Genet Couns. 2017;26(5):1116-1129.
96. Manchanda R, Loggenberg K, Sanderson S, et al. Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi-Jewish community: a randomized controlled trial. J Natl Cancer Inst. 2014;107(1):379.
97. Meiser B, Butow P, Friedlander M, et al. Psychological impact of genetic testing in women from high-risk breast cancer families. Eur J Cancer. 2002;38(15):2025-2031.
98. Metcalfe KA, Mian N, Enmore M, et al. Long-term follow-up of Jewish women with a BRCA1 and BRCA2 mutation who underwent population genetic screening. Breast Cancer Res Treat. 2012;133(2):735-740.
99. Reichelt JG, Møller P, Heimdal K, Dahl AA. Psychological and cancer-specific distress at 18 months post-testing in women with demonstrated BRCA1 mutations for hereditary breast/ovarian cancer. Fam Cancer. 2008;7(3):245-254.
100. Reichelt JG, Heimdal K, Møller P, Dahl AA. BRCA1 testing with definitive results: a prospective study of psychological distress in a large clinic-based sample. Fam Cancer. 2004;3(1):21-28.
101. Shochat T, Dagan E. Sleep disturbances in asymptomatic BRCA1/2 mutation carriers: women at high risk for breast-ovarian cancer. J Sleep Res. 2010;19(2):333-340.
102. Smith KR, West JA, Croyle RT, Botkin JR. Familial context of genetic testing for cancer susceptibility: moderating effect of siblings' test results on psychological distress one to two weeks after BRCA1 mutation testing. Cancer Detect Prev. 1999;8(4 II):385-392.
103. van Dijk S, Timmermans DR, Meijers-Heijboer H, Tibben A, van Asperen CJ, Otten W. Clinical characteristics affect the impact of an uninformative DNA test result: the course of worry and distress experienced by women who apply for genetic testing for breast cancer. N Engl J Med. 2006;24(22):3672-3677.
104. van Oostrom I, Meijers-Heijboer H, Lodder LN, et al. Long-term psychological impact of carrying a BRCA1/2 mutation and prophylactic surgery: a 5-year follow-up study. J Clin Oncol. 2003;21(20):3867-3874.
105. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967-975.
106. Evans DG, Baildam AD, Anderson E, et al. Risk reducing mastectomy: outcomes in 10 European centres. J Med Genet. 2009;46(4):254-258.
107. Flippo-Morton T, Walsh K, Chambers K, et al. Surgical decision making in the BRCA-positive population: institutional experience and comparison with recent literature. Breast J. 2016;22(1):35-44.
108. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. New Engl J Med. 1999;340(2):77-84.
109. Hartmann LC, Sellers TA, Schaid DJ, et al. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst. 2001;93(21):1633-1637.
110. Heemskerk-Gerritsen BA, Menke-Pluijmers MB, Jager A, et al. Substantial breast cancer risk reduction and potential survival benefit after bilateral mastectomy when compared with surveillance in healthy BRCA1 and BRCA2 mutation carriers: a prospective analysis. Ann Oncol. 2013;24(8):2029-2035.
111. Heemskerk-Gerritsen BA, Seynaeve C, van Asperen CJ, et al; Hereditary Breast and Ovarian Cancer Research Group Netherlands. Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. J Natl Cancer Inst. 2015;107(5).
112. Kotsopoulos J, Huzarski T, Gronwald J, et al; Hereditary Breast Cancer Clinical Study Group. Bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2017;109(1).
113. Kramer JL, Velazquez IA, Chen BE, Rosenberg PS, Struewing JP, Greene MH. Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. N Engl J Med. 2005;23(34):8629-8635.
114. Mavaddat N, Peock S, Frost D, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013;105(11):812-822.
115. Olson JE, Sellers TA, Iturria SJ, Hartmann LC. Bilateral oophorectomy and breast cancer risk reduction among women with a family history. Cancer Detect Prev. 2004;28(5):357-360.
116. Rebbeck TR, Lynch HT, Neuhausen SL, et al; Prevention and Observation of Surgical End Points Study Group. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346(21):1616-1622.
117. Shah P, Rosen M, Stopfer J, et al. Prospective study of breast MRI in BRCA1 and BRCA2 mutation carriers: effect of mutation status on cancer incidence. Breast Cancer Res Treat. 2009;118(3):539-546.
118. Skytte AB, Cruger D, Gerster M, et al. Breast cancer after bilateral risk-reducing mastectomy. Clin Genet. 2011;79(5):431-437. d
119. Struewing JP, Watson P, Easton DF, Ponder BA, Lynch HT, Tucker MA. Prophylactic oophorectomy in inherited breast/ovarian cancer families. J Natl Cancer Inst Monogr. 1995(17):33-35.
120. Alamouti R, Hachach-Haram N, Farhadi J. Multidisciplinary management of risk-reducing mastectomy and immediate reconstruction: treatment algorithm and patient satisfaction. Eur J Plast Surg. 2015;38(5):385-390.
121. Arver B, Isaksson K, Atterhem H, et al. Bilateral prophylactic mastectomy in Swedish women at high risk of breast cancer: a national survey. Ann Surg. 2011;253(6):1147-1154.
122. Borreani C, Manoukian S, Bianchi E, et al. The psychological impact of breast and ovarian cancer preventive options in BRCA1 and BRCA2 mutation carriers. Clin Genet. 2014;85(1):7-15.
123. Bourne T, Campell S, Reynolds K. Screening for early familial ovarian cancer with transvaginal ultrasonography and colour blood flow imaging. BMJ. 1993;306(3884):1025-1029.
124. Brandberg Y, Arver B, Johansson H, Wickman M, Sandelin K, Liljegren A. Less correspondence between expectations before and cosmetic results after risk-reducing mastectomy in women who are mutation carriers: a prospective study. Eur J Surg Oncol. 2012;38(1):38-43.
125. Brandberg Y, Sandelin K, Erikson S, et al. Psychological reactions, quality of life, and body image after bilateral prophylactic mastectomy in women at high risk for breast cancer: a prospective 1-year follow-up study. N Engl J Med. 2008;26(24):3943-3949.
126. Bresser PJ, Seynaeve C, Van Gool AR, et al. The course of distress in women at increased risk of breast and ovarian cancer due to an (identified) genetic susceptibility who opt for prophylactic mastectomy and/or salpingo-oophorectomy. Eur J Cancer. 2007;43(1):95-103.
127. den Heijer M, Seynaeve C, Timman R, et al. Body image and psychological distress after prophylactic mastectomy and breast reconstruction in genetically predisposed women: a prospective long-term follow-up study. Eur J Cancer. 2012;48(9):1263-1268.
128. den Heijer M, Seynaeve C, Vanheusden K, et al. Long-term psychological distress in women at risk for hereditary breast cancer adhering to regular surveillance: a risk profile. Psychooncology. 2013;22(3):598-604.
129. Finch A, Metcalfe KA, Chiang JK, et al. The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation. Gynecol Oncol. 2011;121(1):163-168.
130. Gahm J, Wickman M, Brandberg Y. Bilateral prophylactic mastectomy in women with inherited risk of breast cancer--prevalence of pain and discomfort, impact on sexuality, quality of life and feelings of regret two years after surgery. Breast. 2010;19(6):462-469.
131. Gopie JP, Mureau MA, Seynaeve C, et al. Body image issues after bilateral prophylactic mastectomy with breast reconstruction in healthy women at risk for hereditary breast cancer. Fam Cancer. 2013;12(3):479-487.
132. Heemskerk-Gerritsen BA, Brekelmans CT, Menke-Pluymers MB, et al. Prophylactic mastectomy in BRCA1/2 mutation carriers and women at risk of hereditary breast cancer: long-term experiences at the Rotterdam Family Cancer Clinic. Ann Surg Oncol. 2007;14(12):3335-3344.
133. Hermsen BB, Olivier RI, Verheijen RH, et al. No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study. Br J Cancer. 2007;96:1335-1342. 5
134. Isern AE, Tengrup I, Loman N, Olsson H, Ringberg A. Aesthetic outcome, patient satisfaction, and health-related quality of life in women at high risk undergoing prophylactic mastectomy and immediate breast reconstruction. J Plast Reconstr Aesthet Surg. 2008;61(10):1177-1187.
135. Kenkhuis MJ, de Bock GH, Elferink PO, et al. Short-term surgical outcome and safety of risk reducing salpingo-oophorectomy in BRCA1/2 mutation carriers. Maturitas. 2010;66(3):310-314.66(3):310-314.
136. Kriege M, Brekelmans CTM, Boetes C, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004;351(5):427-437.
137. Kriege M, Brekelmans CT, Boetes C, et al. Differences between first and subsequent rounds of the MRISC breast cancer screening program for women with a familial or genetic predisposition. Cancer. 2006;106(11):2318-2326.
138. Leach MO, Boggis CR, Dixon AK, et al; MARIBS Study Group. Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet. 2005;365(9473):1769-1778.
139. Le-Petross HT, Whitman GJ, Atchley DP, et al. Effectiveness of alternating mammography and magnetic resonance imaging for screening women with deleterious BRCA mutations at high risk of breast cancer. Cancer. 2011;117(17):3900-3907.
140. Metcalfe KA, Esplen MJ, Goel V, Narod SA. Psychosocial functioning in women who have undergone bilateral prophylactic mastectomy. Psychooncology. 2004;13(1):14-25.
141. Michelsen TM, Dorum A, Trope CG, Fossa SD, Dahl AA. Fatigue and quality of life after risk-reducing salpingo-oophorectomy in women at increased risk for hereditary breast-ovarian cancer. Int J Gynecol Cancer. 2009;19(6):1029-1036.
142. Nurudeen S, Guo H, Chun Y, et al. Patient experience with breast reconstruction process following bilateral mastectomy in BRCA mutation carriers. Am J Surg. 2017;214(4):687-694.
143. Portnoy DB, Loud JT, Han PK, Mai PL, Greene MH. Effects of false-positive cancer screenings and cancer worry on risk-reducing surgery among BRCA1/2 carriers. Health Psychol. 2015;34(7):709-717.
144. Rijnsburger AJ, Essink-Bot ML, van Dooren S, et al. Impact of screening for breast cancer in high-risk women on health-related quality of life. Br J Cancer. 2004;91(1):69-76.
145. Spiegel TN, Esplen MJ, Hill KA, Wong J, Causer PA, Warner E. Psychological impact of recall on women with BRCA mutations undergoing MRI surveillance. Breast. 2011;20(5):424-430.
146. Stefanek ME, Helzlsouer KJ, Wilcox PM, Houn F. Predictors of and satisfaction with bilateral prophylactic mastectomy. Prev Med. 1995;24(4):412-419.
147. Wasteson E, Sandelin K, Brandberg Y, Wickman M, Arver B. High satisfaction rate ten years after bilateral prophylactic mastectomy-a longitudinal study. Eur J Cancer Care. 2011;20(4):508-513.
148. Vreemann S, Gubern-Merida A, Schlooz-Vries MS, et al. Influence of risk category and screening round on the performance of an MR imaging and mammography screening program in carriers of the BRCA mutation and other women at increased risk. Radiology. 2018;286(2):443-451.
149. Rijnsburger AJ, Obdeijn IM, Kaas R, et al. BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: long-term follow-up of the Dutch MRISC Screening Study. J Clin Oncol. 2010;28(36):5265-5273.
150. Nelson HD, Fu R, McDonagh M, Miller LB, Pappas M, Zakher B. Medication Use for the Risk Reduction of Primary Breast Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2019.
151. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 2005;97(22):1652-1662.
152. Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M. Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst. 2007;99(4):283-290.
153. Veronesi U, Maisonneuve P, Rotmensz N, et al; Italian Tamoxifen Study Group. Tamoxifen for the prevention of breast cancer: late results of the Italian randomized tamoxifen prevention trial among women with hysterectomy. J Natl Cancer Inst. 2007;99(9):727-737.
154. Cuzick J, Forbes JF, Sestak I, et al. Long-term results of tamoxifen prophylaxis for breast cancer—96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst. 2007;99(4):272-282.
155. Grady D, Cauley JA, Geiger MJ, et al; Raloxifene Use for The Heart Trial Investigators. Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk. J Natl Cancer Inst. 2008;100(12):854-861.
156. Lippman ME, Cummings SR, Disch DP, et al. Effect of raloxifene on the incidence of invasive breast cancer in postmenopausal women with osteoporosis categorized by breast cancer risk. Clin Cancer Res. 2006;12(17):5242-5247.
157. Cuzick J, Sestak I, Forbes JF, et al; IBIS-II Investigators. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014;383(9922):1041-1048.
158. Sestak I, Singh S, Cuzick J, et al. Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial.[Erratum appears in Lancet Oncol. 2014;15(13):e587]. Lancet Oncol. 2014;15(13):1460-1468.
159. Spagnolo F, Sestak I, Howell A, Forbes JF, Cuzick J. Anastrozole-induced carpal tunnel syndrome: results from the International Breast Cancer Intervention Study II prevention trial. N Engl J Med. 2016;34(2):139-143.
160. Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. New Engl J Med. 2011;364(25):2381-2391.
161. Maunsell E, Goss PE, Chlebowski RT, et al. Quality of life in MAP.3 (Mammary Prevention 3): a randomized, placebo-controlled trial evaluating exemestane for prevention of breast cancer. N Engl J Med. 2014;32(14):1427-1436.
162. Vogel VG, Costantino JP, Wickerham DL, et al; National Surgical Adjuvant Breast and Bowel Project. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res. 2010;3(6):696-706.
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.36 BRCA indicates breast cancer susceptibility gene.
a Clinically significant pathogenic mutations in the BRCA1 and BRCA2 genes associated with increased risk for breast cancer, ovarian cancer, or both.
b Includes women who may have a previous diagnosis of breast or ovarian cancer but have completed treatment and are considered cancer-free.
c Descriptions of genetic counseling, scope of services, and appropriate clinicians are described in the full report.
d Testing may be conducted on the index patient, her relative with cancer, or her relative with highest risk, as appropriate.
e Includes interpretation of results, determination of eligibility for risk-reducing interventions, and patient decision making.
f Interventions 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.
a Includes reference lists of relevant articles, studies, and systematic reviews; suggestions from reviewers.
b One hundred three studies in 110 publications provided data; some addressed more than 1 KQ.
|Model||Data Collection and Calculation||Population (No.)||Relatives With Breast or Ovarian Cancer||Other Factors||Comparison With Other Models||Reference Standard||Performance Characteristics for Predicting Risk for BRCA1/2 Mutations||Quality
|Evaluates brief versions of BRCAPROb to guide referral to genetic counseling that uses full BRCAPRO||Patients with personal or family cancer history in 3 US hospital databases (4057)||First- and second-degree||No. and types of relatives with breast and ovarian cancer; ages diagnosed||BRCAPRO||Mutation testing||Estimates based on different cutpoints:
BRCAPRO-LYTE: sensitivity, 57%-93%; specificity, 10%-56%
BRCAPRO-LYTE-plus: sensitivity, 39%-76%; specificity, 40%-83%
BRCAPRO-LYTE-simple: sensitivity, 43%-83%; specificity, 29%-79%
|Seven-question Family History Screening39||One positive response to 7 items is referral threshold||Women visiting primary care clinics in Brazil (9218 completed FHS-7, 1246 referred, 902 completed evaluation)||First-degree||Any relatives with breast cancer aged ≤50 y; bilateral breast cancer; breast and ovarian cancer in same person; male breast cancer; ≥2 relatives with breast or ovarian cancer; ≥2 relatives with breast or colon cancer||Criteria for hereditary breast cancer syndromec||Mutation testing||Sensitivity, 88% (95% CI, 83%-91%)
Specificity, 56% (95% CI, 54%-59%)
PPV, 24% (95% CI, 21%-27%)
NPV, 97% (95% CI, 95%-98%)
AUC, 0.83 (95% CI, 0.81-0.85)
|International Breast Cancer Intervention Study Model38, 44, 49||Compares performance with other established models||German Hereditary Breast and Ovarian Cancer Consortium (7352 families); families in cancer genetics clinics in the United Kingdom (1889) and Canada (300)||Female first- and second-degree relatives, affected cousins, and half-sisters||Environmental factors for female index patients only||BOADICEA
|Mutation testing||German study: sensitivity, 77%; specificity, 56.5%
PPV, 36%; NPV, 88.5%
AUC, 0.75 (95% CI, 0.74-0.76)
UK study: AUC, 0.74 (95% CI, 0.71-0.77)
Canadian study: AUC, 0.47 (95% CI, 0.28-0.69)
|Fair to good|
|Manchester scoring system38,40,43,48,49||Assigns points for responses to 12 items; referral threshold ≥10 points per mutation or ≥15 collectively (≥10% mutation probability)||Developed in families with cancer history in the United Kingdom (422); evaluated in 4 additional studies in United Kingdom and Canada (2880)||First-, second-, and third-degree||Type of cancer (breast, ovarian, pancreatic, or prostate), affected family members, and age at diagnosis||BOADICEA
|Mutation testing||Estimates based on different evaluation studies (≥10% mutation probability): sensitivity, 58%-93%; specificity, 33%-71%; AUC, 0.75-0.80||
Fair to good
|Modified Manchester scoring system47||Assigns points for responses; referral threshold ≥10 points per mutation or ≥15 collectively (≥10% mutation probability||German Hereditary Breast and Ovarian Cancer Consortium (9390 families)||First-, second-, and third-degree||New version includes pathology (histology and hormone receptor status) of index patient in addition to original factors: type of cancer (breast, ovarian, pancreatic, or prostate), affected family members, age at diagnosis||Original MSS (MSS-2004) without pathology; MSS-2009 with pathology; recalibrated MSS (MSS-recal) with pathology||Mutation testing||≥10% Mutation probability:
MSS-2004: AUC, 0.77 (95% CI, 0.75-0.79)
MSS-2009: AUC, 0.80 (95% CI, 0.78-0.82)
|Ontario Family History Assessment Tool45,48-50||Assigns points for responses to 17 items; referral threshold ≥10 (≥22% lifetime risk for breast or ovarian cancer)||Developed in families with cancer history in Canada (184); evaluated in 3 additional studies in Canada and United States (3566)||First-, second-, and third-degree||Age at diagnosis; bilateral breast cancer; breast and ovarian cancer in same person; male breast cancer; colon and prostate cancer||Claus
|Mutation testing||Estimates based on different evaluation studies (≥22 lifetime risk): sensitivity, 91%-94%; specificity, 15%-51%
|Fair to good|
|Pedigree Assessment Tool46, 51||Assigns points for responses to 5 items; referral threshold ≥8 points (≥10% mutation probability)||Developed in women without breast cancer presenting for screening mammography at a US community hospital (3906); evaluated in families in United States (520 families)||First-, second-, and third-degree||Breast cancer aged ≤50 y or >50 y; ovarian cancer at any age; male breast cancer; Ashkenazi Jewish ancestry||Myriad II
|Mutation testing||Mutation testing as reference standard (≥10% mutation probability): sensitivity, 95.9%;
PPV, 0.32; NPV, 0.93
Myriad II as reference standard (≥10% mutation probability): sensitivity, 100%; specificity, 93% PPV, 0.63; NPV, 1.00
|Referral Screening Tool41||≥2 Positive responses to 13 items is referral threshold (≥10% mutation probability)||Unselected women undergoing screening mammogram (2464 completed screening tool, 296 randomly evaluated)||First- and second-degree||Breast cancer at age ≤50 y (self or relatives); ovarian cancer at any age (self or relatives); ≥2 relatives aged >50 y with breast cancer on same side of family; male breast cancer; Jewish ancestry||None||Pedigree analysis and estimates of mutation risk based on models (BOADICEA; BRCAPRO; FHAT; Myriad II)d||≥10% Mutation probability: sensitivity, 81%; specificity, 92%
PPV, 0.80; NPV, 0.92
Abbreviations: AUC, area under the receiver operating characteristic curve; BOADICEA, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm; FHAT, Family History Assessment Tool; MSS, Manchester Scoring System; NPV, negative predictive value; PPV, positive predictive value.
a Individual clinical scoring instruments are detailed in Appendix C1 and quality ratings in Appendix B1 of the full report.35
b BRCAPRO-LYTE applies the BRCAPRO model using only information on the numbers and types of first- and second-degree relatives, which relatives are affected with breast and ovarian cancer, and their ages of diagnosis; BRCAPRO-LYTE-plus does not collect data on ages of affected relatives but imputes ages based on a large external data set; BRCAPRO-LYTE-simple imputes the number of relatives for each type of cancer and ages of unaffected relatives.
c Based on evaluation including pedigree analysis, lifetime risk estimates from established models (Claus; Gail; Tyrer-Cuzick; Penn II), American Society of Clinical Oncology criteria, and review by 2 clinical geneticists.
d Detailed 4-generation cancer pedigrees analyzed using 4 established hereditary risk models (BRCAPRO, Myriad II, BOADICEA, FHAT), with a 10% or greater BRCA1/2 mutation probability or FHAT score of 10 or greater as the definition of “high risk.”
|Source||No.||Clinician||Breast Cancer Worry||Anxiety||Depression||Accuracy of Risk Perception||Intent to Participate in Testing||Quality Rating|
|Albada et al,52 2016||89||Geneticist, genetic counselor||NA|
|Bennett et al,54 2008||128||Genetic counselor||–||+||–||–||–||–||NA|
|Bennett et al,55 2009||128||Genetic counselor||–||NA|
|Bloom et al,56 2006||163||Genetic counselor||–||–||–||–||Poor|
|Bowen et al,59 2002||354b||Genetic counselor||–||+||Fair|
|Bowen et al,58
|Bowen et al,57
|221||Psychologist, genetic counselor||–||+||+||–||–||+||Fair|
|Brain et al,60 2002||740b||Geneticist, nurse||–||+||–||+||+||–||Good|
|Brain et al,61 2011||263b||Physician||–||+||NA|
|Braithwaite et al,62 2005||72||Nurse||–||+||–||+||+||–||Fair|
|Burke et al,63
|Cull et al,[ 1998||144||Geneticist, physician||–||–||–||–||+||+||Fair|
|Fry et al,65 2003||263||Geneticist, physician, nurse||–||+||+||–||Fair|
|Gurmankin et al,66 2005||125||Physician||+||–||NA|
|Helmes et al,67 2006||340||Genetic counselor||–||+||+||–||–||+||Fair|
|Hopwood et al,68 1998||174||Genetic counselor||–||–||–||–||+||–||Fair|
|Hopwood et al,69 2004||256||Genetic counselor||–||+||–||–||–||–||NA|
|Kelly et al,70 2008||78||Genetic counselor||–||+||NA|
|Lerman et al,72 1996||227||Genetic counselor||–||–||+||–||Fair|
|Lerman et al,71 1999||364||Nurse, genetic counselor||–||–||+||–||Fair|
|Lobb et al,73 2004||193||Geneticist, genetic counselor, physician||–||–||–||–||–||–||Good|
|Matloff et al,74 2006||64||Genetic counselor||+||–||Fair|
|Mikkelsen et al,75 2007||1971b||Physician||–||–||Fair|
|Mikkelsen et al,76 2009||1971b||Physician||–||+||–||–||–||–||Fair|
|Pieterse et al,77 2011||77||Geneticist, genetic counselor||–||+||+||–||NA|
|Roshanai et al,78 2009||163||Nurse||–||+||–||+||+||–||Fair|
|Watson et al,80 1998||115||Geneticist||–||–||–||–||–||–||+||–||Good|
|Watson et al,81 1999||283||Geneticist||–||–||–||–||–||–||Good|
Abbreviation: NA, not applicable.
a Plus (+) indicates statistically significant relationship with genetic counseling; minus (–) indicates studied, but no statistically significant relationship with genetic counseling; empty cell indicates not studied.
b Uses the same population in more than 1 study.
|Source||Inclusion Criteria||No. With BRCA1/2
|Mean Age at Surgery, y||Cancer Incidence||Mortality||Mean Follow-up, y||Quality Rating|
|Mastectomy vs Surveillance|
|Flippo-Morton et al,107 2016||BRCA1/2 carrier; with or without breast or ovarian cancer||123 BRCA1
1 BRCA1 + BRCA2
|0/38 vs 5/36||NR||NR||2.5||Fair|
et al,110 2013
|BRCA1/2 carrier; no history of cancer||405 BRCA1
|35 (median)||Person-years: 0/1379 vs 57/2017||NR||All-cause person-years: 6/2253 vs 1/1384; HR, 0.20 (95% CI, 0.02-1.68)
Breast cancer person-years: 4/2253 vs 1/1384; HR, 0.29 (95% CI, 0.03-2.61)
|8.5 vs 6.3 (median)||Fair|
|Skytte et al,118 2011||BRCA1/2 carrier||201 BRCA1
|NR||3/96 vs 16/211; HR, 0.39 (95% CI, 0.12-1.36)||NR||NR||NR||Good|
|Domchek et al,105 2010||BRCA1 carrier||415 BRCA1||37||0/43 vs 19/372||NR||NR||2.7||Fair|
|245 BRCA2||39||0/32 vs 15/213||2.5|
|Evans et al,106 2009||Lifetime risk of breast cancer >25%||High-risk; 202 BRCA1/2||NR||Observed vs expected: 307 vs 21.3||NR||NR||7.5||NA|
|Hartmann et al,109 2001
Hartmann et al,108 1999
|Family history of breast cancer||214 High-risk||42||Observed vs expected: 3/214 vs 37; risk reduction, 92% (95% CI, 77%-98%)||2||Observed vs expected: 2/214 vs 10; risk reduction, 81% (95% CI, 31%-98%)||14 (median)||NA|
|425 Moderate-risk||42||Observed vs expected: 4/425 vs 37; risk reduction, 89.5% (P < 0.001)||0||Observed vs expected: 0/425 vs 10; risk reduction, 100% (95% CI, 70%-100%)||14 (median)|
|18 BRCA1 or BRCA2||41||Observed vs expected: 0/18 vs 6.1/18; risk reduction, 100% (95% CI, 51%-100%)||NR||NR||13.4 (median)|
|Salpingo-Oophorectomy or Oophorectomy vs Surveillance|
|Kotsopoulos et al,112 2016||BRCA1/2; no cancer||2969 BRCA1
33.4 (no surgery at baseline)
|Annual incidence, all women: 1.87% vs 1.59%; HR, 0.89 (95% CI, 0.69-1.14)
All ages: BRCA1: HR, 0.97 (95% CI, 0.73-1.29); BRCA2: HR, 0.68 (95% CI, 0.38-1.21)
Age <50 y: BRCA1: HR, 0.84 (95% CI, 0.58-1.21); BRCA2: HR, 0.17 (95% CI, 0.05-0.61)
Heemskerk-Gerritsen et al,111 2015
|BRCA1/2; no cancer||589 BRCA1
33 (no surgery)
|All: 42/346 vs 47/476; HR, 1.09 (95% CI, 0.67-1.77)
BRCA1: HR, 1.21 (95% CI, 0.72-2.06)
BRCA2: HR, 0.54 (95% CI, 0.17-1.66)
Age <51 y: HR, 1.11 (95% CI, 0.65-1.90)
Age ≥51 y: HR, 1.78 (95% CI, 0.52-6.15)
Mavaddat et al,114 2013
|BRCA1/2; no cancer or history of unilateral breast cancer||501 BRCA1
|41.2 at enrollment||18/309 vs 46/679; HR, 0.62 (95% CI, 0.35-1.09)
BRCA1: HR, 0.52 (95% CI, 0.24-1.13)
BRCA2: HR, 0.79 (95% CI, 0.35-1.80)
Age <45 y: HR, 0.39 (95% CI, 0.17-0.87)
Age ≥45 y: HR, 1.14 (95% CI, 0.50-2.61)
|Domchek et al,105 2010||BRCA1 carrier||1003 BRCA1||42||32/236 vs 129/633; HR, 0.63 (95% CI, 0.41-0.96)||6/342 vs 49/661; HR, 0.31 (95% CI, 0.12-0.82)||All-cause: 8/327 vs 43/608; HR, 0.52 (95% CI, 0.24-1.14)||5.6||Fair|
|554 BRCA2||46||7/100 vs 94/401; HR, 0.36 (95% CI, 0.16-0.82)||0/123 vs 14/431||All-cause: 0/120 vs 17/403||5.8|
|Shah et al,117 2009||BRCA1/2 carriers or mutation probability >75%||51 BRCA1
|47 at enrollment (median)||Any oophorectomy: 9/80 vs 2/13
Age ≤40 y: 3/25 vs 8/68
|Kramer et al,113 2005||BRCA1-positive family; no bilateral mastectomy||98 BRCA1-positive||NR||6/33 vs 27/65; HR, 0.38 (95% CI, 0.15-0.97)||NR||NR||Fair|
|353 BRCA1-negative||1/34 vs 4/319|
|222 Unknown mutation status||0/18 vs 5/204|
|Rebbeck et al,116 2002||BRCA1/2; no ovarian cancer or unilateral oophorectomy; no history of breast cancer or mastectomy||459 BRCA1
40.9 (no surgery)
|21/99 vs 60/142; HR, 0.47 (95% CI, 0.29-0.77)
Age <35 y: HR, 0.39 (95% CI, 0.15-1.04)
Age 35-50 y: HR, 0.49 (95% CI, 0.26-0.90)
Age ≥50 y: HR, 0.52 (95% CI, 0.10-2.70)
|2/259 vs 58/292; HR, 0.04 (95% CI, 0.01-0.16)
No history of breast cancer: HR, 0.06 (95% CI, 0.01-0.25)
Age 35-50 y: HR, 0.03 (95% CI, 0.01-0.20)
Age ≥50 y: HR, 0.11 (95% CI, 0.02-0.7)
|NR||8.2 vs 8.8||Fair|
|Olson et al,115 2004||Women with bilateral oophorectomy||55 High-risk||<60||Observed vs expected: 3/55 vs 5.4; RR, 0.56 (95% CI, 0.1-1.33||NR||NR||NA||NA|
|41 High-risk||<50||Observed vs expected: 1/41 vs 3.9; RR, 0.26 (95% CI, 0.01-0.99)|
|193 Moderate-risk||<60||Observed vs expected: 9/193 vs 10.9; RR, 0.83 (95% CI, 0.38-1.44)|
|130 Moderate-risk||<50||Observed vs expected: 5/130 vs 7.7; RR, 0.65 (95% CI, 0.21-1.32)|
|Struewing et al,119 1995||Families with ≥3 cases of ovarian cancer or ≥2 cases ovarian cancer and ≥1 case breast cancer before age 50 y||390 (12 families) first-degree relatives of individuals with breast or ovarian cancer||NR||3/44 vs 14/346||2/44 vs 8/346||NR||NR||Poor|
Abbreviations: BRCA, breast cancer susceptibility gene; EMBRACE, Epidemiological Study of Familial Breast Cancer; HEBON, Hereditary Breast and Ovarian Cancer Research Group Netherlands; HR, hazard ratio; NA, not applicable; NR, not reported; RR, relative risk.
|Populations or Interventions||Studies;
Observations (No.); Study Designs
|Summary of Findings||Consistency and Precision||Other Limitations||Strength of Evidence||Applicability|
|KQ1: Benefits of Risk Assessment, Genetic Counseling, and Genetic Testing|
|Risk assessment; genetic counseling; genetic testing||No studies||NA||NA||NA||Insufficient||NA|
|KQ2a: Accuracy of Familial Risk Assessment Tools By Nonspecialist|
|Risk assessment for BRCA1/2-related cancer risk||14 Discriminatory accuracy studies of 8 risk assessment tools (n = 43,813)||Tools have moderate to good discriminatory accuracy in predicting the probability of familial BRCA1/2-related cancer risk in individuals (AUC, 0.68-0.96)||Consistent; precise||While some studies enrolled small numbers or inadequately described methods, most studies met criteria for fair and good quality||Moderate for benefit||Moderate to high|
|KQ2a: Optimal Ages and Intervals for Risk Assessment|
|Risk assessment for BRCA1/2-related cancer risk||No studies||NA||NA||NA||Insufficient||NA|
|KQ2b: Benefits of Pretest Genetic Counseling|
|Pretest genetic counseling||28 Studies (1 systematic review; 14 RCTs; and 4 cohort, 1 case-control, and 8 before-and-after) (n = 8060)||Genetic counseling decreases cancer worry, anxiety, and depression; increases the accuracy of risk perception; and decreases intention for mutation testing
Face-to-face counseling preferred in some studies
|Consistent; precise||Dissimilar comparison groups; small sizes; dissimilar interventions; heterogeneous outcome measures||High for benefit||High|
|KQ2c: Optimal Testing Approaches|
|BRCA1/2 mutation testing||1 RCT (n = 1034)||Universal testing of Ashkenazi Jews for founder mutations detected more BRCA1/2 carriers than testing only those meeting family history criteria||NA||All participants had genetic counseling, so not a true population approach; not all were tested, so cannot determine accuracy of strategy||Low for benefit||Moderate|
|KQ2d: Optimal Posttest Counseling Approaches|
|Posttest genetic counseling||No studies||NA||NA||NA||Insufficient||NA|
|KQ3a: Harms of Risk Assessment|
|Risk assessment for BRCA1/2-related cancer risk||No studies||NA||NA||NA||Insufficient||NA|
|KQ3b: Harms of Pretest Genetic Counseling|
|Pretest genetic counseling||28 Studies (1 systematic review; 14 RCTs; and 4 cohort, 1 case-control, and 8 before-and-after) (n = 8060)||Genetic counseling did not cause adverse effects in studies but decreased cancer worry, anxiety, and depression; increased the accuracy of risk perception; and decreased intention for mutation testing||Consistent; precise||Dissimilar comparison groups; small sizes; dissimilar interventions; heterogeneous outcome measures||Moderate for harms||Moderate|
|KQ3c: Harms of Genetic Testing|
|BRCA1/2 mutation testing||20 Studies (1 RCT, 13 cohort, 1 case-control, 4 before-and-after, and 1 case series) (n = 4322)||Breast cancer worry and anxiety increase for women with positive results and decrease for others, while risk perception improves||Consistent; precise||Lack of studies with comparison groups; variations in methodology and enrollment criteria; heterogeneous outcome measures; high loss to follow-up||Moderate for benefits and harms (varies by test result)||Moderate|
|KQ3d: Harms of Posttest Counseling|
|Posttest genetic counseling||No studies||NA||NA||NA||Insufficient||NA|
|KQ4: Interventions to Reduce BRCA1/2-Related Cancer and Mortality|
|Intensive screening||No effectiveness trials; 6 studies of test characteristics of screening (n = 5087)||Breast MRI has higher sensitivity than mammography for screening BRCA1/2 carriers (71% vs 41%); specificity is comparable (90% vs 95%)
Sensitivity of screening for ovarian cancer, 43% for TVUS and 71% for CA-125; specificity, 99% for either
|NA||Descriptive studies that do not provide data on effectiveness||Insufficient||NA|
|Risk-reducing medications (tamoxifen, raloxifene, aromatase inhibitors [anastrozole; exemestane])||No trials for BRCA1/2
carriers; 9 RCTs for general populations (n = 74,170)
|Tamoxifen, raloxifene, anastrozole, and exemestane reduced invasive breast cancer and ER+ breast cancer compared with placebo
No differences for ER− or noninvasive breast cancer, all-cause or breast cancer-specific mortality
|Consistent; precise||No results for BRCA1/2 carriers specifically; clinical heterogeneity across trials from varying eligibility criteria, adherence, and ascertainment of certain outcomes||Insufficient for BRCA1/2 carriers specifically; high for benefit fo general populations||High|
|Risk-reducing surgery||6 Observational studies of mastectomy; 7 observational studies of oophorectomy (n = 9938)||Bilateral mastectomy reduced breast cancer incidence 90%-100% and breast cancer mortality 81%-100% for high-risk women and mutation carriers
Oophorectomy or salpingo-oophorectomy reduced breast cancer 37%-83% in some instances; salpingo-oophorectomy reduced ovarian cancer 69%-100%
|Consistent; precise||Lack of studies with comparison groups; variations in methodology and enrollment criteria; heterogeneous outcome measures||Moderate for benefit||High|
|KQ5: Harms of Interventions to Reduce BRCA1/2-Related Cancer and Mortality|
|Intensive screening||9 Observational studies (n = 5628)||For breast cancer screening, false-positive rates, additional imaging, and benign surgical procedures were higher for intensive screening using MRI vs mammography; benign diagnostic surgery rate of 55% for mutation carriers screened with TVUS and CA-12||Consistent; precise||Lack of studies with comparison groups; variations in methodology and enrollment criteria; heterogeneous outcome measures||Low for harm||High|
|Risk-reducing medications (tamoxifen, raloxifene, aromatase inhibitors [anastrozole; exemestane])||No trials for BRCA1/2 carriers; 9 RCTs for general populations (n = 74,170)||Tamoxifen and raloxifene increased thromboembolic events and tamoxifen increased endometrial cancer and cataracts compared with placebo; no differences for DVT, PE, CHD events, or stroke||Consistent; precise||No results for BRCA1/2 carriers specifically; clinical heterogeneity across trials from varying eligibility criteria, adherence, and ascertainment of certain outcomes||Insufficient for BRCA1/2 carriers specifically; high for harm for general populations||High for general populations|
|Risk-reducing surgery||10 Observational studies of mastectomy; 4 observational studies of oophorectomy (n = 3073)||Harms include physical complications of surgery, postsurgical symptoms, and changes in body image; psychological symptoms generally improve over time, and some women have improved anxiety||Inconsistent, imprecise||Lack of studies with comparison groups; variations in methodology and enrollment criteria; heterogeneous outcome measures||Low for harm||Moderate|
Abbreviations: AUC, area under the receiver operator characteristic curve; BRCA, breast cancer susceptibility gene; CA-125, cancer antigen 125; CHD, coronary heart disease; DVT, deep vein thrombosis; ER+, estrogen receptor–positive; ER−, estrogen receptor–negative; KQ, key question; MRI, magnetic resonance imaging; NA, not applicable; PE, pulmonary embolism; RCT, randomized clinical trial; TVUS, transvaginal ultrasound.