BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing
December 15, 2013
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.
A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation
Release Date: December 2013
By: Heidi D. Nelson, MD, MPH; Miranda Pappas, MA; Bernadette Zakher, MBBS; Jennifer Priest Mitchell, BA; Leila Okinaka-Hu, MD; and Rongwei Fu, PhD
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 first published in Annals of Internal Medicine on 24 December 2013. Select for copyright and source information.
Background: Mutations in breast cancer susceptibility genes (BRCA1 and BRCA2) are associated with increased risks for breast, ovarian, and other types of cancer.
Purpose: To review new evidence on the benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women.
Data Sources: MEDLINE and PsycINFO between 2004 and 30 July 2013, the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews from 2004 through the second quarter of 2013, Health Technology Assessment during the fourth quarter of 2012, Scopus, and reference lists.
Study Selection: English-language studies about accuracy of risk assessment and benefits and harms of genetic counseling, genetic testing, and interventions to reduce cancer incidence and mortality.
Data Extraction: Individual investigators extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability by using established criteria.
Data Synthesis: Five referral models accurately estimate individual risk for BRCA mutations. Genetic counseling increases the accuracy of risk perception and decreases the intention for genetic testing among unlikely carriers and cancer-related worry, anxiety, and depression. No trials evaluated the effectiveness of intensive screening or risk-reducing medications in mutation carriers, although false-positive rates, unneeded imaging, and unneeded surgeries were higher with screening. Among high-risk women and mutation carriers, risk-reducing mastectomy decreased breast cancer by 85% to 100% and breast cancer mortality by 81% to 100% compared with women without surgery; risk-reducing salpingo-oophorectomy decreased breast cancer incidence by 37% to 100%, ovarian cancer by 69% to 100%, and all-cause mortality by 55% to 100%.
Limitation: The analysis included only English-language articles; efficacy trials in mutation carriers were lacking.
Conclusion: Studies of risk assessment, genetic counseling, genetic testing, and interventions to reduce cancer and mortality indicate potential benefits and harms that vary according to risk.
Primary Funding Source: Agency for Healthcare Research and Quality.
The U.S. Preventive Services Task Force (USPSTF) recommended in 2005 that women whose family histories are associated with increased risks for clinically significant, or deleterious, mutations in the BRCA1 or BRCA2 gene be referred for genetic counseling and evaluation for mutation testing 1. This recommendation was intended for primary prevention of cancer and applies to women without previous diagnoses of breast or ovarian cancer.
Deleterious mutations in the BRCA1 and BRCA2 genes are associated with increased risks for breast, ovarian, fallopian tube, and peritoneal cancer in women and breast cancer in men 2. They are also, to a lesser degree, associated with pancreatic and early-onset prostate cancer, and BRCA2 mutations are associated with melanoma. Mutations in BRCA genes cluster in families exhibiting an autosomal dominant pattern of transmission and account for 5% to 10% of cases of breast cancer overall 3,4.
Specific BRCA mutations, known as founder mutations, occur among certain ethnic groups, including Ashkenazi Jewish 5-7, black 8, and Hispanic persons 9,10, and in identified families 11-15. Other genes are associated with hereditary susceptibility to breast and ovarian cancer but are not commonly tested, such as PTEN (the Cowden syndrome) and TP53 (the Li-Fraumeni syndrome) 2,16.
Genetic risk assessment and testing involve determining individual risk for BRCA mutations, followed by selective testing of high-risk persons. Characteristics associated with an increased likelihood of BRCA mutations 17-20 include breast and ovarian cancer in relatives and a young age of onset. These and other individual and family characteristics can be used to assess personal mutation risk and the need for referral for additional evaluation. Genetic counseling is the process of identifying and counseling persons at risk for familial or inherited cancer and is recommended before testing 21,22.
Guidelines recommend testing for mutations only when an individual has a personal or family history of cancer suggestive of inherited cancer susceptibility and the results can be adequately interpreted and will aid in management 23. The type of mutation analysis that is required depends on family history. Persons without links to families or groups with known mutations 5-10,12-14 generally have direct DNA sequencing. For appropriate candidates, interventions to reduce cancer risk include earlier, more frequent, or intensive cancer screening; risk-reducing medications; and risk-reducing surgery, including bilateral mastectomy and salpingo-oophorectomy.
This systematic review is an update of a prior review 1,24,25 for the USPSTF on the effectiveness and adverse effects of risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. Its purpose is to evaluate and summarize research addressing specific key questions important to the USPSTF as it considers new recommendations for primary care practice.
This research is part of a comprehensive systematic review that includes an additional analysis of studies of the prevalence and penetrance of BRCA mutations that is not included in this manuscript 26. We followed a standard protocol consistent with the Agency for Healthcare Research and Quality (AHRQ) methods for systematic reviews 27. On the basis of evidence gaps identified from a prior review 24,25, the USPSTF and AHRQ determined the key questions for this update by using the methods of the USPSTF 28. Investigators created an analytic framework incorporating the key questions and outlining the patient populations, interventions, outcomes, and potential adverse effects (Appendix Figure 1). A work plan was externally reviewed and modified.
The target population includes women without cancer or known BRCA mutations who are seen in clinical settings applicable to U.S. primary care practice, although the ideal candidate for mutation testing could be a male or female relative with cancer. The conditions of interest are mutation carrier status and BRCA-related cancer (predominantly breast, ovarian, fallopian tube, and peritoneal). Although other types of cancer are also considered during familial risk assessment, studies with these cancer outcomes are outside the scope of this review.
We searched MEDLINE from 2004 to 30 July 2013, the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews from 2004 through the second quarter of 2013, and Health Technology Assessment during the fourth quarter of 2012 for relevant English-language studies, systematic reviews, and meta-analyses. We manually reviewed reference lists of articles and reviewed citations of key studies by using Scopus.
Research published in 2004 or later and done in the United States or in populations that receive services and interventions applicable to medical practice in the United States was reviewed. Randomized, controlled trials (RCTs); systematic reviews; prospective and retrospective cohort studies; case-control studies; and diagnostic accuracy evaluations were included if they addressed the accuracy of risk assessment methods, outcomes of genetic counseling and testing, and the effectiveness of interventions to reduce BRCA-related cancer and mortality among mutation carriers.
Risk assessment methods were included if they were designed to guide referrals to genetic counselors or other genetic specialists and were usable by nonspecialists in genetics in clinical settings (that is, methods that were brief and nontechnical and did not require special training to administer or interpret). Evaluation of comprehensive models used in the practice of genetic counseling was outside the scope of this review, which focuses on primary care practice. Interventions included intensive screening, risk-reducing medications, and risk-reducing surgery. Only risk-reducing medications approved by the U.S. Food and Drug Administration (that is, tamoxifen and raloxifene) were considered, consistent with the scope of the USPSTF.
Studies of any design were included if they described potential adverse effects, including inaccurate risk assessment; inappropriate testing; false-positive and false-negative results; false reassurance; incomplete testing; misinterpretation of results; anxiety; cancer-related worry; immediate and long-term harms associated with interventions; and ethical, legal, and social implications. For adverse effects of interventions, studies were included that enrolled women at high risk for BRCA-related cancer regardless of their mutation status.
After an initial review of abstracts, we reviewed full-text articles by using additional inclusion criteria. Studies from the prior review that met inclusion criteria for the update were included to build on previous relevant research. Appendix Figure 2 shows the results of the search and selection process.
Data Abstraction and Quality Assessment
An investigator abstracted data about the study design and setting; participant characteristics; procedures for data collection; number of participants enrolled and lost to follow-up; methods of exposure and outcome ascertainment; analytic methods, including adjustment for confounders; and outcomes. A second investigator confirmed the accuracy of key data. Two investigators used predefined criteria for RCTs; systematic reviews; and cohort, case-control, and diagnostic accuracy studies developed by the USPSTF 28,29 to rate the quality of studies (good, fair, or poor) and resolved discrepancies by consensus.
Quality could not be assessed for many studies with designs that did not have predefined criteria, such as descriptive, cross-sectional, and pre-post studies, and case series. The applicability of studies was determined using the population, intervention, comparator, outcomes, timing of outcomes measurement, and setting format adapted to this topic 30.
Data Synthesis and Analysis
Because of heterogeneity across studies, results were not combined in a quantitative meta-analysis. We assessed the aggregate quality of the body of evidence (good, fair, or poor) by using methods that the USPSTF developed on the basis of the number, quality, and size of studies and consistency of results between studies 28. Studies were considered consistent if outcomes were generally in the same direction of effect and ranges of effect sizes were narrow.
Role of the Funding Source
This research was funded by AHRQ. Investigators worked with AHRQ staff and USPSTF members to define the scope, analytic framework, and key questions; resolve issues arising during the project; and review the final report to ensure that it met basic methodological standards for systematic reviews. The draft report was reviewed by content experts, USPSTF members, AHRQ program officers, and collaborative partners and was posted for public comment for 4 weeks during April 2013. The funding source had no role in the selection, critical appraisal, or synthesis of evidence. The investigators were solely responsible for the content and the decision to submit the manuscript for publication.
Accuracy and Adverse Effects of Referral Models to Estimate Individual Risk for BRCA Mutations
Risk models estimate the likelihood of BRCA mutations in individual persons, and some were developed to guide patient referrals to genetic counselors or other genetic specialists for more comprehensive evaluations. Ten studies describing performance characteristics of the Ontario Family History Assessment Tool (FHAT) 31-33, Manchester scoring system 33-36, Referral Screening Tool (RST) 37,38, Pedigree Assessment Tool (PAT) 39, and Family History Screen-7 (FHS-7) 40 met inclusion criteria for this review (Appendix Table 1). Included studies met criteria for fair or good quality and determined the sensitivity and specificity of models by comparing results of mutation carriers versus noncarriers or referral models versus more complex models, such as the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm 41,42, BRCAPRO 43-45, and Myriad II 18 (Appendix Table 2). No studies described adverse effects of the risk models. Studies of the RST, PAT, and FHS-7 were published after the prior USPSTF systematic review.
Models were evaluated in patient populations in the United States (RST and PAT), Canada (FHAT), the United Kingdom (Manchester scoring system), and Brazil (FHS-7). Most studies defined the referral threshold as 10% estimated probability of a BRCA mutation. The FHAT and Manchester scoring system were evaluated in selected populations of known mutation carriers and noncarriers. Sensitivity was high for both models in most studies (94% for the FHAT 31,32 and 87% to 93% for the Manchester scoring system 34-36. Lower sensitivity estimates (70% for the FHAT and 58% for the Manchester scoring system) came from a study of both models that included 200 mutation carriers and 100 noncarriers 33, which represented a patient spectrum different from that of the other studies.
The RST, PAT, and FHS-7 were evaluated in large samples of women having screening mammography or visiting primary care clinics. The sensitivity of the RST was high compared with that of the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (89%), BRCAPRO (91%), and Myriad II (91%) 37. A revised Web-based version that includes more information on family history reported slightly higher sensitivity values 38. The PAT had 100% sensitivity compared with Myriad II 39, and the FHS-7 had 88% sensitivity compared with a genetic evaluation that included kindred analysis, risk estimates using multiple models, and clinical criteria 40.
Benefits and Adverse Effects of Genetic Counseling to Determine Eligibility for Genetic Testing
Twenty-seven studies met inclusion criteria, including 16 published since the prior review 46-63 and 11 included previously 64-74 (Appendix Table 3). Studies provided data about accuracy of risk perception; intention for genetic testing; and distress, measured as breast cancer-related worry, anxiety, or depression.
Although studies included in the prior USPSTF review were inconclusive 64,66-69,71-74, 8 new studies consistently reported improved accuracy of the perception of risk for breast cancer after genetic counseling 50,54-56,58,59,61,72. A single study reported decreased accuracy 51. Only 1 study evaluated perception of risk for ovarian cancer and reported decreased accuracy after counseling 57. A fair-quality systematic review of 19 studies published before February 2007 indicated that risk perception was accurate for 42% of women before counseling and for 58% after 63. Accuracy improved when counseling provided information about family history, heredity, and personal risk estimates and facilitated informed decision making and adaptation to personal risk.
Intention to Participate in Genetic Testing
Two new studies reported decreased intention to have genetic testing after genetic counseling among women unlikely to be carriers 50,55, which is consistent with prior studies 64,67,70. These include a study comparing telephone counseling, in-person counseling, and no counseling that indicated that women in the 2 counseling groups were less likely to pursue genetic testing than those in the noncounseling group 55. A fair-quality RCT reported decreased interest in genetic testing 6 months after group and individual counseling compared with no counseling 50.
Cancer-Related Worry, Anxiety, and Depression
No new studies reported increased breast cancer-related worry among women who received genetic counseling, and 8 studies reported decreases 48,50-53,55,56,60; 1 poor-quality RCT reported no changes 49. These results are consistent with prior studies indicating that breast cancer-related worry usually decreases after genetic counseling 65-67,69-71,73,74. No studies reported statistically significant increases in anxiety and depression after genetic counseling; 3 reported statistically significant decreases 52,61,62, and 3 reported no changes 48,56,60. Studies in the prior review also indicated that measures of anxiety and depression generally decreased or did not differ with counseling 65,66,68,69,72-74.
Adverse Effects of Genetic Testing
Thirteen new observational studies 75-89 and 1 included previously 90 (Appendix Table 4) provided data about distress due to BRCA testing, measured as breast cancer-related worry, anxiety, or depression or other psychosocial outcomes. No studies described other adverse effects of testing, such as false-positive or false-negative results or unneeded risk-reducing interventions.
Five studies reported statistically significant increases in breast cancer-related worry after receipt of BRCA test results 76,87-90. These results were confined to mutation carriers before versus after testing 88, mutation carriers compared with noncarriers 87, 89 or compared with women who were not tested 90, and women with a family history that indicates high risk for breast cancer compared with untested low-risk women 76. One study reported a decrease in breast cancer-related worry for both carriers and noncarriers 78.
Studies reported decreased anxiety scores after testing regardless of mutation status 75 and among noncarriers only 82. Prospective cohort studies found statistically significantly higher anxiety scores for mutation carriers versus noncarriers 83,87, women with family histories of breast cancer who were not tested versus mutation carriers 79,80, and mutation carriers and noncarriers 78. Although all women in 1 study had high anxiety scores, noncarriers had lower anxiety scores at 1-week follow-up than carriers and women who were not tested 90. Four studies reported no differences in anxiety over 1 year 77, 85 or among carriers, noncarriers, and age-matched control participants 76,84.
Women with family histories of breast cancer who did not have genetic testing had higher depression scores than mutation carriers in 1 study, although scores did not reach the threshold for clinical depression 80. Noncarriers had lower depression scores at 4-month follow-up than carriers and women who were not tested in another study 90. Four studies reported no differences in depression over time 75,85 or among carriers, noncarriers, and age-matched control participants 76,84, with all scores below the case threshold.
Mutation carriers had more subjective sleep problems than noncarriers and age-matched control participants, although actual sleep duration, latency, and wakefulness, as measured by a wrist monitor, showed no differences among groups 86.
Effectiveness and Adverse Effects of Risk-Reducing Interventions in BRCA Mutation Carriers
Breast Cancer. No studies of the effectiveness of intensive screening met inclusion criteria. Five studies that enrolled mutation carriers and other high-risk women described adverse effects 91-95. The Dutch MRISC (Magnetic Resonance Imaging [MRI] Screening) study reported statistically significantly higher false-positive rates with MRI than with mammography on the first and subsequent screening rounds (first, 14.0% vs. 5.5%; subsequent, 8.2% vs. 4.6%; P < 0.001 for both comparisons) 91. False-negative rates for MRI were lower than those for mammography, although numbers were small 91. A study of every-6-month screening found similar false-positive rates for MRI (11%) and mammography (15%) 92. Recall rates for annual MRI were higher than those for annual mammography in a descriptive study conducted in the United Kingdom (MRI, 11.0% per woman-year; mammography, 3.9%; combined, 13.0%) 93. In that study, 245 of 279 total recalls were for benign findings, amounting to 8.5 recalls per cancer case detected.
These studies also reported additional imaging procedures or biopsies that may have been unnecessary because final results were benign and women may never have had these procedures if the original screening test had not been done 92,96. In the Dutch MRISC study, 43% of women with unneeded biopsies had preceding screening MRIs and 28% had mammography 96. Alternating MRI with mammography screening every 6 months yielded a greater proportion of unneeded imaging (targeted ultrasonography) in women screened with mammography than with MRI (mammography, 8 of 11; MRI, 4 of 8), although rates of unneeded biopsies were similar (mammography, 3 of 11; MRI, 2 of 8) 92.
Discomfort, pain, and anxiety of women having intensive screening with annual mammography, MRI, and biannual clinical breast examination were similar to those of women having only biannual clinical breast examination in a fair-quality prospective cohort study 94. Most women had no anxiety after each type of screening. In a pre-post study of screening with MRI, mammography, ultrasonography, and clinical breast examination, women who were recalled reported higher anxiety scores approximately 1 month after screening than those who were not recalled (8.8 vs. 5.9; P = 0.03) 95. Among-group differences were not statistically significant after 6 months.
Ovarian Cancer. No studies of the effectiveness of intensive screening met inclusion criteria. Adverse effects were described in a study of annual measurements of serum cancer antigen-125 (CA-125) and transvaginal ultrasonography in 459 BRCA mutation carriers (mean, 2.4 screening visits [1.6 per year]) 97. Abnormalities were detected in 3% (38 of 1116) of screening visits. Of 26 diagnostic procedures, cancer was not detected in 67% (4 of 6) after abnormal serum CA-125 measurement compared with 100% (9 of 9) after abnormal transvaginal ultrasound. Combined methods resulted in an unneeded rate of diagnostic surgery of 55% (6 of 11) 97. In a study of screening with annual serum CA-125 measurements and transvaginal ultrasonography, women with abnormal results had statistically significantly higher cancer-related distress 1 week after receiving results than those with normal results, although long-term distress, anxiety, and depression scores were not higher 98.
Breast Cancer. No trials evaluated the efficacy of risk-reducing medications in BRCA mutation carriers, although placebo-controlled trials of tamoxifen and raloxifene indicated reduced risk for estrogen receptor-positive breast cancer for women at various risk levels 26,99,100.
Adverse effects for trial participants are relevant to mutation carriers. Women using tamoxifen and raloxifene had more thromboembolic events than women using placebo (tamoxifen risk ratio [RR], 1.93 [95% CI, 1.41 to 2.64]; 4 trials and raloxifene RR, 1.60 [CI, 1.15 to 2.23]; 2 trials) 99,100. Coronary heart disease events and stroke were not increased in placebo-controlled trials, although women randomly assigned to raloxifene had higher stroke mortality than placebo recipients in the RUTH (Raloxifene Use for the Heart) trial (RR, 1.49 [CI, 1.00 to 2.24]) 101. Tamoxifen caused more cases of endometrial cancer (RR, 2.13 [CI, 1.36 to 3.32]; 3 trials) and was related to more benign gynecologic conditions; surgical procedures, including hysterectomy; and uterine bleeding than placebo 99,100. Women receiving tamoxifen had more cataract surgeries than those receiving placebo in the NSABP (National Surgical Adjuvant Breast and Bowel Project) P-1 trial 102. The most common adverse effects were vasomotor symptoms and vaginal discharge, itching, or dryness for tamoxifen and vasomotor symptoms and leg cramps for raloxifene 99,100.
Bilateral Mastectomy. A prospective cohort study of women with BRCA mutations indicated that none of 75 women with risk-reducing mastectomies was diagnosed with breast cancer during follow-up compared with 34 of 585 (5.8%) without mastectomies 103. A cohort study of mutation carriers in Denmark found that 3 of 96 women who had mastectomies were diagnosed with breast cancer versus 16 of 211 who did not (hazard ratio [HR], 0.39 [CI, 0.12 to 1.36]), although the study was inadequately powered for this outcome 104. A descriptive study found that none of 307 women who had BRCA mutations or were otherwise considered to be at high risk and had mastectomies was diagnosed with breast cancer during follow-up, whereas 21.3 were expected 105, consistent with results of an earlier study of 18 mutation carriers 106,107.
Adverse effects include surgical complications, long-term physical effects, and distress. In a case series of 122 women who had risk-reducing mastectomy, 64.4% reported postsurgical numbness, pain, tingling, infection, swelling, breast hardness, bleeding, organizing hematoma, failed reconstruction, breathing problems, thrombosis, and pulmonary embolism 108. Most women (87.3%) reported postmastectomy pain and discomfort, and 21.8% reported that pain affected their daily lives in a follow-up study of 59 high-risk women 109. Women's pain scores did not statistically significantly differ before mastectomy, 6 months after mastectomy, and 1 year after mastectomy in another study 110.
In a study of 90 high-risk women with risk-reducing bilateral mastectomies, including 50 mutation carriers, anxiety scores statistically significantly decreased after surgery (mean Hospital Anxiety and Depression Scale scores: before surgery, 5.59; 6 months after surgery, 3.80; 1 year after surgery, 3.83; P < 0.001) 110,111. Women also reported less pleasure in sexual activity 1 year after surgery than 6 months after surgery and before surgery (mean Sexual Activity Questionnaire scores: before surgery, 12.28; 6 months after surgery, 12.21; 1 year after surgery, 11.18; P = 0.005). Depression scores, body image, and other concerns did not change. Other studies indicated no statistically significant changes in psychological or sexual activity measures after mastectomy 108,109,112.
Salpingo-Oophorectomy and Oophorectomy. In a prospective study of 1557 BRCA mutation carriers, salpingo-oophorectomy was statistically significantly associated with reduced incidence of ovarian or primary peritoneal cancer (1.3% vs. 5.8%; HR, 0.28 [CI, 0.12 to 0.69]), breast cancer (11.6% vs. 21.6%; HR, 0.54 [CI, 0.37 to 0.79]), and all-cause mortality (1.8% vs. 5.9%; HR, 0.45 [CI, 0.21 to 0.95]) 103. In this study, salpingo-oophorectomy did not reduce breast cancer- and ovarian cancer-specific mortality, although the study may have been underpowered for these outcomes. Oophorectomy was also associated with reduced breast cancer incidence in a prospective study of women from families with known BRCA1 mutation carriers (18% vs. 42%; HR, 0.38 [CI, 0.15 to 0.97]) 113. Risk reduction was most pronounced for women who had the procedure at younger ages in this study, as well as in a retrospective study of risk-reducing oophorectomy 114.
Few studies described adverse effects. Most women reported worse vasomotor symptoms and sexual function after risk-reducing salpingo-oophorectomy in a small pre-post study of mutation carriers 115. In another small pre-post study, mutation carriers reported an increase in somatization; a decrease in cancer-related distress; and no change in health-related quality of life, anxiety, or depression after salpingo-oophorectomy 116.
No studies directly addressed the effectiveness of risk assessment, genetic counseling, and genetic testing in reducing cancer incidence and mortality (Table). Five referral models accurately estimated individual risk for BRCA mutations, with most sensitivity measures greater than 85%. However, reference standards and study designs varied, and some models have been evaluated only in single studies. Risk was based on self-reported information, which potentially compromises model accuracy. The sensitivity and specificity of self-reported history of cancer in first-degree relatives have been estimated as 65% and 99% for breast cancer 117 and 50% and 99% for ovarian cancer, respectively 118.
Genetic counseling increases the accuracy of risk perception; decreases intention for mutation testing among women who are unlikely carriers; and decreases cancer-related worry, anxiety, and depression. Limitations of studies included differences in designs and measures, dissimilar comparison groups, and small sizes. Risk perception improved after receipt of test results, and breast cancer-related worry and anxiety increased for women with positive results and decreased for others, although results were inconsistent. Studies were limited by high loss to follow-up and differences between comparison groups. Other relevant adverse effects of genetic testing were not studied, including false-positive or false-negative results, genetic discrimination, and insurability.
No trials evaluated the effectiveness of intensive screening in reducing the incidence of BRCA-related cancer and mortality. Higher rates of false-positive test results, unneeded imaging, and unneeded surgeries with screening were reported. No trials of risk-reducing medications provided results for BRCA mutation carriers, and whether efficacy in carriers differs from that in noncarriers is unclear. In trials, tamoxifen and raloxifene increased thromboembolic events and tamoxifen increased endometrial cancer and cataracts. Both caused undesirable effects for some women, such as vasomotor symptoms.
For high-risk women and mutation carriers, risk-reducing bilateral mastectomy reduced breast cancer incidence and mortality and oophorectomy or salpingo-oophorectomy reduced breast and ovarian cancer incidence and all-cause mortality. Comparison groups varied among studies, although results were consistent. Some women had physical complications of risk-reducing surgery, postsurgical symptoms, or changes in body image, whereas some women had less anxiety. Studies were descriptive and lacked important outcomes, and the few available studies had small numbers of participants and no comparison groups.
Limitations of this review include the use of only English-language articles and studies applicable to the United States, although these studies are most relevant to the USPSTF. The review focused on 5 key questions that restricted its scope, and men were not explicitly included except as family members of the women under evaluation. The number, quality, and applicability of included studies varied widely. Data were not available to determine the optimum age for testing and how the age at testing influences benefits and harms. Whether testing for BRCA mutations reduces cause-specific or all-cause mortality and improves quality of life is unknown. The harms associated with receiving a false-negative result or a result indicating mutations of unknown significance are unknown. Evidence of harms often relied on small descriptive studies with brief follow-up, and the long-term effect of risk assessment, counseling, and testing is unknown.
Several factors not evaluated in studies influence treatment effects. Effectiveness of salpingo-oophorectomy for reducing breast cancer risk depends on the age at which the procedure is done and decreases after menopause. However, how and when the benefit-harm ratio shifts for women facing this decision is uncertain. Also, the type of risk-reducing intervention that a mutation carrier selects may depend on her specific mutation. For example, women with BRCA1 mutations have higher risks for ovarian cancer than those with BRCA2 mutations 119,120 and may consider their surgical options differently. Medications reduce risk for estrogen receptor-positive breast cancer 100 and consequently may be a more favorable choice for women with BRCA2 mutations, for whom 77% of breast cancer cases are estrogen receptor-positive 121. How these factors influence patient decision making and eventual clinical outcomes is unknown.
To determine the appropriateness of risk assessment and testing for BRCA mutations in primary care, research on access to testing; effectiveness of screening approaches, including risk stratification; use of system supports; and patient acceptance and education is needed. Trials comparing types of providers and protocols could address who should perform these services, how they should be performed , and what skills are required. The consequences of identifying women as high-risk, as well as genetic testing of women and their relatives, require more study. Well-designed investigations using standardized measures and enrolling participants that reflect the general population, including women from minority groups, are needed.
An expanded database or registry of patients receiving genetic counseling and testing for BRCA mutations would provide essential information about predictors of cancer, response to interventions, and other modifying factors. Traditionally, all patients clinically tested through direct DNA sequencing in the United States used a single private laboratory and patient data were inaccessible. Developing a centralized accessible database with key variables to address these issues as testing practices change in the wake of the recent U.S. Supreme Court decision on DNA patents 122 would be a major advance in this field.
Additional research on interventions is needed. Practice standards for screening have preceded supporting evidence despite known harms of overscreening. For example, although intensive screening with annual transvaginal ultrasonography and serum CA-125 measurement is recommended for high-risk women 21, no efficacy trials are available. The PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial reported no mortality benefit of screening average-risk women by using transvaginal ultrasonography and serum CA-125 measurement compared with usual care after 12 years of follow-up 123 and did not report outcomes for high-risk women, including BRCA mutation carriers. Also, a study of 3532 European women who were at increased risk for ovarian cancer, had unknown BRCA status, received transvaginal ultrasonography and CA-125 measurement, and were followed for up to 16 years indicated no stage shifts in disease incidence 124.
Trials of risk-reducing medications in mutation carriers, including aromatase inhibitors, and measurement of long-term outcomes are also needed. Comparisons of salpingo-oophorectomy versus more limited surgeries, such as salpingectomy alone, would inform current practice. Studies of factors related to acceptance of risk-reducing interventions based on genetic information would be useful, such as determining whether cancer incidence in relatives is reduced because they adopt risk-reducing interventions. This information could improve patient decision making and lead to better health outcomes.
The process of risk assessment and referral, evaluation by genetic counselors, genetic testing, and use of intensive screening and risk-reducing medications and surgeries is complex. Each step requires careful interpretation of information, consideration of risks, weighing of benefits and harms, and shared decision making before moving to the next step. Services must be well-integrated and highly personalized to optimize benefits and minimize harms for women as well as their families. Additional studies are necessary to better inform practice.
Source: This article was first published in Annals of Internal Medicine (2013; 24 Dec).
Disclaimer: The findings and conclusions in this review are those of the authors, who are responsible for its content, and do not necessarily represent the views of the AHRQ. No statement in this review should be construed as an official position of the AHRQ or of the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank Andrew Hamilton, MLS, MS, who conducted literature searches, and Amanda Brunton, BS, who provided assistance; both are affiliated with Oregon Health & Science University.
Financial Support: By AHRQ under contract HHSA-290-2007-10057-1-EPC3.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1684.
Requests for Single Reprints: Heidi D. Nelson, MD, MPH, Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, Mailcode BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098; e-mail, firstname.lastname@example.org.
1. U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2005;143:362-79.
2. Lindor NM, McMaster ML, Lindor CJ, Greene MH; National Cancer Institute, Division of Cancer Prevention, Community Oncology and Prevention Trials Research Group. Concise handbook of familial cancer susceptibility syndromes: second edition. J Natl Cancer Inst Monogr. 2008:1-93.
3. Whittemore AS, Gong G, John EM, McGuire V, Li FP, Ostrow KL, et al. Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev. 2004;13:2078-83. [PMID: 15598764]
4. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer. 2000;83(10):1301-08.
5. Neuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Swensen J, et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet. 1996;13:126-8. [PMID: 8673092]
6. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336:1401-8. [PMID: 9145676]
7. Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996;14:185-7.
8. Weitzel JN, Lagos V, Blazer KR, Nelson R, Ricker C, Herzog J, et al. Prevalence of BRCA mutations and founder effect in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev. 2005;14:1666-71. [PMID: 16030099]
9. Weitzel JN, Lagos VI, Herzog JS, Judkins T, Hendrickson B, Ho JS, et al. Evidence for common ancestral origin of a recurring BRCA1 genomic rearrangement identified in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev. 2007;16:1615-20. [PMID: 17646271]
10. Mefford HC, Baumbach L, Panguluri RC, Whitfield-Broome C, Szabo C, Smith S, et al. Evidence for a BRCA1 founder mutation in families of West African ancestry [Letter]. Am J Hum Genet. 1999;65:575-8. [PMID: 10417303]
11. Peelen T, van Vliet M, Petrij-Bosch A, Mieremet R, Szabo C, van den Ouweland AM, et al. A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet. 1997;60:1041-9. [PMID: 9150151]
12. Arason A, Jonasdottir A, Barkardottir RB, Bergthorsson JT, Teare MD, Easton DF, et al. A population study of mutations and LOH at breast cancer gene loci in tumours from sister pairs: two recurrent mutations seem to account for all BRCA1/BRCA2 linked breast cancer in Iceland. J Med Genet. 1998;35:446-9. [PMID: 9643283]
13. Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet. 1996;13:117-9. [PMID: 8673089]
14. Einbeigi Z, Bergman A, Kindblom LG, Martinsson T, Meis-Kindblom JM, Nordling M, et al. A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer. Eur J Cancer. 2001;37:1904-9. [PMID: 11576847]
15. Tonin PN, Mes-Masson AM, Futreal PA, Morgan K, Mahon M, Foulkes WD, et al. Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am J Hum Genet. 1998;63:1341-51. [PMID: 9792861]
16. National Cancer Institute. Genetics of Breast and Ovarian Cancer (PDQ). Bethesda, MD: National Institutes of Health; 2013. Accessed at www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional on 9 September 2013.
17. Couch FJ, DeShano ML, Blackwood MA, Calzone K, Stopfer J, Campeau L, et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med. 1997;336:1409-15. [PMID: 9145677]
18. Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20:1480-90. [PMID: 11896095]
19. Shattuck-Eidens D, Oliphant A, McClure M, McBride C, Gupte J, Rubano T, et al. BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA. 1997;278:1242-50. [PMID: 9333265]
20. Srivastava A, McKinnon W, Wood ME. Risk of breast and ovarian cancer in women with strong family histories. Oncology (Williston Park). 2001;15:889-902. [PMID: 11499690]
21. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Fort Washington, PA: National Comprehensive Cancer Network; 2013. Accessed at www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf on 27 February 2013.
22. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer Screening and Diagnosis. Fort Washington, PA: National Comprehensive Cancer Network; 2011. Accessed at www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf on 10 December 2013.
23. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, adopted on February 20, 1996. J Clin Oncol. 1996;14:1730-6. [PMID: 8622094]
24. Nelson HD, Huffman LH, Fu R, Harris EL, Walker M, Bougatsos C. Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility. Evidence Synthesis No. 37. Rockville, MD: Agency for Healthcare Research and Quality; 2005.
25. Nelson HD, Huffman LH, Fu R, Harris EL; U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2005;143:362-79. [PMID: 16144895]
26. Nelson HD, Fu R, Goddard K, Mitchell Priest J, Okinaka-Hu L, Pappas M, Zakher B. 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.
27. U.S. Preventive Services Task Force. Procedure Manual. Rockville, MD: U.S. Preventive Services Task Force; 2008. Accessed at https://www.uspreventiveservicestaskforce.org/uspstf/procedure-manual on 30 April 2020.
28. Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al; Methods Work Group, Third US Preventive Services Task Force. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001;20:21-35. [PMID: 11306229]
29. Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM; Cochrane Diagnostic Test Accuracy Working Group. Systematic reviews of diagnostic test accuracy. Ann Intern Med. 2008;149:889-97. [PMID: 19075208]
30. Atkins D, Chang SM, Gartlehner G, Buckley DI, Whitlock EP, Berliner E, et al. Assessing applicability when comparing medical interventions: AHRQ and the Effective Health Care Program. J Clin Epidemiol. 2011;64:1198-207. [PMID: 21463926]
31. Gilpin CA, Carson N, Hunter AG. A preliminary validation of a family history assessment form to select women at risk for breast or ovarian cancer for referral to a genetics center. Clin Genet. 2000;58:299-308. [PMID: 11076055]
32. Parmigiani G, Chen S, Iversen ES Jr, Friebel TM, Finkelstein DM, Anton-Culver H, et al. Validity of models for predicting BRCA1 and BRCA2 mutations. Ann Intern Med. 2007;147(7):441-50.
33. 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.
34. Evans DG, Eccles DM, Rahman N, Young K, Bulman M, Amir E, et al. A new scoring system for the chances of identifying a BRCA 1/2 mutation outperforms existing models including BRCAPRO. J Med Genet. 2004;41:474-80.
35. Barcenas CH, Hosain GM, Arun B, Zong J, Zhou X, Chen J, et al. Assessing BRCA carrier probabilities in extended families. J Clin Oncol. 2006;24(3):354-60.
36. Antoniou AC, Hardy R, Walker L, Evans DG, Shenton A, Eeles R, 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):425-31.
37. 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):783-9.
38. Bellcross C. Further development and evaluation of a breast/ovarian cancer genetics referral screening tool [Letter]. Genet Med. 2010;12:240. [PMID: 20395744]
39. 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):1769-76.
40. Ashton-Prolla P, Giacomazzi J, Schmidt AV, Roth FL, Palmero EI, Kalakun L, et al. Development and validation of a simple questionnaire for the identification of hereditary breast cancer in primary care. BMC Cancer. 2009;9:283.
41. Antoniou AC, Cunningham AP, Peto J, Evans DG, Lalloo F, Narod SA, et al. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions. Br J Cancer. 2008;98:1457-66. [PMID: 18349832]
42. Antoniou AC, Pharoah PD, McMullan G, Day NE, Stratton MR, Peto J, et al. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer. 2002;86(1):76-83.
43. Berry DA, Parmigiani G, Sanchez J, Schildkraut J, Winer E. Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst. 1997;89:227-38. [PMID: 9017003]
44. Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet. 1998;62:145-58. [PMID: 9443863]
45. Berry DA, Iversen ES Jr, Gudbjartsson DF, Hiller EH, Garber JE, Peshkin BN, et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol. 2002;20:2701-12. [PMID: 12039933]
46. 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):1729-36.
47. Bennett P, Wilkinson C, Turner J, Edwards RT, France B, Griffith G, et al. Factors associated with intrusive cancer-related worries in women undergoing cancer genetic risk assessment. Fam Cancer. 2009;8(2):159-65.
48. Bennett P, Wilkinson C, Turner J, Brain K, Edwards RT, Griffith G, et al. Psychological factors associated with emotional responses to receiving genetic risk information. J Genet Couns. 2008;17:234-41.
49. 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):379-84.
50. Bowen DJ, Burke W, Culver JO, Press N, Crystal S. Effects of counseling Ashkenazi Jewish women about breast cancer risk. Cultur Divers Ethni Minor Psychol. 2006;12(1):45-56.
51. 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;20:984-91.
52. 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):433-9.
53. Fry A, Cull A, Appleton S, Rush R, Holloway S, Gorman D, et al. A randomised controlled trial of breast cancer genetics services in South East Scotland: psychological impact. Br J Cancer. 2003;89:653-9.
54. 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):523-9.
55. 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.
56. Hopwood P, Wonderling D, Watson M, Cull A, Douglas F, Cole T, et al. A randomised comparison of UK genetic risk counselling services for familial cancer: psychosocial outcomes. Br J Cancer. 2004;91(5):884-92.
57. 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):135-42.
58. 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):843-56.
59. 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):457-64.
60. Mikkelsen EM, Sunde L, Johansen C, Johnsen SP. Psychosocial consequences of genetic counseling: a population-based follow-up study. Breast J. 2009;15(1):61-8.
61. 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):425-31.
62. 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.
63. 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):217-28.
64. 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;4:359-65. [PMID: 12394349]
65. Bowen DJ, Burke W, McTiernan A, Yasui Y, Andersen MR. Breast cancer risk counseling improves women's functioning. Patient Educ Couns. 2004;53:79-86. [PMID: 15062908]
66. 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;86:233-8. [PMID: 11870512]
67. Burke W, Culver JO, Bowen D, Lowry D, Durfy S, McTiernan A, et al. Genetic counseling for women with an intermediate family history of breast cancer. Am J Med Genet. 2000;90:361-8. [PMID: 10706356]
68. Cull A, Miller H, Porterfield T, Mackay J, Anderson ED, Steel CM, et al. The use of videotaped information in cancer genetic counselling: a randomized evaluation study. Br J Cancer. 1998;77:830-7. [PMID: 9514066]
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;7:402-12. [PMID: 9809331]
70. Lerman C, Hughes C, Benkendorf JL, Biesecker B, Kerner J, Willison J, et al. Racial differences in testing motivation and psychological distress following pretest education for BRCA1 gene testing. Cancer Epidemiol Biomarkers Prev. 1999;8:361-7. [PMID: 10207641]
71. 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;15:75-83. [PMID: 8681923]
72. Lobb EA, Butow PN, Barratt A, Meiser B, Gaff C, Young MA, et al. Communication and information-giving in high-risk breast cancer consultations: influence on patient outcomes. Br J Cancer. 2004;90:321-7. [PMID: 14735171]
73. Watson M, Lloyd S, Davidson J, Meyer L, Eeles R, Ebbs S, 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;79:868-74. [PMID: 10070883]
74. Watson M, Duvivier V, Wade Walsh M, Ashley S, Davidson J, Papaikonomou M, et al. Family history of breast cancer: what do women understand and recall about their genetic risk? J Med Genet. 1998;35:731-8. [PMID: 9733031]
75. 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;3:109-16. [PMID: 15340261]
76. Dagan E, Shochat T. Quality of life in asymptomatic BRCA1/2 mutation carriers. Prev Med. 2009;48:193-6. [PMID: 19084553]
77. Ertmanski S, Metcalfe K, Trempala J, Glowacka MD, Lubinski J, Narod SA, et al. Identification of patients at high risk of psychological distress after BRCA1 genetic testing. Genet Test Mol Biomarkers. 2009;13:325-30. [PMID: 19405874]
78. Foster C, Watson M, Eeles R, Eccles D, Ashley S, Davidson 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;96:718-24. [PMID: 17285126]
79. Geirdal AØ, 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;17:49-57. [PMID: 17385192]
80. Geirdal AØ, Reichelt JG, Dahl AA, Heimdal K, Maehle L, Stormorken A, et al. Psychological distress in women at risk of hereditary breast/ovarian or HNPCC cancers in the absence of demonstrated mutations. Fam Cancer. 2005; 4:121-6. [PMID: 15951962]
81. Julian-Reynier C, Mancini J, Mouret-Fourme E, Gauthier-Villars M, Bonadona V, Berthet P, 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;19:500-6. [PMID: 21267012]
82. Kinney AY, Bloor LE, Mandal D, Simonsen SE, Baty BJ, Holubkov R, 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;104:2508-16. [PMID: 16222692]
83. Low CA, Bower JE, Kwan L, Seldon J. Benefit finding in response to BRCA1/2 testing. Ann Behav Med. 2008;35:61-9. [PMID: 18347905]
84. 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;3:21-8. [PMID: 15131402]
85. 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;7:245-54. [PMID: 18219587]
86. Shochat T, Dagan E. Sleep disturbances in asymptomatic BRCA1/2 mutation carriers: women at high risk for breast-ovarian cancer. J Sleep Res. 2010;19:333-40. [PMID: 20337906]
87. 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. J Clin Oncol. 2006;24:3672-7. [PMID: 16877736]
88. Metcalfe KA, Mian N, Enmore M, Poll A, Llacuachaqui M, Nanda S, 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;133:735-40. [PMID: 22240989]
89. Graves KD, Vegella P, Poggi EA, Peshkin BN, Tong A, Isaacs C, et al. Long-term psychosocial outcomes of BRCA1/BRCA2 testing: differences across affected status and risk-reducing surgery choice. Cancer Epidemiol Biomarkers Prev. 2012;21:445-55. [PMID: 22328347]
90. Meiser B, Butow P, Friedlander M, Barratt A, Schnieden V, Watson M, et al. Psychological impact of genetic testing in women from high-risk breast cancer families. Eur J Cancer. 2002;38:2025-31. [PMID: 12376208]
91. Kriege M, Brekelmans CT, Boetes C, Muller SH, Zonderland HM, Obdeijn IM, et al; Dutch MRI Screening (MRISC) Study Group. 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):2318-26.
92. Le-Petross HT, Whitman GJ, Atchley DP, Yuan Y, Gutierrez-Barrera A, Hortobagyi GN, 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):3900-07.
93. Leach MO, Boggis CR, Dixon AK, Easton DF, Eeles RA, Evans DG, 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;365:1769-78. [PMID: 15910949]
94. Rijnsburger AJ, Essink-Bot ML, van Dooren S, Borsboom GJ, Seynaeve C, Bartels CC, et al. Impact of screening for breast cancer in high-risk women on health-related quality of life. Br J Cancer. 2004;91:69-76. [PMID: 15199386]
95. 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;20:424-30. [PMID: 21612928]
96. Kriege M, Brekelmans CT, Boetes C, Besnard PE, Zonderland HM, Obdeijn IM, et al; Magnetic Resonance Imaging Screening Study Group. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004;351:427-37. [PMID: 15282350]
97. Hermsen BB, Olivier RI, Verheijen RH, van Beurden M, de Hullu JA, Massuger LF, et al. No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study. Br J Cancer. 2007;96:1335-42. [PMID: 17426707]
98. Brain KE, Lifford KJ, Fraser L, Rosenthal AN, Rogers MT, Lancastle D, et al. Psychological outcomes of familial ovarian cancer screening: no evidence of long-term harm. Gynecol Oncol. 2012;127:556-63. [PMID: 22943881]
99. Nelson HD, Fu R, Humphrey L, Smith ME, Griffin JC, Nygren P. Comparative Effectiveness of Medications to Reduce Risk of Primary Breast Cancer in Women. Comparative Effectiveness Review No. 17. Rockville, MD: Agency for Healthcare Research and Quality; 2009.
100. Nelson HD, Smith ME, Griffin JC, Fu R. Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;158:604-14.
101. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, et al; Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-37. [PMID: 16837676]
102. Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, 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):1652-62.
103. Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967-75.
104. Skytte AB, Crüger D, Gerster M, Laenkholm AV, Lang C, Brøndum-Nielsen K, et al. Breast cancer after bilateral risk-reducing mastectomy. Clin Genet. 2011;79(5):431-7.
105. Evans DG, Baildam AD, Anderson E, Brain A, Shenton A, Vasen HF, et al. Risk reducing mastectomy: outcomes in 10 European centres. J Med Genet. 2009;46:254-8. [PMID: 18996907]
106. Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999;340:77-84. [PMID: 9887158]
107. Hartmann LC, Sellers TA, Schaid DJ, Frank TS, Soderberg CL, Sitta DL, et al. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst. 2001;93:1633-7. [PMID: 11698567]
108. Metcalfe KA, Esplen MJ, Goel V, Narod SA. Psychosocial functioning in women who have undergone bilateral prophylactic mastectomy. Psychooncology. 2004;13(1):14-25.
109. 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):462-9.
110. Brandberg Y, Sandelin K, Erikson S, Jurell G, Liljegren A, Lindblom A, 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. J Clin Oncol. 2008;26(24):3943-9.
111. 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.
112. 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 (Engl). 2011;20(4):508-13.
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. J Clin Oncol. 2005;23:8629-35. [PMID: 16314625]
114. 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;28:357-60. [PMID: 15542261]
115. Finch A, Metcalfe KA, Chiang JK, Elit L, McLaughlin J, Springate C, 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):163-8.
116. Finch A, Metcalfe KA, Chiang J, Elit L, McLaughlin J, Springate C, et al. The impact of prophylactic salpingo-oophorectomy on quality of life and psychological distress in women with a BRCA mutation. Psychooncology. 2013;22:212-9.
117. Mai PL, Garceau AO, Graubard BI, Dunn M, McNeel TS, Gonsalves L, et al. Confirmation of family cancer history reported in a population-based survey. J Natl Cancer Inst. 2011;103:788-97. [PMID: 21562245]
118. Kerber RA, Slattery ML. Comparison of self-reported and database-linked family history of cancer data in a case-control study. Am J Epidemiol. 1997;146:244-8. [PMID: 9247008]
119. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117-30.
120. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25:1329-33.
121. Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, et al; HEBON. 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;21:134-47. [PMID: 22144499]
122. Association for Molecular Pathology v. Myriad Genetics, Inc., No. 12-398, slip op. (2013).
123. Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al; PLCO Project Team. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011;305:2295-303. [PMID: 21642681]
124. Evans DG, Lennard F, Pointon LJ, Ramus SJ, Gayther SA, Sodha N, et al; UK Study of MRI Screening for Breast Cancer in Women at High Risk (MARIBS). Eligibility for magnetic resonance imaging screening in the United Kingdom: effect of strict selection criteria and anonymous DNA testing on breast cancer incidence in the MARIBS Study. Cancer Epidemiol Biomarkers Prev. 2009;18:2123-31. [PMID: 19567506]
125. Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer. 2004;91:1580-90. [PMID: 15381934]
126. Euhus DM BD, Parmigiani G, Iversen ES, Frawley W. CancerGene [computer program]. Version 4.3. Dallas, TX: University of Texas Southwestern Medical Center at Dallas; 2006.
127. Penn II BRCA1 and BRCA2 Mutation Risk Evaluation Model [computer program]. Accessed at www.afcri.upenn.edu/itacc/penn2/ on 9 September 2013.
|New Studies*||Design||Limitation||Consistency||Applicability||Overall Quality||Finding|
|Effectiveness of risk assessment, genetic counseling, and genetic testing to reduce BRCA-related cancer and mortality|
|Accuracy and adverse effects of referral models to estimate individual risk for BRCA mutations|
|8 studies of 5 models; no studies of adverse effects||Diagnostic accuracy||Reference standards and study designs varied; risk was based on self-reported information||Consistent||High||Good||Risk models report sensitivity estimates >85% for the FHAT, Manchester scoring system, RST, PAT, and FHS-7.|
|Benefits and adverse effects of genetic counseling to determine eligibility for genetic testing|
|16 studies of the accuracy of risk perception, intention for genetic testing, and distress||RCT, cohort, case–control, pre–post||Noncomparable groups; small size; outcome measures varied||Consistent||High||Fair||Counseling increased the accuracy of risk perception and decreased intention for mutation testing among unlikely carriers as well as cancer-related worry, anxiety,and depression.|
|Adverse effects of genetic testing|
|13 studies of risk perception and distress||RCT, cohort case–control, pre–post||No studies of other outcomes; high loss to follow-up; comparison groups and measures varied||Mixed||High||Fair||Breast cancer–related worry and anxiety increased for women with positive results and decreased for others, although results differed across studies. Risk perception improved after receipt of test results.|
|Effectiveness of risk-reducing interventions|
|No studies of intensive screening or risk-reducing medications among BRCA mutation carriers||_||_||_||_||_||_|
|Risk-reducing surgery: 3 studies of mastectomy and 3 of oophorectomy or salpingo-oophorectomy||Cohort||Comparison groups varied||Consistent||High||Fair||For high-risk women, including mutation carriers, mastectomy reduced breast cancer by 85% to 100% and breast cancer mortality by 81% to 100%; salpingo-oophorectomy reduced breast cancer by 37% to 100%, ovarian cancer by 69% to 100%, and all-cause mortality by 55% to 100%.|
|Adverse effects of risk-reducing interventions in BRCA mutation carriers|
|Intensive screening: 3 studies of physical harms of breast cancer screening and 2 of anxiety; 1 study of physical harms of ovarian cancer screening and 1 of cancer-related distress||Cohort||No RCTs; screening intervals and false-positive calculations varied among studies; some studies lacked within-cohort comparison groups||Consistent||High||Poor||False-positive rates, unnecessary imaging, and unneeded surgeries were higher with screening. Some women had transient cancer-related distress or anxiety if screening results were abnormal.|
|Risk-reducing medications: 6 placebo-controlled trials (4 of tamoxifen and 2 of raloxifene) and 1 head-to-head trial in a systematic review||RCT||No results for BRCA mutation carriers; trials were heterogeneous; data on long-term effects were incomplete||Consistent||High||Good||Tamoxifen and raloxifene increased thromboembolic events compared with placebo. Tamoxifen increased endometrial cancer and cataracts compared with raloxifene. Both caused adverse effects for some women|
|Risk-reducing surgery: 6 studies of complications, physical effects, or distress||Case series, pre–post||Lack of studies; small numbers of participants; no comparison groups||NA||Low||Poor||Some women had physical complications of surgery, postsurgical symptoms, changes in body image, and less anxiety|
FHAT = Ontario Family History Assessment Tool; FHS-7 = Family History Screen-7; NA = not applicable; PAT = Pedigree Assessment Tool; RCT = randomized, controlled trial; RST = Referral Screening Tool.
* Studies published in 2004 or later.
1. Do risk assessment, genetic counseling, and genetic testing lead to reduced incidence of BRCA-related cancer and reduced cause-specific and all-cause mortality?
2a. What is the accuracy of methods to assess familial cancer risk for BRCA-related cancer when done by a nonspecialist in genetics in a clinical setting?
2b. What are the benefits of genetic counseling in determining eligibility for genetic testing for BRCA-related cancer? Potential benefits include improved accuracy of risk assessment and pretest probability for testing and improved patient knowledge, risk perception, satisfaction, and health and psychological outcomes.
2c. Among women with increased risk for BRCA-related cancer, what is the clinical validity of genetic testing for deleterious mutations?
3. What are the potential adverse effects of 3a) risk assessment, 3b) genetic counseling, and 3c) genetic testing? Adverse effects include, but may not be limited to, inaccurate risk assessment; inappropriate testing; false-positive and false-negative results; adverse effect on the patient's relationships with family; false reassurance; incomplete testing; misinterpretation of the test result; anxiety; worry about cancer; and ethical, legal, and social implications.
4. Do interventions reduce the incidence of BRCA-related cancer and death for women with increased risk? Interventions include intensive screening (earlier and more frequent mammography and breast MRI), use of risk-reducing medications (tamoxifen and raloxifene), and risk-reducing surgery (mastectomy and salpingo-oophorectomy).
5. What are the potential adverse effects of interventions to reduce risk for BRCA-related cancer? Adverse effects include, but may not be limited to, immediate and long-term harms associated with breast imaging, risk-reducing medications, and risk-reducing surgery and ethical, legal, and social implications.
KQ = key question; MRI = magnetic resonance imaging.
* Clinically significant mutations of the BRCA1 or BRCA2 gene or related syndromes.
† Testing may be done on the unaffected woman, the relative with cancer, or the relative with the highest risk, as appropriate.
‡ No known mutation in relatives and none detected in the patient.
§ Known mutation in relatives but none detected in the patient.
|| Interventions include increased early detection through intensive screening (earlier and more frequent mammography and breast MRI), risk-reducing medications (tamoxifen and raloxifene), and risk-reducing surgery (mastectomy and salpingo-oophorectomy).
Figure 1 is a flow diagram of risk assessment, genetic counseling, and genetic testing. Women without cancer or known deleterious BRCA mutations, which are clinically significant mutations of BRCA1, BRCA2, or related syndromes, are assessed for their familial cancer risk. These women may experience adverse effects as they are determined to have either no increased risk or increased risk for BRCA mutations. Women with an increased risk for BRCA mutations are referred for genetic counseling, during which they may experience adverse effects. Following genetic counseling, women with an increased risk for BRCA mutations are referred for genetic testing, during which they may experience adverse effects. Testing may be done on the unaffected woman or her relative with cancer as appropriate. Women who undergo genetic counseling may be found to be true negative, which means there is a known mutation in their relatives but none detected in the patient, or they may have an uninformative negative status, meaning there is no known mutation in their relatives and none detected in the patient. They may also have a variant of uncertain significance or a BRCA mutation may be detected. For women with status that is not a true negative, they may be referred for interventions, including increased early detection through intensive screening (earlier and more frequent mammography, breast MRI), medications (such as tamoxifen or raloxifene), and risk-reducing surgery (such as mastectomy or oophorectomy). Women who undergo interventions may experience adverse effects. Women who undergo interventions may also have reduced incidence of BRCA-related cancer and reduced cause-specific and all-cause mortality.
* Identified from reference lists, hand-searching, suggestions from experts, and other methods.|
† Studies that provided data and contributed to the body of evidence were considered to be "included." Studies may contribute data to >1 key question.
This number includes studies included from the prior review as well as this updated review.
Appendix Figure 2 is a flow chart that summarizes the search and selection of articles. There were 5499 citations identified by searching MEDLINE, Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and other sources, including reference lists, hand searching, and suggestions by experts. Of these, 3860 were excluded at the abstract level because they did not address a key question. The remaining 1639 articles were pulled for review at the full-text level to further review for inclusion. There were 1567 full-text articles excluded. Seventy-two articles were included in the final report and may have provided data for more than one key question. There were 0 articles for key question 1, 10 for key question 2a, 27 for key questions 2b and 3b, 70 for key question 2c, 0 for key question 3a, 14 for key question 3c, 7 for key question 4, and 15 for key question 5.
|Model||Data Collection and Calculation*||Relatives With Breast or Ovarian Cancer||Additional Risk Factors in Model||Accuracy Studies|
|Study, Year (Reference)||Population||Reference Standard||Sensitivity, %||Specificity, %||PPV||NPV|
|FHAT||Clinical scoring tool; referral threshold of 10 is equivalent to a 2-fold increase in risk for breast or ovarian cancer.||First-, second-, and third-degree||Age at diagnosis, bilateral breast cancer, breast and ovarian cancer in the same person, breast cancer in men, colon and prostate cancer||Gilpin et al, 200031
Parmigiani et al, 200732
Panchal et al, 200833
|35 carriers and 149 noncarriers
33 carriers and 559 noncarriers
200 carriers and 100 noncarriers
|Manchester scoring system||Clinical scoring tool; referral threshold of 10 for BRCA1- or BRCA2-specific scores or 15 combined. Not intended for Ashkenazi Jewish persons.||First-, second-, and third-degree||Type of cancer (breast, ovarian, pancreatic, or prostate), affected family members, age at diagnosis||Evans et al, 200434
Barcenas et al, 200635
Panchal et al, 200833
Antoniou et al, 200836
|23 carriers and 235 noncarriers
69 carriers and 306 noncarriers
200 carriers and 100 noncarriers
365 carriers and 1569 noncarriers
|RST||Clinical checklist of 13 items; referral threshold of 2 positive responses.||First- and second-degree||Breast cancer in women ≤50 y (self or relatives), ovarian cancer at any age (self or relatives), ≥2 cases of breast cancer in women aged >50 y on the same side of the family; breast cancer in men; Jewish ancestry||Bellcross et al, 200937||296 women randomly selected from 2462 tested while having screening mammography||Correctly assigns to high mutation probability compared with BOADICEA, BRCAPRO, and Myriad II models at 10% thresholds||BOADICEA: 89
Myriad II: 91
Myriad II: 78
Myriad II: 0.34
Myriad II: 0.99
|PAT||Clinical scoring tool; optimum referral threshold of 8.||First-, second-, and third-degree||Breast cancer in women aged ≤50 y or >50 y, ovarian cancer at any age, breast cancer in men, Ashkenazi Jewish ancestry||Hoskins et al, 200639||737 women identified at potentially increased risk from 3906 tested while having screening mammography**||Correctly assigns to high mutation probability compared with the Myriad II model at the 10% threshold||100||93||0.63||1.00|
|FHS-7||Clinical checklist of 7 items; referral threshold of 1 positive response.||First-degree||Any relatives with breast cancer at age ≤50 y, bilateral breast cancer, breast and ovarian cancer in the same person, breast cancer in men, ≥2 relatives with breast and/or ovarian cancer, ≥2 relatives with breast and/or colon cancer||Ashton-Prolla et al, 200940||885 women with ≥1 positive response and 910 with no positive responses from 9218 women tested in primary care clinics||Correctly assigns to high mutation probability compared with genetic evaluation††||88||56||0.63||1.00|
BOADICEA = Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm; FHAT = Ontario Family History Assessment Tool; FHS-7 = Family History Screen-7; NPV = negative predictive value; PAT = Pedigree Assessment Tool; PPV = positive predictive value; RST = Referral Screening Tool.
* Referral threshold indicates estimated probability to initiate a referral, most set at 10%.
† Positive likelihood ratio of 1.38.
‡ Negative likelihood ratio of 0.18.
§ Defined as high-risk by any of the models.
ǁ Corrected for general populations: 0.39.
¶ Corrected for general populations: 0.78.
** Defined as potentially at increased risk by the Gail model for 5-y risk for breast cancer of 6.7%, lifetime risk of 15%, or ≥1 case of breast or ovarian cancer in any family member.
†† Evaluation included kindred analysis, breast cancer risk estimates, Penn II BRCA1 and BRCA2 Mutation Risk Evaluation Model mutation risk estimate, and American Society of Clinical Oncology criteria.
|BOADICEA42,125||Web-based||All persons||Includes breast, ovarian, prostate, and pancreatic cancer. Family history data for first-, second-, and third-degree relatives are entered for persons with and without cancer.|
|BRCAPRO43-45||CaGene computer program126||All persons||Includes breast cancer in men and women and ovarian cancer. Bayesian model using first- and second-degree family history includes age at diagnosis, ethnicity, and size of family to estimate the age-specific probability of a BRCA mutation. Generates conditional or posterior probabilities.|
|Myriad II18||CaGene computer program126 or tables||All persons||Includes breast cancer in men and women and ovarian cancer. Logistic regression model developed from data on women with early-onset breast cancer and/or ovarian cancer with ≥2 first- or second-degree relatives with early breast or ovarian cancer.|
|Penn II127||Web-based||Families with cases of breast cancer||Includes breast, ovarian, prostate, and pancreatic cancer. Uses a 1-page questionnaire to solicit data for first-, second-, and third-degree relatives. Determines the probability of a BRCA mutation in the person as well as family members with cancer.|
BOADICEA = Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm; CaGene = Cancer Gene; Penn II = Penn II, BRCA1 and BRCA2 Mutation Risk Evaluation Model.
|Study, Year (Reference)||Participants, n||Design||Genetic Counseling Provider||Setting||Measure||Outcome||Quality Rating|
|Accuracy of Risk Perception||Intention to Participate in Testing||Worry||Anxiety||Depression|
|Bennett et al, 200848||128||Pre-post||Genetic counselor||Cancer genetics service center||DUKE-SSQ, HADS, IES, MCMQ, NSI||_||_||Decrease||NS||NS||NA|
|Bennett et al, 200947||128||Pre-post||Genetic counselor||Cancer genetics service center||DUKE-SSQ, IES, MCMQ||_||_||NS||_||_||NA|
|Bloom et al, 200649||163||RCT||Counselor||Telephone counseling||NSI||NS||_||NS||_||_||Poor*†‡|
|Bowen et al, 200650||221||RCT||Psychologist, genetic counselor||University||NSI, BSI||Increase||Decrease||Decrease||_||_||Fair*|
|Brain et al, 201151||263||Pre-post||Clinician||NR||CW||_||_||Decrease||_||_||NA|
|Braithwaite et al, 200552||72||RCT||Clinical nurse specialist||NR||NSI, STAI, HADS||Increase||_||Decrease||Decrease||_||Fair*|
|Fry et al, 200353||263||RCT||Genetic specialist, breast surgeon||Familial breast cancer clinic||CWS||Increase||_||Decrease||_||_||Fair§|
|Gurmankin et al, 200554||125||Pre-post||Clinician||University cancer risk evaluation program||STAI, NSI||Increase||_||_||_||_||NA|
|Helmes et al, 200655||340||RCT||Genetic counselor||NR||NSI||Increase||Decrease||Decrease||_||_||Fair*|
|Hopwood et al, 200456||256||Pre-post||Genetic counselor||Cancer genetic service centers||NSI, GHQ, CWS||NS||_||Decrease||NS||_||NA|
|Kelly et al, 200857||78||Pre-post||Genetic counselor||NR||NSI||Decrease||_||_||_||_||NA|
|Matloff et al, 200658||64||RCT||Genetic counselor||NR||NSI||Increase||_||_||_||_||Fair*|
|Mikkelsen et al, 200759||1971||Prospective||Physician||Clinical department||IES||NS||_||_||_||_||Fair†|
|Mikkelsen et al, 200960||1971||Prospective||Physician||Clinical department||HADS||_||_||Decrease||NS||NS||Fair†|
|Pieterse et al, 201161||77||Pre-post||Clinical geneticist, genetic counselor||Department of medical genetics||VAS, NSI, PPC, STAI, IES||Increase||_||_||Decrease||_||NA|
|Roshanai et al, 200962||163||RCT||Specialist nurse||Cancer genetic clinic||SPIKES, HADS||Increase||_||_||Decrease||Decrease||Fair*|
|Bowen et al, 200264||354||RCT||Genetic or health counselor||NR||NSI||_||Decrease||_||_||_||Fair¶|
|Bowen et al, 200465||354||RCT||Genetic or health counselor||NR||NSI||Increase||_||NS||Decrease||NS||Fairǁ¶|
|Brain et al, 200266||740||RCT||Clinical geneticist, genetic nurse specialist||NR||STAI, NSI||Increase||_||Mixed**||Decrease||_||Good|
|Burke et al, 200067||356||RCT||Genetic counselor||Medical office||NSI||Increase||Decrease||NS||_||_||Fairǁ¶|
|Cull et al, 199868||144||RCT||Geneticist, breast surgeon||Breast cancer family clinic||NSI, STAI, GHQ||Mixed§||_||_||NS||NS||Good|
|Hopwood et al, 199869||174||Prospective||Clinician||Family history clinics||NSI, GHQ, PAS||Increase||_||NS||NS||_||Fair††|
|Lerman et al, 199671||227||RCT||Genetic counselor||Cancer centers||IES||Increase||_||NS||NS||_||Fairǁ¶|
|Lerman et al, 199970||364||RCT||Oncology nurse, genetic counselor||Hospital cancer center||IES||_||Increase||NS||_||_||Fair§ǁ¶|
|Lobb et al, 200472||193||Longitudinal||Clinical geneticist, oncologist, genetic counselor||NR||NSI, IES, HADS||NS||_||_||NS||NS||Good|
|Watson et al, 199874||115||RCT||Clinical geneticist||Hospitals||GHQ-12, CWS, VAS||Increase||-||NS||NS||NS||Good|
|Watson et al, 199973||283||Prospective||Clinical geneticist||Genetic counseling centers||NSI, GHQ, IES, STAI||NS||-||NS||NS||-||Good|
BSI = Brief Symptom Inventory; CWS = Cancer Worry Scale; CWS-R = Cancer Worry Scale-Revised; Duke-UNC SSQ = Duke-University of North Carolina Functional Social Support Questionnaire; GHQ = General Health Questionnaire; GHQ-12 = 12-item General Health Questionnaire; HADS = Hospital Anxiety and Depression Scale; IES = Impact of Events Scale; MCMQ = Medical Coping Modes Questionnaire; NA = not available; NR = not reported; NS = not statistically significant; NSI = Non Standard Instrument; PAS = Psychiatric Assessment Schedule; PPC = Perceived Personal Control; RCT = randomized, controlled trial; SPIKES = Setting, Patient's Perception, Invitation, Knowledge, Exploring/Empathy, Strategy/Summary; STAI = State-Trait Anxiety Inventory; VAS = visual analog scale.
* Inadequate reporting of randomization technique49, 50, 52, 55, 58, 62.
† Noncomparable groups at baseline49, 59, 60.
‡ No specified eligibility criteria49.
§ High attrition53, 68 or attrition not reported65.
ǁ Allocation concealment not reported64, 65, 70, 71.
¶ No intention-to-treat analysis65, 67, 70, 71.
** Results varied by group.
†† Unclear whether participants were from random or consecutive groups69.
|Study, Year (Reference)||Participants, n||Design||Mutation Status||Genetic Counseling Provider||Comparison||Measure||Outcome||Quality Rating|
|Arver et al, 200475||63||Pre-post||Positive or negative||Genetically trained oncologist, oncology nurse||A: Before test
B: 2 mo after test
C: 1 y after test
|HADS, SF-36||-||Decrease (B, C vs. A)||NS||NA|
|Dagan and Shochat, 200976||73||Case- control||Positive or negative||NR||A: Carriers
C: Age-matched control participants
|HRQOL, CRW, BSI||Increase (A, B vs. C)||NS||NS||Fair*|
|Ertmanski et al, 200977||56||Pre-post||Positive||NR||A: Before test
B: 1 mo after test
C: 1 y after test
|Foster et al, 200778||154||Prospective||Positive or negative||NR||A: Carriers
|GHQ, CWS-R||Decrease (A, B)||Increase (A, B)||-||Fair*†|
|Geirdal et al, 200580||10,244||Prospective||Positive or unknown||NR||A: Positive
B: Not tested but family history
C: Not tested, 10,000 age-matched control participants
|HADS, GHQ, BHS, IES||-||Increase (B vs. A)||Increase (B vs. A)||Good|
|Geirdal and Dahl, 200879||242||Prospective||Positive or unknown||NR||A: Positive
B: Not tested but family history
|HADS, COPE||-||Increase (B vs. A)||-||Good|
|Kinney et al, 200582||52||Prospective||Positive or negative||Genetic professional||A: Carriers
|STAI, IES, CES-D||-||Decrease (B)||-||Poor*†|
|Low et al, 200883||47||Prospective||Positive or negative/ uncertain||Genetic counselor||A: Positive
B: True-negative and uncertain
|IES-R, COPE, PTGII||-||Increase (A vs. B)||v||Fair*†‡|
|Metcalfe et al, 201288||17||Pre-post||Positive||NR||A: Before test
B: 1 y after test
C: 2 y after test
|IES||Increase (B vs. A, C)||-||-||NA|
|Reichelt et al, 200484||209||Prospective||Positive, negative, or unknown||Medical geneticist, genetic counselor||A: Carriers
|HADS, GHQ, BHS, IES||-||NS||NS||Good|
|Reichelt et al, 200885||181||Pre-post||Positive or true-negative||Genetic counselor||A: Before test
B: 6 wk after test
C: 18 mo after test
|van Dijk et al, 200687||132||Prospective||Positive, true-negative, or uncertain||NR||A: Positive
|IES, NSI||Increase (A vs. B, C)||Increase (A vs. B,||-||Good|
|Meiser et al, 200290||143||Prospective||Positive or negative||NR||A: Carriers
C: Not tested
|BDI, IES, MBSS, STAI, NSI||Increase (A vs. C)||Decrease (B vs. A, C)||Decrease (B vs. A, C)||Good|
BDI = Beck Depression Inventory; BHS = Beck Hopelessness Scale; BSI = Brief Symptom Inventory; CES-D = Center for Epidemiologic Studies-Depression Scale; COPE = Emotional Approach Coping Scale; CRW = Cancer-Related Worry Scale; CWS-R = Cancer-Related Worry Scale-Revised; GHQ = General Health Questionnaire; HADS = Hospital Anxiety and Depression Scale; HRQOL = Health-Related Quality of Life; IES = Impact of Events Scale; IES-R = Impact of Events Scale-Revised; MBSS = Miller Behavioral Style Scale; NA = not applicable; NR = not reported; NS = not statistically significant; NSI = Non Standard Instrument; PTGI = Post-Traumatic Growth Inventory; SF-36 = Swedish 36-Item Short Form Health Survey; STAI = State-Trait Anxiety Inventory.