Data Synthesis

Do Risk Assessment and BRCA Mutation Testing Lead to a Reduction in the Incidence of Breast and Ovarian Cancer and Cause-Specific or All-Cause Mortality?

Although several studies describe risk assessment methods that are relevant to primary care, none demonstrate that a screening approach enlisting risk assessment in a primary care setting followed by BRCA mutation testing and preventive interventions for appropriate candidates ultimately reduces the incidence of breast and ovarian cancer and cause-specific or all-cause mortality.

How Well Does Risk Assessment for Cancer Susceptibility by a Clinician in a Primary Care Setting Select Candidates for BRCA Mutation Testing?

Determination of Family History

Family history of breast and ovarian cancer is the most important factor for determining risk for a clinically significant BRCA mutation in a woman without cancer or a known mutation in her family. A systematic review of studies of validated self-reported family histories addressed the accuracy of family cancer history information.⁵⁴ Only 1 study determined the sensitivity and specificity of a family history of breast or ovarian cancer in first-degree relatives reported by individuals without cancer.⁵⁵ In this study, a report of breast cancer in a first-degree relative had a sensitivity of 82% and a specificity of 91%.⁵⁵ A report of ovarian cancer in a first-degree relative was less reliable, with a sensitivity of 50% and a specificity of 99%.⁵⁵ Overall, accuracy was better in studies of first-degree rather than second-degree relatives.⁵⁴

Tools To Assess Risk for BRCA Mutations

Tools to assess risk for clinically significant BRCA mutations have been developed from data on previously tested women; however, no studies have examined their effectiveness in a screening population in a primary care setting.⁵⁶ Much of the data used to develop the models are from women with existing cancer. Models with potential clinical applications^22-24,57-72 are described in Table 2. Experts in the field consider mutation testing for women with a 10% or greater probability according to these estimations to be an appropriate threshold.⁷³ Tools specifically designed for primary care that assess risk and guide referral have compared well with established models, such as BRCAPRO.^67-70

Referral Guidelines

Referral guidelines have been developed by health maintenance organizations,⁷⁴ professional organizations^19,20 cancer programs,^75-79 state and national health programs,^80-83 and investigators⁸⁴ to help primary care clinicians identify women at potentially increased risk for clinically significant BRCA mutations (Table 3). Although specific items vary among the guidelines, most include questions about personal and family history of BRCA mutations, breast and ovarian cancer, age of diagnosis, bilateral breast cancer, and Ashkenazi Jewish heritage. Most guidelines are intended to lead to a referral for more extensive genetic evaluation and counseling, not directly to testing. There is currently no consensus or gold standard about the use of referral guidelines, and the effectiveness of this approach has not been evaluated.

What Are the Benefits of Genetic Counseling before Testing?

No studies describe cancer or mortality outcomes related to genetic counseling, although 10 randomized, controlled trials report psychological and behavioral outcomes.^27-33,85-87 Trials examined the impact of genetic counseling on breast cancer worry, anxiety, depression, perception of cancer risk, and intent to participate in genetic testing. Trials were conducted in highly selected samples of women, and results may not be generalizable to a screening population.

Results of 9 trials indicated either decreased measures of psychological distress^{27,30-33,85-87} or no effect^29,30,32,86 after genetic counseling. These include 5 trials reporting decreased breast cancer worry,^27,31-33,86 3 reporting decreased anxiety,^27,85,87 and 1 reporting decreased depression (85). Findings are consistent with a meta-analysis of 12 randomized, controlled trials and prospective studies indicating that genetic counseling for breast cancer led to significant decreases in generalized anxiety, although the reduction in psychological distress was not significant (88). Five trials reported increased accuracy of perception of cancer risk among women who received genetic counseling.^{27,29,30,33,86,87} One study showed less accurate risk perception after genetic counseling,⁸⁵ and 1 had mixed results.³⁰ Three studies examining the intention to participate in genetic testing after counseling reported inconsistent results.^28,31,87

Among Women with Family Histories Predicting an Average, Moderate, or High Risk for a Deleterious Mutation, How Well Does BRCA Mutation Testing Predict Risk for Breast and Ovarian Cancer?

Prevalence

No direct measures of the prevalence of clinically significant BRCA1 or BRCA2 mutations in the general, non- Jewish U.S. population have been published. Models estimate the prevalence to be about 1 in 300 to 500 persons.^41-44 For BRCA1 , 1 model estimates a 0.12% prevalence rate.⁷ The prevalence among women with a strong family history of cancer is estimated to be 8.7% on the basis of 1 report from clinical referral populations that considered both BRCA1 and BRCA2 mutations together.²¹

Additional prevalence estimates for individuals from referral populations with various levels of family history range from 3.4% (no breast cancer diagnosed in relatives <50 years of age and no ovarian cancer) to 15.5% (breast cancer diagnosed in a relative < 50 years of age and ovarian cancer diagnosed at any age).³⁴ On the basis of these estimates, the prevalence of BRCA1 and BRCA2 mutations in women at average risk could be considered to be as high as 0.24%, moderate risk to be 0.24% to 3.4%, and high risk to be 8.7% and above. In the absence of direct measures, it can be assumed that half of the mutations would be in BRCA1 and half would be in BRCA2 .

Penetrance

Penetrance is the probability of developing breast or ovarian cancer among women who have a clinically significant BRCA1 or BRCA2 mutation. Published reports of penetrance describe estimates of BRCA1 and BRCA2 mutations ranging from 35% to 84% for breast cancer and 10% to 50% for ovarian cancer, calculated to age 70 years, for non-Ashkenazi Jewish women or those unselected for ethnicity.^{3,41,42,89-92} Studies use a variety of research laboratory techniques, including a 2-step process in testing to detect clinically significant mutations that differ from the DNA sequencing available clinically. Use of these techniques may underestimate prevalence by one third.⁹³ In addition, studies do not report the mutations' location on the gene, a factor that may influence penetrance.^92,94 Studies focus on women with existing breast and ovarian cancer and thereby introduce bias, since breast or ovarian cancer survivors may have different mutation frequencies than women with newly diagnosed cancer. Many studies estimated penetrance from families without the benefit of genetic testing of all family members.^{3,41,42,89-92,95-97} Such estimates are typically based on family members of women who have breast or ovarian cancer (probands) who probably have additional risk factors for breast cancer that affect penetrance.⁹⁸

To determine penetrance, we estimated values for the range of potential prevalence rates for each risk group (data not shown).⁴⁸ Estimates of prevalence rates of mutations for the general population for use in the outcomes table were assumed to be 0.12% for average-risk women, 1.5% for moderate-risk women, and 8.68% for high-risk women. This combination of prevalence rates reflects an overall population mutation rate of 1 in 397.

For breast cancer, 7 studies provide data on the probability of a BRCA1 mutation if breast or ovarian cancer is present,^{24,42,43,99-102} and 3 provide these data for a BRCA2 mutation.^42,43,101 BRCA1 penetrance estimates to age 75 years are 68.6% (95% CI, 47.7% to 84.0%) in average-risk groups,¹⁰² 49.9% (CI, 27.5% to 72.3%) in moderate-risk groups,¹⁰² and 60.5% (CI, 52.3% to 68.2%) in high-risk groups.^24,42,99,102 For BRCA2 penetrance, data are available only for the high-risk group (53.0% [CI, 42.2% to 63.5%]).⁴²

For ovarian cancer, 6 studies provide data on the probability of a BRCA1 mutation^{57,92,99,102-104} and 2 show data for a BRCA2 mutation.^92,104 BRCA1 penetrance estimates to age 75 years are 29.2% (CI, 20.3% to 40.1%) in average-risk groups,^92,104 55.1% (CI, 48.4% to 61.5%) in moderate-risk groups,^{57,92,102,103} and 26.1% (CI, 22.0% to 30.8%) in high-risk groups.^99,104 Respective estimates for BRCA2 are 34.2% (CI, 22.9% to 47.6%),⁹² 27.0% (CI, 17.3% to 39.6%),⁹² and 6.4% (CI, 3.4% to 11.8%).¹⁰⁴ These penetrance estimates are similar to results of a combined analysis of 22 studies based on case series data from women unselected for cancer family history.⁸⁹ Breast and ovarian cancer risk estimates to age 70 years for women who have a BRCA1 mutation were 65% (CI, 44% to 78%) and 39% (CI, 18% to 54%), respectively; for BRCA2 mutation carriers, breast and ovarian cancer risks were 45% (CI, 31% to 56%) and 11% (CI, 2% to 19%), respectively.

What Are the Adverse Effects of Risk Assessment, Genetic Counseling, and Testing?

Adverse effects include the potential for false-positive and false-negative results at each step of screening that lead to inappropriate reassurance or interventions. No studies directly address these issues. Fifty-seven studies describe another potential adverse effect, emotional distress. Of these, 9 studies met criteria for fair to good quality.^105-113 One randomized, controlled trial¹⁰⁶ and 8 observational studies with before-after,¹¹³ case series,¹⁰⁵ longitudinal,¹¹⁰ prospective cohort,^{107,109,111,112} and noncomparative¹⁰⁸ designs assessed breast cancer risk assessment, genetic testing, or both and their subsequent impact on distress measured as breast cancer worry, anxiety, or depression. All studies included genetic counseling. Studies varied in the number of distress indicators reported, and followup periods ranged from immediate to 6 months. Only 2 studies distinguished between mutation carriers and noncarriers.^109,111 Studies were conducted in highly selected samples of women, and results may not be generalizable to a screening population.

Overall, more studies showed decreased^{106,107,110,111,113} rather than increased¹¹² breast cancer worry or anxiety after risk assessment and testing, and 3 studies with depression outcomes had mixed results.^110,111,114 Distress varied according to whether studies evaluated risk assessment, genetic testing, or both. In 4 studies that evaluated risk assessment,^{106,108,110,113} most measures of breast cancer worry,^106,110 anxiety,^110,113 and depression¹¹⁰ decreased, and only 1 measure of breast cancer worry increased.^{106,108,110,113} When genetic testing was evaluated, breast cancer worry¹⁰⁵ and anxiety¹¹² increased, and results for depression were mixed (decreased for women who did not carry the mutation and increased for those who declined to obtain test results).¹⁰⁹

How Well Do Interventions Reduce the Incidence and Mortality of Breast and Ovarian Cancer in Women Identified as High Risk by History, Positive Genetic Test Results, or Both? What Are the Adverse Effects of Interventions?

Intensive Cancer Screening

No trials have studied the effectiveness of intensive cancer screening for BRCA mutation carriers in reducing mortality. Table 4 describes available observational studies of breast cancer screening.^115-126 Descriptive studies report increased risks for interval cancer (cancer occurring between mammograms) in BRCA mutation carriers with and without previous cancer undergoing annual mammographic screening,^115,125-127 implying that yearly mammograms may miss the highly proliferative types of cancer that are more common in BRCA mutation carriers.^128-130

To improve detection of early breast cancer in BRCAmutation carriers, 4 intensive cancer screening methods were compared in 236 women with known mutations.¹²⁴ Women underwent 1 to 3 annual breast cancer screening examinations, including magnetic resonance imaging (MRI), mammography, and ultrasonography, with clinical breast examinations provided every 6 months. Magnetic resonance imaging was more sensitive for detecting breast cancer (sensitivity, 77%; specificity, 95.4%) than was mammography (sensitivity, 36%; specificity, 99.8%), ultrasonography (sensitivity, 33%; specificity, 96%), or clinical breast examination alone (sensitivity, 9%; specificity, 99.3%). Use of MRI, ultrasonography, and mammography together had a sensitivity of 95%. Only 1 case of interval cancer was reported, and 14% of women had biopsy findings that proved to be benign.

Data are limited on benefits of intensive screening strategies for ovarian cancer in BRCA mutation carriers. One study using transvaginal ultrasonography to screen 1610 women with a family history of ovarian cancer found 3.8% abnormal scans, and only 3 of 61 women with abnormal scans had ovarian cancer.¹³¹

We identified no studies describing the adverse effects of intensive cancer screening for breast or ovarian cancer. Potential adverse effects include inconvenience of frequent examinations and procedures, exposure to ionizing radiation that could increase risk for breast cancer,¹³² cost, harms resulting from false-positive findings and subsequent testing and biopsies, and false reassurance for women who may have increased risks for developing cancer between periodic cancer screening tests.

Chemoprevention

Four randomized, placebo-controlled prevention trials of tamoxifen^133-136 and 1 trial of raloxifene¹³⁷ with breast cancer incidence and mortality outcomes have been published (Table 5), and a trial comparing these agents is in progress.^138,139 The raloxifene trial was not powered to measure breast cancer outcomes.¹³⁷ None of the trials specifically evaluated chemoprevention for women with BRCA mutations, although a genomic analysis of women developing breast cancer in 1 tamoxifen trial has been published.¹⁴⁰ No trials of chemoprevention for ovarian cancer have been published. Three tamoxifen trials had inclusion criteria based on assessment of risk for breast cancer.^133-135 Two other trials did not assess participants for breast cancer risk, and women in these studies could have lower risks for breast cancer than the general population on the basis of eligibility criteria.^{136,137,141-143}

Combining all trials in a meta-analysis resulted in a relative risk for total breast cancer of 0.62 (CI, 0.46 to 0.83) (Figure 2). Results were similar when we included only the 3 tamoxifen trials that used family history of breast cancer as an inclusion criterion^133-135 and when we included only the 4 tamoxifen trials.^133-136 Few deaths from breast cancer were reported in all the trials, and mortality did not differ between treatment and placebo groups. The relative risk (0.39 [CI, 0.20 to 0.79]) was further reduced for estrogen receptor-positive breast cancer (4 trials;^{133-134,136-137}). This treatment effect could vary depending on the type of mutation because the proportion of estrogen receptor-positive tumors varies from 28% among women with BRCA1 mutations to 63% among those with BRCA2 mutations.¹⁴⁰

Several adverse effects were reported in the tamoxifen and raloxifene trials (Table 5). All trials indicated increased risk (2.21 [CI, 1.63 to 2.98]) for thromboembolic events, including pulmonary embolism and deep venous thrombosis (5 trials).^133-137 Three trials reported that tamoxifen use was associated with an increased incidence of stroke (1.50 [CI, 1.01 to 2.24]),^133,134,136 3 showed an increase in endometrial cancer (2.42 [CI, 1.46 to 4.03]),^133-135 and 1 showed an increase in all-cause death (2.27 [CI, 1.12 to 4.60]).¹³³ Trials reported significantly increased cataracts;¹³⁴ hot flashes;^133-135,144 vaginal discharge, bleeding, and other gynecologic problems;^133-135,144 brittle nails;¹³³ and mood changes,¹³⁵ among other symptoms.^137,141,144

No randomized, controlled trials of oral contraceptives to prevent breast or ovarian cancer have been published. Observational studies indicate associations between oral contraceptives and reduced ovarian cancer in the general population^145-147 as well as BRCA mutation carriers^148,149 and an increase in breast cancer among women with family histories of breast cancer¹⁵⁰ and mutation carriers.¹⁵¹

Prophylactic Surgery

No randomized, controlled trials of prophylactic surgery have been conducted, and cohort studies are methodologically limited.¹⁵² Bias may be introduced when treatment and comparison groups are not comparable, confounders are not considered,^127,153 and surgical procedures vary.^154-160

Four studies of prophylactic bilateral mastectomy in high-risk women have been published, including 2 retrospective cohort studies based on medical records at the Mayo Clinic,^161,162 a prospective cohort study of mutation carriers in the Netherlands,¹²⁷ and a study of mutation carriers with prospective and retrospective cohort data from multiple centers in North America and Europe.¹⁶³ Results were consistent, indicating an 85% to 100% risk reduction for breast cancer despite differences in study designs and comparison groups that included sisters,¹⁶¹ matched controls,¹⁶³ a surveillance group,¹²⁷ and penetrance models.¹⁶²

Little information exists about the complications of prophylactic mastectomy in healthy high-risk women, and data from patients with breast cancer may not be generalizable. In a series of 112 high-risk women (79 mutation carriers) who had prophylactic mastectomies with immediate reconstruction, 21% had complications, including hematoma, infection, contracture, or implant rupture.¹⁶⁴ Use of autologous tissue may eliminate the need for silicone implants but may result in higher complication rates.¹⁶³

Four studies of prophylactic oophorectomy met inclusion criteria: a retrospective study of families with breast and ovarian cancer,¹⁶⁵ 2 retrospective cohort studies of mutation carriers undergoing oophorectomy compared with matched comparison groups in North America and Europe,^166,167 and a prospective cohort study of mutation carriers undergoing elective oophorectomy or surveillance.¹⁵³ All studies reported reduced risks for ovarian and breast cancer with prophylactic oophorectomy, although numbers of cases were small and the CIs for the only prospective study crossed 1.0 for both outcomes.¹⁵³ Overall, the risk reduction ranged from 85% to 100% for ovarian cancer and from 53% to 68% for breast cancer. One study found that oophorectomy after 50 years of age was not associated with substantial reduction in breast cancer risk,¹⁶⁶ consistent with other studies of oophorectomy in the general population.^168-171

Surgical complications attributable to prophylactic oophorectomy are not well described and may vary with the type of surgical technique.¹⁷² Only 1 study of prophylactic oophorectomy in BRCA mutation carriers reported surgical complications.¹⁵³ In this study, 4 of 80 women experienced complications, including wound infection, perforation of the bladder, distal obstruction of the small bowel attributed to adhesions, and perforation of the uterus.¹⁵³ Premenopausal high-risk women are not only the most likely to benefit from prophylactic oophorectomy but are also the most likely to experience additional side effects from surgery, including loss of fertility and induction of premature menopause.

Tubal ligation has been associated with a decreased risk for invasive epithelial ovarian cancer in observational studies.^146,173,174 A matched case-control study of mutation carriers with and without ovarian cancer indicated a reduced odds ratio among controls who underwent previous tubal ligation, after adjustment for oral contraceptive use, parity, history of breast cancer, and ethnic group (odds ratio, 0.39 [CI, 0.22 to 0.70]).¹⁷⁵ This protective effect was present only among BRCA1 mutation carriers, although the number of BRCA2 carriers was small in this study.

Few descriptive studies of the psychosocial impact of prophylactic mastectomy or oophorectomy on high-risk patients have been published. Patient surveys indicate that although 57% of women at high risk for breast cancer consider prophylactic mastectomy an option,¹⁷⁶ only 16% to 20% rate it a favorable option,^177,178 and only 9% to 17% of women actually proceed with the surgery.^176,178,179 Descriptive studies report improved concern about cancer after prophylactic surgeries^180-182 but also dissatisfaction with reconstruction,¹⁷⁶ appearance,¹⁸⁰ feelings of femininity,¹⁸⁰ and sexual relationships,¹⁸⁰ although several studies are inconclusive.^183-186

Genetic Risk Assessment Strategies

In the absence of direct evidence, we developed an outcomes table to determine the magnitude of potential benefits and adverse effects of screening for inherited breast and ovarian cancer susceptibility in the general population, stratified by average, moderate, and high risk for mutations according to family history as previously defined.

Results for the general population (Table 6) assume prevalence rates of mutations of 0.12% for average-risk, 1.5% for moderate-risk, and 8.68% for high-risk women and a 50/50 ratio of BRCA1 and BRCA2 mutations. This combination of prevalence rates reflects an overall population mutation rate of 1 in 397. The number needed to screen for benefit (NNSB) to prevent 1 case of breast cancer in a hypothetical cohort of 100,000 women depends on which prevention therapy is chosen. For women with average risk, the NNSB to prevent 1 case of breast cancer by age 75 years with chemoprevention is 12,862 (CI, 5425 to 64,048); for mastectomy, 11,049 (CI, 6243 to 27,037); and for oophorectomy, 4100 (CI, 1985 to 255,926). In comparison, trials of screening with mammography among women age 39 to 74 years indicate that approximately 550 to 3500 need to be invited for screening to prevent 1 death from breast cancer 13 to 20 years after randomization.¹⁸⁷ Approximately 7072 (CI, 3610 to 584,750) women with average risk need to be screened to prevent 1 case of ovarian cancer by undergoing oophorectomy. The NNSB for all treatment options, and for breast and ovarian cancer outcomes, decreases as risk for mutations increases (see outcomes for moderate- and high-risk women in Table 6). Under the assumptions of the outcomes table, if 100,000 women in the general population underwent testing for BRCA mutations, 16 cases of breast cancer would be prevented with mastectomy and 31 cases of ovarian cancer would be prevented with oophorectomy (Figure 3).

Table 6 also describes adverse effects. The number needed to treat with tamoxifen or raloxifene to cause a thromboembolic event each year is 1042 (CI, 641 to 2719), and the number needed to treat to cause a case of endometrial cancer each year is 2686 (CI, 1228 to 15 726) (tamoxifen only). Use of chemoprevention is a long-term prevention strategy, so these estimates require adjustment depending on the projected length of therapy. Only 5 women need to be treated with mastectomy in order to have 1 surgical complication; for oophorectomy, the number is 20. The numbers of women undergoing treatment and experiencing adverse effects increase with each successive risk group.

Sensitivity analyses indicate that preventing breast and ovarian cancer cases that occur by age 40 to 50 years requires higher NNSB values than those needed for cases that occur by age 75 years, and the prevalence ratios of BRCA1 and BRCA2 do not substantially influence the NNSB (data not shown). In addition, if lower prevalence assumptions are used, the NNSB increases (data not shown).

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Discussion

Little is known about BRCA mutations in the general population, and most data originate from studies of highly selected women with existing cancer or strong family histories of cancer. Tools assessing individual risks for mutations and referral guidelines have been developed, but their accuracy, effectiveness, and adverse effects in primary care settings are unknown. Risk assessment tools are recommended as an adjuvant to genetic counseling.⁶³ Women assessed as high risk in primary care settings may not necessarily be candidates for mutation testing but could be offered more definitive risk assessment by referral to genetic counseling or application of detailed risk assessment instruments. Risk assessment, genetic counseling, and mutation testing did not cause adverse psychological outcomes, and counseling improved distress and risk perception in the highly selected populations studied. However, long-term effects are unknown, studies did not evaluate psychological aspects of medical outcomes, and little is known about the impact of testing on family members.

Currently available prevention interventions include intensive cancer screening, chemoprevention, and prophylactic mastectomy and oophorectomy. Intensive cancer screening studies are descriptive and inconclusive, and recent studies suggest improved breast cancer detection using MRI. A meta-analysis of randomized, controlled trials of tamoxifen and raloxifene indicates significant risk reduction for breast cancer in women with varying levels of family history risk for breast cancer. Results also show significantly increased risks for thromboembolic events and, for tamoxifen, increased endometrial cancer. Observational studies of prophylactic surgeries report reduced risks for breast and ovarian cancer in mutation carriers.

Estimating mutation prevalence and penetrance and stratifying by average-, moderate-, and high-risk groups based on family history can be used to determine the yield of screening in populations that would present to primary care clinicians. Applying these estimates to an outcomes table that considers treatment effects provides calculations of benefits and adverse effects for main outcomes. The NNSB to prevent 1 case of breast or ovarian cancer is high among low-risk women and decreases as risk increases. Adverse effects also increase as more women are subjected to therapies.

Although the outcomes table estimates can be useful, caution is necessary in extrapolating too far from the primary data. The quality and generalizability of studies vary and may not support the assumptions. Only limited data describe the range of risk associated with BRCA mutations, genetic heterogeneity, and moderating factors outside the gene. Data are not available to determine the optimal age to test and how the age at testing influences estimates of benefits and adverse effects. All estimates in the outcomes table are based on cases of cancer, not mortality. It is not known whether testing for BRCA mutations reduces cause-specific or all-cause mortality and improves quality of life. The adverse effects associated with receiving a false-negative test result (12% to 15% with DNA sequencing), or a result indicating mutations of unknown significance (approximately 13%), are not known. Nonquantitative measures, such as ethical, legal, and social implications, are not factored into the outcomes table. Treatment effects are influenced by several factors, including age at which treatment is initiated,¹⁶⁶ type of mutation,^89,140 adherence, and cost. It is not known how these differences influence patient decisionmaking.

To determine the appropriateness of risk assessment and testing for BRCA mutations in primary care, more information is needed about the impact of screening in the general population. Issues such as access to testing, effectiveness of screening approaches (including risk stratification), use of system supports, and patient acceptance and education require additional study. Who should perform risk assessment and genetic counseling services, how these services should be provided, and what skills are needed are unresolved questions. What happens after patients are identified as high risk in clinical settings and the consequences of genetic testing on individuals and their relatives are unknown. Well-designed investigations using standardized measures and enrolling participants who reflect the general population, including minority women, are needed. An expanded database or registry of patients counseled and tested for BRCA mutations would provide useful information about predictors of cancer, response to interventions, and other modifying factors. Current research resources that may help address some of these questions include the National Cancer Institute-funded Cancer Genetics Network⁵² and Breast and Ovarian Cancer Family Registries.¹⁸⁸ Additional research on interventions is needed, including chemoprevention trials of mutation carriers, evaluation of the effect of age at intervention, measurement of long-term outcomes, and factors related to acceptance of preventive interventions. This information could improve patient decisionmaking and lead to better health outcomes.

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