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Clinical Guidelines |

Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Systematic Evidence Review for the U.S. Preventive Services Task Force FREE

Heidi D. Nelson, MD, MPH; Laurie Hoyt Huffman, MS; Rongwei Fu, PhD; and Emily L. Harris, PhD, MPH
[+] Article and Author Information

From Oregon Health & Science University and Kaiser Permanente Center for Health Research, Portland, Oregon.


Acknowledgments: The authors thank Miranda Walker, BA; Christina Bougatsos, BS; Andrew Hamilton, MLS, MS; Mark Helfand, MD, MPH; Wylie Burke, MD, PhD; Gurvaneet Randhawa, MD, MPH; members of the USPSTF; and reviewers for their contributions to this project.

Grant Support: This study was conducted by the Oregon Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality, contract 290-02-0024, Task Order no. 2, Rockville, Maryland.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Heidi D. Nelson, MD, MPH, Oregon Health & Science University, Mail Code BICC 504, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239; e-mail, nelsonh@ohsu.edu.

Current Author Addresses: Dr. Nelson and Ms. Hoyt Huffman: Oregon Health & Science University, Mail Code BICC, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239.

Dr. Fu: Oregon Health & Science University, Mail Code CB 669, 3181 SW Sam Jackson Park Road, Portland, OR 97239.

Dr. Harris: Kaiser Permanente Center for Health Research, 3800 North Interstate Avenue, Portland, OR 97227.


Ann Intern Med. 2005;143(5):362-379. doi:10.7326/0003-4819-143-5-200509060-00012
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Background: Clinically significant mutations of BRCA1 and BRCA2 genes are associated with increased susceptibility for breast and ovarian cancer. Although these mutations are uncommon, public interest in testing for them is growing.

Purpose: To determine benefits and harms of screening for inherited breast and ovarian cancer susceptibility in the general population of women without cancer presenting for primary health care in the United States.

Data Sources: MEDLINE (1966 to 1 October 2004), Cochrane Library databases, reference lists, reviews, Web sites, and experts.

Study Selection: Eligibility was determined by inclusion criteria specific to key questions about risk assessment, genetic counseling, mutation testing, prevention interventions, and potential adverse effects.

Data Extraction: After review of studies, data were extracted, entered into evidence tables, and summarized by using descriptive or statistical methods. Study quality was rated by using predefined criteria.

Data Synthesis: Tools assessing risks for mutations and referral guidelines have been developed; their accuracy, effectiveness, and adverse effects in primary care settings are unknown. 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. Intensive cancer screening studies are inconclusive. Chemoprevention trials indicate risk reduction for breast cancer in women with varying levels of risk, as well as increased adverse effects. Observational studies of prophylactic surgeries report reduced risks for breast and ovarian cancer in mutation carriers.

Limitations: No data describe the range of risk associated with BRCA mutations, genetic heterogeneity, and moderating factors; studies conducted in highly selected populations contain biases; and information on adverse effects is incomplete.

Conclusions: A primary care approach to screening for inherited breast and ovarian cancer susceptibility has not been evaluated, and evidence is lacking to determine benefits and harms for the general population.

Clinically significant, or deleterious, mutations of BRCA1 and BRCA2 genes are associated with increased susceptibility for breast and ovarian cancer (12). These mutations increase a woman's lifetime risk for breast cancer to 60% to 85% (34) and risk for ovarian cancer to 26% (BRCA1) and 10% (BRCA2) (58). Specific BRCA mutations are clustered among certain ethnic groups, such as Ashkenazi Jews (911), and in the Netherlands (12), Iceland (1314), and Sweden (15). Additional germline mutations associated with familial breast or ovarian cancer have been identified, and others are suspected (1617). BRCA1 and BRCA2 mutations are also associated with increased risk for prostate cancer, and BRCA2 mutations are associated with increased risk for pancreatic and stomach cancer and melanoma (18).

Screening for inherited breast and ovarian cancer susceptibility is a 2-step process: assessment of risk for clinically significant BRCA mutations followed by genetic testing of high-risk individuals. Guidelines recommend testing for mutations only when an individual has personal or family history features suggestive of inherited cancer susceptibility, when the test result can be adequately interpreted, and when results will aid in management (1920). Several characteristics are associated with an increased likelihood of clinically significant BRCA mutations, including young age at breast cancer diagnosis, bilateral breast cancer, history of both breast and ovarian cancer, multiple cases of breast cancer in a family, both breast and ovarian cancer in a family, and Ashkenazi Jewish heritage (2124). Risk status requires reevaluation when personal or family cancer history changes. Genetic counseling is recommended before mutation testing (25). Several approaches are in practice, including educational; decision-making; and psychosocial support (2627) provided by genetic counselors (2830), nurse educators (3133), or other professionals.

The type of mutation analysis required depends on family history. Individuals from families or ethnic groups with known mutations can be tested specifically for them. Several clinical laboratories in the United States test for specific mutations or sequence-specific exons. Individuals without linkages to others with known mutations undergo direct DNA sequencing. In these cases, guidelines recommend that testing begin with a relative who has known breast or ovarian cancer to determine whether a clinically significant mutation is segregating in the family (19). Myriad Genetic Laboratories provides direct DNA sequencing in the United States and reports analytic sensitivity and specificity exceeding 99% (34). Approximately 12% of high-risk families without a BRCA1 or BRCA2 coding-region mutation may have other clinically significant genomic rearrangements (3435). Test results include not only positive (denoting a deleterious mutation) and negative (no mutation found) interpretations but also variants of uncertain clinical significance; this last group represents up to 13% of results (21). The results of genetic testing could lead to prevention interventions for reducing risk or mortality in mutation carriers. Experts recommend earlier and more frequent cancer screening, chemoprevention, and prophylactic surgery (Table 1) (3640).

Table Jump PlaceholderTable 1.  Detection and Prevention Recommendations

Although clinically significant BRCA mutations are estimated to occur in 1 in 300 to 500 persons in the general population (4144), public interest in testing is growing, and physicians are increasingly faced with this issue while providing primary health care. Women often overestimate their risks for breast cancer or BRCA mutations (32, 4546), and most women responding to surveys, including women at average and moderate risk, report a strong desire for genetic testing (27, 47), even though only those at high risk would potentially benefit. Concerns about cancer, publicized scientific advances, incomplete understanding of testing and interventions, and direct-to-consumer advertising probably influence these perceptions, increasing demand for genetic testing services (47).

The objective of this systematic evidence review is to determine the benefits and harms of screening for inherited breast and ovarian cancer susceptibility in the general population of women presenting for primary health care in the United States. This review was prepared for the U.S. Preventive Services Task Force (USPSTF) and examines a chain of evidence about genetic risk assessment in primary care settings; impact of genetic counseling; ability to predict cancer risk in women with average, moderate, and high risks for clinically significant mutations; benefits of prevention interventions; and potential adverse effects. A review of studies about Ashkenazi Jewish women specifically is reported elsewhere (48).

The analytic framework in Figure 1 outlines the patient population, interventions, and health outcomes. This report focuses on the following key questions:

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Figure 1.
Analytic framework.KQBRCABRCABRCABRCA1BRCA2

Key question ( ) 1: Do risk assessment and mutation testing lead to a reduction in the incidence of breast and ovarian cancer and cause-specific or all-cause mortality? KQ 2A: How well does risk assessment for cancer susceptibility by a clinician in a primary care setting select candidates for mutation testing? KQ 2B: What are the benefits of genetic counseling before testing? KQ 2C: Among women with family histories predicting an average, moderate, or high risk for a deleterious mutation, how well does mutation testing predict risk for breast and ovarian cancer? KQ 3: What are the adverse effects of risk assessment, genetic counseling, and testing? KQ 4: 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? KQ 5: What are the adverse effects of interventions? *Indicates clinically significant mutation of or .

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1. 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?

2A. How well does risk assessment for cancer susceptibility by a clinician in a primary care setting select candidates for BRCA mutation testing?

2B. What are the benefits of genetic counseling before testing?

2C. 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?

3. What are the adverse effects of risk assessment, genetic counseling, and testing?

4. 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?

5. What are the adverse effects of interventions?

We identified relevant papers from multiple searches of MEDLINE (1966 to 1 October 2004) and the Cochrane Library databases; we obtained additional papers by reviewing reference lists of pertinent studies, reviews, editorials, and Web sites and by consulting experts (Appendix Figure). Investigators reviewed all abstracts and determined eligibility by applying inclusion and exclusion criteria specific to key questions (Appendix Table). We then reviewed full-text papers of included abstracts for relevance. Studies about patients with current or past breast or ovarian cancer were excluded unless they addressed genetic testing issues in women without cancer. Data were extracted from each included study, entered into evidence tables, and summarized by using descriptive or statistical methods or both. Two reviewers independently rated the quality of studies using criteria specific to different study designs developed by the USPSTF (Appendix 1) (49). When reviewers disagreed, a final rating was determined by reevaluations by the 2 initial reviewers and a third reviewer if needed. Only studies rated good or fair in quality were included, although studies with designs that do not have quality rating criteria, such as descriptive studies, were also included if relevant to the key questions.

To estimate risks for breast and ovarian cancer due to clinically significant BRCA mutations, the screening population was stratified into groups at average, moderate, and high risk for being a mutation carrier based on history of breast or ovarian cancer in first- and second-degree relatives. This approach allows use of published data that describe risks in similar terms. The following definitions were used: average risk—no first-degree relatives and no more than 1 second-degree relative on each side of the family with breast or ovarian cancer; moderate risk—1 first-degree relative or 2 second-degree relatives on the same side of the family with breast or ovarian cancer; and high risk—at least 2 first-degree relatives with breast or ovarian cancer. On the basis of pooled data from more than 100 000 women without breast cancer from 52 epidemiologic studies, approximately 92.7% of the screening population would be expected to be average risk, 6.9% moderate risk, and 0.4% high risk according to these definitions (50).

Risks for breast and ovarian cancer in mutation carriers have been primarily calculated from families of women with existing breast and ovarian cancer. To determine benefits and adverse effects of genetic testing in average-, moderate-, and high-risk groups, we estimated mutation prevalence as well as the probability of developing cancer given the presence of the mutation (penetrance) for each risk group. Penetrance was calculated from data about the prevalence of BRCA mutations in women with and without breast and ovarian cancer; the probability of breast or ovarian cancer in the U.S. population estimated from Surveillance, Epidemiology, and End Result (SEER) data (51) by using DevCan software (52); and relative risks for breast and ovarian cancer in moderate- and high-risk groups. Penetrance estimates were based on the Bayes theorem and stratified by cancer type (breast or ovarian), risk group (average, moderate, and high), and age whenever data were available. Appendix 2 provides additional details of this method (48).

We also performed a meta-analysis of chemoprevention trials to more precisely estimate effectiveness and adverse effects. All chemoprevention trials reported relative risk (RR) estimates, and the logarithm of the RR (logRR) and the corresponding standard errors were calculated for each trial and used in the meta-analysis. The overall estimates of RR were obtained by using a random-effects model (53).

We developed an outcomes table to determine the magnitude of potential benefits and adverse effects of testing for BRCA mutations in the general population based on best estimates from published studies and results of analyses when available. Variation associated with these estimates was incorporated by using Monte Carlo simulations. The sampling distributions for estimates were either the underlying distribution on which calculation of the 95% CI was based when available, or one that best approximated the point estimate and CI (Appendix 3). The point estimates and 95% CIs of outcome variables were based on 1 000 000 simulations. Since there are no direct estimates of BRCA mutation prevalence for average- and moderate-risk groups, sensitivity analyses were conducted by assuming a range of prevalence values. Prevalence values were chosen such that when they were summed across the 3 risk groups, the total fell within the range for the general population (1 in 300 to 500) (4144). Calculations assumed that women are cancer free at age 20 years, and outcomes were calculated to age 40 years for breast cancer, age 50 years for ovarian cancer, and age 75 years for both because results at these ages were most often reported by studies. We assumed that half of the mutations would be in BRCA1 and half in BRCA2, and we did sensitivity analyses to determine whether this ratio (40/60, 50/50, 60/40) affects outcomes.

This research was funded by the Centers for Disease Control and Prevention under a contract with the Agency for Healthcare Research and Quality to support the work of the USPSTF. Agency staff and Task Force members participated in the initial design of the study, and, along with content experts, reviewed reports. The authors are responsible for the content of the manuscript and the decision to submit it for publication.

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 (2224, 5772) 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 (6770).

Table Jump PlaceholderTable 2.  Tools To Assess Risk forBRCAMutation
Referral Guidelines

Referral guidelines have been developed by health maintenance organizations (74), professional organizations (1920), cancer programs (7579), state and national health programs (8083), and investigators (84) 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.

Table Jump PlaceholderTable 3.  Criteria for Referral for Genetic Counseling and Testing
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 (2733, 8587). 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, 3033, 8587) or no effect (2930, 32, 86) after genetic counseling. These include 5 trials reporting decreased breast cancer worry (27, 3133, 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, 2930, 33, 8687). 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 (4144). 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, 4142, 8992). 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, 4142, 8992, 9597). 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, 4243, 99102), and 3 provide these data for a BRCA2 mutation (4243, 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, 102104) 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, 102103), 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 (105113). One randomized, controlled trial (106) and 8 observational studies with before-after (113), case series (105), longitudinal (110), prospective cohort (107, 109, 111112), and noncomparative (108) 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 follow-up 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 (106107, 110111, 113) rather than increased (112) breast cancer worry or anxiety after risk assessment and testing, and 3 studies with depression outcomes had mixed results (110111, 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 depression (110) decreased, and only 1 measure of breast cancer worry increased (106, 108, 110, 113). When genetic testing was evaluated, breast cancer worry (105) and anxiety (112) 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 (115126). 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, 125127), implying that yearly mammograms may miss the highly proliferative types of cancer that are more common in BRCA mutation carriers (128130).

Table Jump PlaceholderTable 4.  Intensive Cancer Screening Studies of Women with Familial Breast Cancer Risk

To improve detection of early breast cancer in BRCA mutation 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 (133136) and 1 trial of raloxifene (137) with breast cancer incidence and mortality outcomes have been published (Table 5), and a trial comparing these agents is in progress (138139). 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 (133135). 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 (136137, 141143).

Table Jump PlaceholderTable 5.  Randomized, Placebo-Controlled Trials of Chemoprevention for Breast Cancer

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 (133135) and when we included only the 4 tamoxifen trials (133136). 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).

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Figure 2.
Relative risks for breast cancer in chemoprevention trials.

Error bars represent 95% CIs. IBIS = International Breast Cancer Intervention Study.

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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]) (133134, 136), 3 showed an increase in endometrial cancer (2.42 [CI, 1.46 to 4.03]) (133135), 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 (133135, 144); vaginal discharge, bleeding, and other gynecologic problems (133135, 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 (145147) as well as BRCA mutation carriers (148149) and an increase in breast cancer among women with family histories of breast cancer (150) 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 (154160).

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 (161162), 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 (166167), 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 (168171).

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, 173174). 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 (177178), and only 9% to 17% of women actually proceed with the surgery (176, 178179). Descriptive studies report improved concern about cancer after prophylactic surgeries (180182) but also dissatisfaction with reconstruction (176), appearance (180), feelings of femininity (180), and sexual relationships (180), although several studies are inconclusive (183186).

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 Jump PlaceholderTable 6.  Outcomes Table Summary
Table Jump PlaceholderAppendix Table.  Inclusion and Exclusion Criteria according to Key Question
Grahic Jump Location
Figure 3.
Yield of testing forBRCAmutations in a hypothetical population based on assumptions in Table 6.

NNS = number needed to screen. *Based on estimates for mastectomy. †Based on estimates for oophorectomy.

Grahic Jump Location
Grahic Jump Location
Appendix Figure.
Yield of literature search and review.

ELSI = ethical, legal, and social implications.

Grahic Jump Location

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).

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 decision making.

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 Network (52) 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 decision making and lead to better health outcomes.

Appendix 1
Diagnostic Accuracy Studies
Criteria

  1. Screening test relevant, available for primary care, adequately described.

  2. Credible reference standard, performed regardless of test results.

  3. Reference standard interpreted independently of screening test.

  4. Indeterminate results handled in a reasonable manner.

  5. Spectrum of patients included in study.

  6. Sample size.

  7. Administration of reliable screening test.

Definition of Ratings Based on Above Criteria

Good: Evaluates relevant available screening test; uses a credible reference standard; interprets reference standard independently of screening test; assesses reliability of test; has few or handles indeterminate results in a reasonable manner; includes large number (>100) broad-spectrum patients with and without disease.

Fair: Evaluates relevant available screening test; uses reasonable although not best standard; interprets reference standard independently of screening test; has moderate sample size (50 to 100 participants), and includes a “medium” spectrum of patients.

Poor: Has important limitations, such as inappropriate reference standard, improperly administered screening test, biased ascertainment of reference standard, or very small sample size of very narrow selected spectrum of patients.

Randomized, Controlled Trials and Cohort Studies
Criteria

  1. Initial assembly of comparable groups: randomized, controlled trials—adequate randomization, including concealment and statement of whether potential confounders were distributed equally among groups; cohort studies—consideration of potential confounders with either restriction or measurement for adjustment in the analysis; consideration of inception cohorts.

  2. Maintenance of comparable groups (includes attrition, crossovers, adherence, and contamination).

  3. Important differential loss to follow-up or overall high loss to follow-up.

  4. Measurements: equal, reliable, and valid (includes masking of outcome assessment).

  5. Clear definition of interventions.

  6. Important outcomes considered.

  7. Analysis: adjustment for potential confounders for cohort studies, or intention-to-treat analysis for randomized, controlled trials.

Definition of Ratings Based on Above Criteria

Good: Meets all criteria—comparable groups are assembled initially and maintained throughout the study (follow-up ≥80%), reliable and valid measurement instruments are used and applied equally to the groups, interventions are spelled out clearly, important outcomes are considered, and appropriate attention to confounders in analysis.

Fair: Studies will be graded “fair” if any or all of the following problems occur, without the important limitations noted in the “poor” category below: Generally comparable groups are assembled initially but some question remains as to whether some (although not major) differences occurred in follow-up, measurement instruments are acceptable (although not the best) and generally applied equally, some but not all important outcomes are considered, and some but not all potential confounders are accounted for.

Poor: Studies will be graded “poor” if any of the following major limitations exists: Groups assembled initially are not close to being comparable or maintained throughout the study, unreliable or invalid measurement instruments are used or not applied at all equally among groups (including failure to mask outcome assessment), and key confounders are given little or no attention.

Case–Control Studies
Criteria

  1. Accurate ascertainment of cases.

  2. Nonbiased selection of case-patients and controls, with exclusion criteria applied equally to both.

  3. Response rate.

  4. Diagnostic testing procedures applied equally to each group.

  5. Measurement of exposure accurate and applied equally to each group.

  6. Appropriate attention to potential confounding variable.

Definition of Ratings Based on Above Criteria

Good: Appropriate ascertainment of cases and nonbiased selection of case-patients and controls, exclusion criteria applied equally to case-patients and controls, response rate of 80% or greater, diagnostic procedures and measurements accurate and applied equally to case-patients and controls, and appropriate attention to confounding variables.

Fair: Recent, relevant, without major apparent selection or diagnostic work-up bias but with response rate less than 80% or attention to some but not all important confounding variables.

Poor: Major selection or diagnostic work-up biases, response rates less than 50%, or inattention to confounding variables.

Appendix 2

The meta-analysis of penetrance was based on the Bayes theorem and stratified by cancer type (breast or ovarian), risk group (average, moderate, and high), and age. The penetrance of BRCA mutations is the probability of developing cancer given that a clinically significant BRCA mutation is present. Let D+ denote “individual has cancer,” D denote “individual does not has cancer,” G denote “individual has a clinically significant BRCA mutation,” penetrance is then denoted as P(D+|G) By the Bayes theorem, penetrance is given by:

where P(D) = 1 − P(D+). In our analysis, we assume P(D+) is fixed. For the average-risk group, the estimate of P(D+) from Surveillance, Epidemiology, and End Results (SEER) data using DevCan software (52) is used in the calculation of penetrance. When family history is present, the estimate of P(D+) is obtained by multiplying the SEER estimate by the relative risk for cancer with a positive family history. P(G|D+) and P(G|D) are the prevalences of BRCA mutations from the cancer-affected and cancer-unaffected populations, respectively, and are estimated from different studies in a meta-analysis by using a random-effects model (53).

The 95% CI of P(D+|G) is calculated as follows. Modifying equation (1), we have:

then,

Assuming that P(G|D+) and P(G|D) are independent with each other, standard calculation using delta-method shows:

Usually, logit(P(D+|G)) is assumed to be normally distributed and the 95% CI of logit(P(D+|G)) is given as

where Z0.975 is the 97.5% quantile of the standard normal distribution. The 95% CI of P(D+|G) is obtained by converting the above interval back to the original scale.

For some risk groups, there are no data from genetic testing studies with which to estimate P(G|D), and we used the best point estimates available in the literature. However, SEs associated with the point estimates are usually not available. Under such conditions, the second part of equation 3 on the right side would be zero, and the 95% CI for the penetrance would be underestimated.

Equation 1 provides the formula to calculate penetrance in general. It is easy to extend equation 1 to calculate penetrance of BRCA mutations by a particular age or with a positive family history. For example, if we are interested in penetrance of BRCA mutations by age x, we substitute D+ by D+ by age x, denoted by

in equation (1), which gives

In this analysis, we assume

In our analysis, we calculated penetrance of breast cancer to ages 40 and 75 years and ovarian cancer to ages 50 and 75 years to be consistent with how age was considered by the studies.

For penetrance of BRCA mutations when a positive family history is present,

We conducted a sensitivity analysis in the average-risk groups by calculating penetrance 2 ways: including and excluding studies of women with family history of breast or ovarian cancer. Calculation of 95% CI for penetrance in equations 4 and 5 is similar to that described above, with appropriate substitution of terms.

Appendix 3

Several estimates were used to develop the outcomes table. This appendix provides 2 examples of specification of sampling distributions for these estimates.

1. Sampling Distribution for Penetrance P(D+|G):

The estimate of P(D+|G) is obtained from our analysis. We assumed that logit(P(D+|G)), denoted as logit(P) for concise notation, is approximately normally distributed and estimated logit(P) and its variance from data available in the literature. Estimate of P(D+|G) and its CI is obtained by transforming logit(P) and its CI (see Appendix 2 for more information).

In Monte Carlo simulation, random samples for the estimate of P(D+|G) are obtained as follows. First, random samples of logit(P) are drawn from the following normal distribution:

where

are estimated values for logit(P) and its variance. Then, by transformation, random samples for estimates of P(D+|G) are obtained as:

2. Sampling Distribution for Relative Risk

When developing the outcomes table, the estimates of relative risk (RR) are obtained from published studies. Usually, the point estimate

and its 95% CI (RRL, RRU) are reported. Since ln(RR) is usually assumed to be approximately normally distributed, we calculate

and,

where Z0.975 is the 97.5% quantile of the standard normal distribution. Random samples of RR are obtained by first drawing random samples of ln(RR) from

and then transforming to RR by taking exponentiation.

If we recalculate the 95% CI for RR by using

the resulting CI usually agrees very well with the reported (RRL, RRU).

Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S. et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994; 266:66-71. PubMed
CrossRef
 
Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J. et al.  Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995; 378:789-92. PubMed
 
Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL.  Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002; 94:1365-72. PubMed
 
Thompson D, Easton DF.  Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002; 94:1358-65. PubMed
 
Easton DF, Ford D, Bishop DT.  Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995; 56:265-71. PubMed
 
Ford D, Easton DF.  The genetics of breast and ovarian cancer. Br J Cancer. 1995; 72:805-12. PubMed
 
Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE.  Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994; 343:692-5. PubMed
 
Easton DF, Bishop DT, Ford D, Crockford GP.  Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993; 52:678-701. PubMed
 
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. PubMed
 
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. PubMed
 
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. PubMed
 
Peelen T, vanVliet 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. PubMed
 
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. PubMed
 
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. PubMed
 
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. PubMed
 
Wooster R, Weber BL.  Breast and ovarian cancer. N Engl J Med. 2003; 348:2339-47. PubMed
 
Lindor NM, Greene MH.  The concise handbook of family cancer syndromes. Mayo Familial Cancer Program. J Natl Cancer Inst. 1998; 90:1039-71. PubMed
 
Liede A, Karlan BY, Narod SA.  Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004; 22:735-42. PubMed
 
American College of Medical Genetics Professional Practice and Guidelines Committee.  Genetic susceptibility to breast and ovarian cancer: assessment, counseling, and testing guidelines executive summary. 1999. Accessed athttp://www.health.state.ny.us/nysdoh/cancer/obcancer/contents.htmon 18 July 2005.
 
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; discussion 1737-40. [PMID: 8622094]
 
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. PubMed
 
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. PubMed
 
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. PubMed
 
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. PubMed
 
.  Genetic counseling. Am J Hum Genet. 1975; 27:240-2. PubMed
 
Skinner CS, Schildkraut JM, Berry D, Calingaert B, Marcom PK, Sugarman J. et al.  Pre-counseling education materials for BRCA testing: does tailoring make a difference? Genet Test. 2002; 6:93-105. PubMed
 
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. PubMed
 
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. PubMed
 
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. PubMed
 
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. PubMed
 
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. PubMed
 
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. PubMed
 
Lerman C, Lustbader E, Rimer B, Daly M, Miller S, Sands C. et al.  Effects of individualized breast cancer risk counseling: a randomized trial. J Natl Cancer Inst. 1995; 87:286-92. PubMed
 
Myriad Genetics. Accessed athttp://www.myriadtests.com/home.htmon 30 April 2004.
 
Unger MA, Nathanson KL, Calzone K, Antin-Ozerkis D, Shih HA, Martin AM. et al.  Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Genet. 2000; 67:841-50. PubMed
 
U.S. Preventive Services Task Force.  Screening for breast cancer: recommendations and rationale. Ann Intern Med. 2002; 137:344-6. PubMed
 
Burke W, Daly M, Garber J, Botkin J, Kahn MJ, Lynch P. et al.  Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA. 1997; 277:997-1003. PubMed
 
U.S. Preventive Services Task Force.  Recommendations and rationale. Screening for ovarian cancer. Accessed athttp://www.ahrq.gov/clinic/3rduspstf/ovariancan/ovcanrs.htmon 19 October 2004.
 
.  NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA. 1995; 273:491-7. PubMed
 
U.S. Preventive Services Task Force.  Chemoprevention of breast cancer: recommendations and rationale. Ann Intern Med. 2002; 137:56-8. PubMed
 
.  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; 83:1301-8. PubMed
 
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; 86:76-83. PubMed
 
Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N. et al.  Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999; 91:943-9. PubMed
 
Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF.  Risk models for familial ovarian and breast cancer. Genet Epidemiol. 2000; 18:173-90. PubMed
 
Bowen D, Christensen C, Powers D, Graves D, Anderson C.  Effects of counseling and ethnic identity on perceived risk and cancer worry in African American women. Journal of Clinical Psychology Medical Settings. 1998; 5:365-79.
 
Lerman C, Trock B, Rimer BK, Jepson C, Brody D, Boyce A.  Psychological side effects of breast cancer screening. Health Psychol. 1991; 10:259-67. PubMed
 
.  Genetic testing for breast and ovarian cancer susceptibility: evaluating direct-to-consumer marketing—Atlanta, Denver, Raleigh-Durham, and Seattle, 2003. MMWR Morb Mortal Wkly Rep. 2004; 53:603-6. PubMed
 
Nelson HD, Huffman L, Fu R, Harris E, Walker M, Bougatsos C.  Genetic risk assessment and testing for breast and ovarian cancer susceptibility. Evidence Synthesis (Prepared by the Oregon Health & Science University Evidence-based Practice Center under contract 290-97-0018). Rockville, MD: Agency for Healthcare Research and Quality; 2005 [In press].
 
Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM. et al.  Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001; 20:21-35. PubMed
 
Collaborative Group on Hormonal Factors in Breast Cancer.  Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet. 2001; 358:1389-99. PubMed
 
Ries LA, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, et al.  SEER cancer statistics review, 1975-2001. Bethesda, MD: National Cancer Institute. Accessed athttp://seer.cancer.gov/csr/1975_2001on 19 October 2004.
 
Cancer Genetics Network. Accessed athttp://epi.grants.cancer.gov/CGN/on 20 March 2005.
 
DerSimonian R, Laird N.  Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-88. PubMed
 
Murff HJ, Spigel DR, Syngal S.  Does this patient have a family history of cancer? An evidence-based analysis of the accuracy of family cancer history. JAMA. 2004; 292:1480-9. PubMed
 
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. PubMed
 
Domchek SM, Eisen A, Calzone K, Stopfer J, Blackwood A, Weber BL.  Application of breast cancer risk prediction models in clinical practice. J Clin Oncol. 2003; 21:593-601. PubMed
 
Frank TS, Manley SA, Olopade OI, Cummings S, Garber JE, Bernhardt B. et al.  Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998; 16:2417-25. PubMed
 
Blackwood MA, Yang H, Margolin A. et al.  Predicted probability of breast cancer susceptibility gene mutations. Breast Cancer Research and Treatment. 2001; 69:223.
 
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. PubMed
 
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. PubMed
 
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. PubMed
 
Euhus DM, Smith KC, Robinson L, Stucky A, Olopade OI, Cummings S. et al.  Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO. J Natl Cancer Inst. 2002; 94:844-51. PubMed
 
Euhus D.  Risk modeling in breast cancer. Breast J. 2004; 10:Suppl 1S10-2. PubMed
 
CancerGene with BRCAPRO. Accessed athttp://astor.som.jhmi.edu/BayesMendel/brcapro.htmlon 30 April 2004.
 
Cyrillic Software. User information. Accessed athttp://www.cyrillicsoftware.comon 30 April 2004.
 
Tyrer J, Duffy SW, Cuzick J.  A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004; 23:1111-30. PubMed
 
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. PubMed
 
Evans DG, Eccles DM, Rahman N, Young K, Bulman M, Amir E. et al.  A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet. 2004; 41:474-80. PubMed
 
Emery J, Walton R, Coulson A, Glasspool D, Ziebland S, Fox J.  Computer support for recording and interpreting family histories of breast and ovarian cancer in primary care (RAGs): qualitative evaluation with simulated patients. BMJ. 1999; 319:32-6. PubMed
 
Emery J, Walton R, Murphy M, Austoker J, Yudkin P, Chapman C. et al.  Computer support for interpreting family histories of breast and ovarian cancer in primary care: comparative study with simulated cases. BMJ. 2000; 321:28-32. PubMed
 
Progeny Software. User information. Accessed athttp://www.progeny2000.comon 20 June 2004.
 
Coulson AS, Glasspool DW, Fox J, Emery J.  RAGs: a novel approach to computerized genetic risk assessment and decision support from pedigrees. Methods Inf Med. 2001; 40:315-22. PubMed
 
Statement of the American Society of Clinical Oncology. Genetic testing for cancer susceptibility: indications for genetic testing. SEER Data. Accessed athttp://seer.cancer.gov/studies/epidemiology/study18.htmlon 30 March 2005.
 
Mouchawar J, ValentineGoins K, Somkin C, Puleo E, HensleyAlford S, Geiger AM. et al.  Guidelines for breast and ovarian cancer genetic counseling referral: adoption and implementation in HMOs. Genet Med. 2003; 5:444-50. PubMed
 
Breast cancer risk reduction. Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Accessed athttp://www.nccn.org/professionals/physician_gls/PDF/breast.pdfon 27 June 2005.
 
Møller P, Evans G, Haites N, Vasen H, Reis MM, Anderson E. et al.  Guidelines for follow-up of women at high risk for inherited breast cancer: consensus statement from the Biomed 2 Demonstration Programme on Inherited Breast Cancer. Dis Markers. 1999; 15:207-11. PubMed
 
Fries MH, Holt C, Carpenter I, Carter CL, Daniels J, Flanagan J. et al.  Guidelines for evaluation of patients at risk for inherited breast and ovarian cancer: recommendations of the Department of Defense Familial Breast/Ovarian Cancer Research Project. Mil Med. 2002; 167:93-8. PubMed
 
Lucassen A, Watson E, Harcourt J, Rose P, O'Grady J.  Guidelines for referral to a regional genetics service: GPs respond by referring more appropriate cases. Fam Pract. 2001; 18:135-40. PubMed
 
Elwyn G, Iredale R, Gray J.  Reactions of GPs to a triage-controlled referral system for cancer genetics. Fam Pract. 2002; 19:65-71. PubMed
 
Genetic susceptibility to breast and ovarian cancer: assessment, counseling and testing guidelines. New York State Department of Health. Accessed athttp://www.health.state.ny.us/nysdoh/cancer/obcancer/pp6-12.htmon 18 March 2004.
 
National Breast Cancer Centre.  Advice about familial aspects of breast cancer and ovarian cancer—a guide for health professionals. Sydney: National Breast Cancer Center. Accessed athttp://www.nbcc.org.au/bestpractice/resources/BOG_BreastOvarianGuideSimpl.pdfon 30 March 2005.
 
de Bock GH, VlietVlieland TP, Hageman GC, Oosterwijk JC, Springer MP, Kievit J.  The assessment of genetic risk of breast cancer: a set of GP guidelines. Fam Pract. 1999; 16:71-7. PubMed
 
Eccles DM, Evans DG, Mackay J.  Guidelines for a genetic risk based approach to advising women with a family history of breast cancer. UK Cancer Family Study Group (UKCFSG). J Med Genet. 2000; 37:203-9. PubMed
 
Hampel H, Sweet K, Westman JA, Offit K, Eng C.  Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J Med Genet. 2004; 41:81-91. PubMed
 
Lobb E, Butow P, Meiser B, Barratt A, Kirk J, Gattas M. et al.  The use of audiotapes in consultations with women from high risk breast cancer families: a randomised trial [Letter]. J Med Genet. 2002; 39:697-703. PubMed
 
Watson M, Duvivier V, WadeWalsh 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. PubMed
 
Green MJ, Peterson SK, Baker MW, Harper GR, Friedman LC, Rubinstein WS. et al.  Effect of a computer-based decision aid on knowledge, perceptions, and intentions about genetic testing for breast cancer susceptibility: a randomized controlled trial. JAMA. 2004; 292:442-52. PubMed
 
Meiser B, Halliday JL.  What is the impact of genetic counselling in women at increased risk of developing hereditary breast cancer? A meta-analytic review. Soc Sci Med. 2002; 54:1463-70. PubMed
 
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. PubMed
 
Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P. et al.  Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998; 62:676-89. PubMed
 
Hopper JL, Southey MC, Dite GS, Jolley DJ, Giles GG, McCredie MR. et al.  Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev. 1999; 8:741-7. PubMed
 
Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E. et al.  Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001; 68:700-10. PubMed
 
Eng C, Brody LC, Wagner TM, Devilee P, Vijg J, Szabo C. et al.  Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1. J Med Genet. 2001; 38:824-33. PubMed
 
Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA. et al.  Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997; 15:103-5. PubMed
 
King MC, Marks JH, Mandell JB.  Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003; 302:643-6. PubMed
 
Moslehi R, Chu W, Karlan B, Fishman D, Risch H, Fields A. et al.  BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet. 2000; 66:1259-72. PubMed
 
Satagopan JM, Offit K, Foulkes W, Robson ME, Wacholder S, Eng CM. et al.  The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev. 2001; 10:467-73. PubMed
 
Begg CB.  On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst. 2002; 94:1221-6. PubMed
 
Eccles DM, Simmonds P, Goddard J, Coultas M, Lalloo F, Evans G. et al.  Management of hereditary breast cancer. European Familial Breast Cancer Collaborative Group. Dis Markers. 1999; 15:187-9. PubMed
 
Langston AA, Malone KE, Thompson JD, Daling JR, Ostrander EA.  BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med. 1996; 334:137-42. PubMed
 
Malone KE, Daling JR, Neal C, Suter NM, O'Brien C, Cushing-Haugen K. et al.  Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer. 2000; 88:1393-402. PubMed
 
Anton-Culver H, Cohen PF, Gildea ME, Ziogas A.  Characteristics of BRCA1 mutations in a population-based case series of breast and ovarian cancer. Eur J Cancer. 2000; 36:1200-8. PubMed
 
Stratton JF, Gayther SA, Russell P, Dearden J, Gore M, Blake P. et al.  Contribution of BRCA1 mutations to ovarian cancer. N Engl J Med. 1997; 336:1125-30. PubMed
 
Gayther SA, Russell P, Harrington P, Antoniou AC, Easton DF, Ponder BA.  The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am J Hum Genet. 1999; 65:1021-9. PubMed
 
Bish A, Sutton S, Jacobs C, Levene S, Ramirez A, Hodgson S.  No news is (not necessarily) good news: impact of preliminary results for BRCA1 mutation searches. Genet Med. 2002; 4:353-8. PubMed
 
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. PubMed
 
Friedman LC, Webb JA, Richards CS, Lynch GR, Kaplan AL, Brunicardi FC. et al.  Psychological impact of receiving negative BRCA1 mutation test results in Ashkenazim. Genet Med. 1999; 1:74-9. PubMed
 
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. PubMed
 
Lerman C, Hughes C, Lemon SJ, Main D, Snyder C, Durham C. et al.  What you don't know can hurt you: adverse psychologic effects in members of BRCA1-linked and BRCA2-linked families who decline genetic testing. J Clin Oncol. 1998; 16:1650-4. PubMed
 
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. PubMed
 
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. PubMed
 
Smith KR, West JA, Croyle RT, Botkin JR.  Familial context of genetic testing for cancer susceptibility: moderating effect of siblings' test results on psychological distress one to two weeks after BRCA1 mutation testing. Cancer Epidemiol Biomarkers Prev. 1999; 8:385-92. PubMed
 
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. PubMed
 
Lerman C, Peshkin BN, Hughes C, Issacs C.  Family disclosure in genetic testing for cancer susceptibility; determinants and consequence. Journal of Health Care Law and Policy. 1998; 1:353-72.
 
Brekelmans CT, Seynaeve C, Bartels CC, Tilanus-Linthorst MM, Meijers-Heijboer EJ, Crepin CM. et al.  Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol. 2001; 19:924-30. PubMed
 
Chart PL, Franssen E.  Management of women at increased risk for breast cancer: preliminary results from a new program. CMAJ. 1997; 157:1235-42. PubMed
 
Gui GP, Hogben RK, Walsh G, A'Hern R, Eeles R.  The incidence of breast cancer from screening women according to predicted family history risk: does annual clinical examination add to mammography? Eur J Cancer. 2001; 37:1668-73. PubMed
 
Kollias J, Sibbering DM, Blamey RW, Holland PA, Obuszko Z, Wilson AR. et al.  Screening women aged less than 50 years with a family history of breast cancer. Eur J Cancer. 1998; 34:878-83. PubMed
 
Lai MS, Yen MF, Kuo HS, Koong SL, Chen TH, Duffy SW.  Efficacy of breast-cancer screening for female relatives of breast-cancer-index cases: Taiwan multicentre cancer screening (TAMCAS). Int J Cancer. 1998; 78:21-6. PubMed
 
Lalloo F, Boggis CR, Evans DG, Shenton A, Threlfall AG, Howell A.  Screening by mammography, women with a family history of breast cancer. Eur J Cancer. 1998; 34:937-40. PubMed
 
Møller P, Maehle L, Heimdal K, Dørum A, Tretli S, Helgerud P. et al.  Inherited breast carcinoma—prospective findings in 1,194 women at risk. Acta Oncol. 1996; 35:Suppl 87-11. PubMed
 
Saetersdal A, Dørum A, Heimdal K, Helgerud P, Sager EM, Bøhler P. et al.  Inherited predisposition to breast carcinoma. Results of first round examination of 537 women at risk. Anticancer Res. 1996; 16:1989-92. PubMed
 
Tilanus-Linthorst MM, Bartels CC, Obdeijn AI, Oudkerk M.  Earlier detection of breast cancer by surveillance of women at familial risk. Eur J Cancer. 2000; 36:514-9. PubMed
 
Warner E, Plewes DB, Hill KA, Causer PA, Zubovits JT, Jong RA. et al.  Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA. 2004; 292:1317-25. PubMed
 
Komenaka IK, Ditkoff BA, Joseph KA, Russo D, Gorroochurn P, Ward M. et al.  The development of interval breast malignancies in patients with BRCA mutations. Cancer. 2004; 100:2079-83. PubMed
 
Scheuer L, Kauff N, Robson M, Kelly B, Barakat R, Satagopan J. et al.  Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol. 2002; 20:1260-8. PubMed
 
Meijers-Heijboer H, vanGeel B, vanPutten WL, Henzen-Logmans SC, Seynaeve C, Menke-Pluymers MB. et al.  Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2001; 345:159-64. PubMed
 
.  Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet. 1997; 349:1505-10. PubMed
 
Fracheboud J, deKoning HJ, Beemsterboer PM, Boer R, Hendriks JH, Verbeek AL. et al.  Nation-wide breast cancer screening in The Netherlands: results of initial and subsequent screening 1990-1995. National Evaluation Team for Breast Cancer Screening. Int J Cancer. 1998; 75:694-8. PubMed
 
Day NE, Williams DR, Khaw KT.  Breast cancer screening programmes: the development of a monitoring and evaluation system. Br J Cancer. 1989; 59:954-8. PubMed
 
Bourne TH, Campbell S, Reynolds KM, Whitehead MI, Hampson J, Royston P. et al.  Screening for early familial ovarian cancer with transvaginal ultrasonography and colour blood flow imaging. BMJ. 1993; 306:1025-9. PubMed
 
Law J.  Cancers detected and induced in mammographic screening: new screening schedules and younger women with family history. Br J Radiol. 1997; 70:62-9. PubMed
 
Cuzick J, Forbes J, Edwards R, Baum M, Cawthorn S, Coates A. et al.  First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002; 360:817-24. PubMed
 
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM. et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998; 90:1371-88. PubMed
 
Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M. et al.  Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet. 1998; 352:98-101. PubMed
 
Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C. et al.  Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet. 1998; 352:93-7. PubMed
 
Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA. et al.  The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999; 281:2189-97. PubMed
 
Phase III randomized study of tamoxifen and raloxifene (STAR) for the prevention of breast cancer. 2004. Accessed athttp://www.cancer.gov/clinicaltrials/view_clinicaltrials.aspx?version=healthprofessional&cdrid=67081&protocolsearchid=884140on 20 April 2004.
 
Wickerham DL.  Tamoxifen versus raloxifene in the prevention of breast cancer. Eur J Cancer. 2002; 38:Suppl 6S20-1. PubMed
 
King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K. et al.  Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001; 286:2251-6. PubMed
 
Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW. et al.  Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat. 2001; 65:125-34. PubMed
 
Cauley JA, Lucas FL, Kuller LH, Vogt MT, Browner WS, Cummings SR.  Bone mineral density and risk of breast cancer in older women: the study of osteoporotic fractures. Study of Osteoporotic Fractures Research Group. JAMA. 1996; 276:1404-8. PubMed
 
Cauley JA, Lucas FL, Kuller LH, Stone K, Browner W, Cummings SR.  Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 1999; 130:270-7. PubMed
 
Day R.  Quality of life and tamoxifen in a breast cancer prevention trial: a summary of findings from the NSABP P-1 study. National Surgical Adjuvant Breast and Bowel Project. Ann N Y Acad Sci. 2001; 949:143-50. PubMed
 
Gwinn ML, Lee NC, Rhodes PH, Layde PM, Rubin GL.  Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer. J Clin Epidemiol. 1990; 43:559-68. PubMed
 
Whittemore AS, Harris R, Itnyre J.  Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992; 136:1184-203. PubMed
 
Franceschi S, Parazzini F, Negri E, Booth M, LaVecchia C, Beral V. et al.  Pooled analysis of 3 European case-control studies of epithelial ovarian cancer: III. Oral contraceptive use. Int J Cancer. 1991; 49:61-5. PubMed
 
Narod SA, Risch H, Moslehi R, Dørum A, Neuhausen S, Olsson H. et al.  Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med. 1998; 339:424-8. PubMed
 
McGuire V, Felberg A, Mills M, Ostrow KL, DiCioccio R, John EM. et al.  Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations. Am J Epidemiol. 2004; 160:613-8. PubMed
 
Grabrick DM, Hartmann LC, Cerhan JR, Vierkant RA, Therneau TM, Vachon CM. et al.  Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA. 2000; 284:1791-8. PubMed
 
Ursin G, Henderson BE, Haile RW, Pike MC, Zhou N, Diep A. et al.  Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res. 1997; 57:3678-81. PubMed
 
Klaren HM, van'tVeer LJ, vanLeeuwen FE, Rookus MA.  Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst. 2003; 95:941-7. PubMed
 
Kauff ND, Satagopan JM, Robson ME, Scheuer L, Hensley M, Hudis CA. et al.  Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002; 346:1609-15. PubMed
 
Goodnight JE Jr, Quagliana JM, Morton DL.  Failure of subcutaneous mastectomy to prevent the development of breast cancer. J Surg Oncol. 1984; 26:198-201. PubMed
 
Pennisi VR, Capozzi A.  Subcutaneous mastectomy data: a final statistical analysis of 1500 patients. Aesthetic Plast Surg. 1989; 13:15-21. PubMed
 
Paley PJ, Swisher EM, Garcia RL, Agoff SN, Greer BE, Peters KL. et al.  Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol. 2001; 80:176-80. PubMed
 
Aziz S, Kuperstein G, Rosen B, Cole D, Nedelcu R, McLaughlin J. et al.  A genetic epidemiological study of carcinoma of the fallopian tube. Gynecol Oncol. 2001; 80:341-5. PubMed
 
Tobacman JK, Greene MH, Tucker MA, Costa J, Kase R, Fraumeni JF Jr.  Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet. 1982; 2:795-7. PubMed
 
Piver MS, Jishi MF, Tsukada Y, Nava G.  Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer. 1993; 71:2751-5. PubMed
 
Bandera CA, Muto MG, Schorge JO, Berkowitz RS, Rubin SC, Mok SC.  BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum. Obstet Gynecol. 1998; 92:596-600. PubMed
 
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. PubMed
 
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. PubMed
 
Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, van'tVeer L, Garber JE. et al.  Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2004; 22:1055-62. PubMed
 
Contant CM, Menke-Pluijmers MB, Seynaeve C, Meijers-Heijboer EJ, Klijn JG, Verhoog LC. et al.  Clinical experience of prophylactic mastectomy followed by immediate breast reconstruction in women at hereditary risk of breast cancer (HB(O)C) or a proven BRCA1 and BRCA2 germ-line mutation. Eur J Surg Oncol. 2002; 28:627-32. PubMed
 
Struewing JP, Watson P, Easton DF, Ponder BA, Lynch HT, Tucker MA.  Prophylactic oophorectomy in inherited breast/ovarian cancer families. J Natl Cancer Inst Monogr. 1995; 33-5. PubMed
 
Rebbeck TR, Levin AM, Eisen A, Snyder C, Watson P, Cannon-Albright L. et al.  Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst. 1999; 91:1475-9. PubMed
 
Rebbeck TR.  Prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. Eur J Cancer. 2002; 38:Suppl 6S15-7. PubMed
 
Brinton LA, Schairer C, Hoover RN, Fraumeni JF Jr.  Menstrual factors and risk of breast cancer. Cancer Invest. 1988; 6:245-54. PubMed
 
Meijer WJ, vanLindert AC.  Prophylactic oophorectomy. Eur J Obstet Gynecol Reprod Biol. 1992; 47:59-65. PubMed
 
Parazzini F, Braga C, LaVecchia C, Negri E, Acerboni S, Franceschi S.  Hysterectomy, oophorectomy in premenopause, and risk of breast cancer. Obstet Gynecol. 1997; 90:453-6. PubMed
 
Schairer C, Persson I, Falkeborn M, Naessen T, Troisi R, Brinton LA.  Breast cancer risk associated with gynecologic surgery and indications for such surgery. Int J Cancer. 1997; 70:150-4. PubMed
 
Eisen A, Rebbeck TR, Wood WC, Weber BL.  Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer. J Clin Oncol. 2000; 18:1980-95. PubMed
 
Hankinson SE, Hunter DJ, Colditz GA, Willett WC, Stampfer MJ, Rosner B. et al.  Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA. 1993; 270:2813-8. PubMed
 
Rosenblatt KA, Thomas DB.  Reduced risk of ovarian cancer in women with a tubal ligation or hysterectomy. The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. Cancer Epidemiol Biomarkers Prev. 1996; 5:933-5. PubMed
 
Narod SA, Sun P, Ghadirian P, Lynch H, Isaacs C, Garber J. et al.  Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet. 2001; 357:1467-70. PubMed
 
Stefanek ME.  Bilateral prophylactic mastectomy: issues and concerns. J Natl Cancer Inst Monogr. 1995; 37-42. PubMed
 
Eisinger F, Reynier CJ, Chabal F, Luquet C, Moatti JP, Sobol H.  Acceptable strategies for dealing with hereditary breast/ovarian cancer risk [Letter]. J Natl Cancer Inst. 1997; 89:731. PubMed
 
Grana G, Daly M, Sands C.  The role of prophylactic mastectomy in managing genetic risk [Abstract]. Breast Cancer Research and Treatment. 1994; 32:Suppl72.
 
Lerman C, Narod S, Schulman K, Hughes C, Gomez-Caminero A, Bonney G. et al.  BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes. JAMA. 1996; 275:1885-92. PubMed
 
Frost MH, Schaid DJ, Sellers TA, Slezak JM, Arnold PG, Woods JE. et al.  Long-term satisfaction and psychological and social function following bilateral prophylactic mastectomy. JAMA. 2000; 284:319-24. PubMed
 
Hatcher MB, Fallowfield L, A'Hern R.  The psychosocial impact of bilateral prophylactic mastectomy: prospective study using questionnaires and semistructured interviews. BMJ. 2001; 322:76. PubMed
 
Tiller K, Meiser B, Butow P, Clifton M, Thewes B, Friedlander M. et al.  Psychological impact of prophylactic oophorectomy in women at increased risk of developing ovarian cancer: a prospective study. Gynecol Oncol. 2002; 86:212-9. PubMed
 
Nathorst-Böös J, vonSchoultz B, Carlström K.  Elective ovarian removal and estrogen replacement therapy—effects on sexual life, psychological well-being and androgen status. J Psychosom Obstet Gynaecol. 1993; 14:283-93. PubMed
 
Dennerstein L, Wood C, Burrows GD.  Sexual response following hysterectomy and oophorecomy. Obstet Gynecol. 1977; 49:92-6. PubMed
 
Everson SA, Matthews KA, Guzick DS, Wing RR, Kuller LH.  Effects of surgical menopause on psychological characteristics and lipid levels: the Healthy Women Study. Health Psychol. 1995; 14:435-43. PubMed
 
Fry A, Busby-Earle C, Rush R, Cull A.  Prophylactic oophorectomy versus screening: psychosocial outcomes in women at increased risk of ovarian cancer. Psychooncology. 2001; 10:231-41. PubMed
 
Humphrey LL, Helfand M, Chan BK, Woolf SH.  Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002; 137:347-60. PubMed
 
Breast and ovarian cancer family registries. National Cancer Institute. Accessed athttp://epi.grants.cancer.gov/on 20 March 2005.
 

Figures

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Figure 1.
Analytic framework.KQBRCABRCABRCABRCA1BRCA2

Key question ( ) 1: Do risk assessment and mutation testing lead to a reduction in the incidence of breast and ovarian cancer and cause-specific or all-cause mortality? KQ 2A: How well does risk assessment for cancer susceptibility by a clinician in a primary care setting select candidates for mutation testing? KQ 2B: What are the benefits of genetic counseling before testing? KQ 2C: Among women with family histories predicting an average, moderate, or high risk for a deleterious mutation, how well does mutation testing predict risk for breast and ovarian cancer? KQ 3: What are the adverse effects of risk assessment, genetic counseling, and testing? KQ 4: 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? KQ 5: What are the adverse effects of interventions? *Indicates clinically significant mutation of or .

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Figure 2.
Relative risks for breast cancer in chemoprevention trials.

Error bars represent 95% CIs. IBIS = International Breast Cancer Intervention Study.

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Figure 3.
Yield of testing forBRCAmutations in a hypothetical population based on assumptions in Table 6.

NNS = number needed to screen. *Based on estimates for mastectomy. †Based on estimates for oophorectomy.

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Appendix Figure.
Yield of literature search and review.

ELSI = ethical, legal, and social implications.

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Tables

Table Jump PlaceholderTable 1.  Detection and Prevention Recommendations
Table Jump PlaceholderTable 2.  Tools To Assess Risk forBRCAMutation
Table Jump PlaceholderTable 3.  Criteria for Referral for Genetic Counseling and Testing
Table Jump PlaceholderTable 4.  Intensive Cancer Screening Studies of Women with Familial Breast Cancer Risk
Table Jump PlaceholderTable 5.  Randomized, Placebo-Controlled Trials of Chemoprevention for Breast Cancer
Table Jump PlaceholderTable 6.  Outcomes Table Summary
Table Jump PlaceholderAppendix Table.  Inclusion and Exclusion Criteria according to Key Question

References

Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S. et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994; 266:66-71. PubMed
CrossRef
 
Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J. et al.  Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995; 378:789-92. PubMed
 
Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL.  Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002; 94:1365-72. PubMed
 
Thompson D, Easton DF.  Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002; 94:1358-65. PubMed
 
Easton DF, Ford D, Bishop DT.  Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995; 56:265-71. PubMed
 
Ford D, Easton DF.  The genetics of breast and ovarian cancer. Br J Cancer. 1995; 72:805-12. PubMed
 
Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE.  Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994; 343:692-5. PubMed
 
Easton DF, Bishop DT, Ford D, Crockford GP.  Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993; 52:678-701. PubMed
 
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. PubMed
 
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. PubMed
 
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. PubMed
 
Peelen T, vanVliet 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. PubMed
 
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.