Laurie Hoyt Huffman

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

Clinically significant, or deleterious, mutations of BRCA1 and BRCA2 genes are associated with increased susceptibility for breast and ovarian cancer (1, 2). These mutations increase a womans lifetime risk for breast cancer to 60% to 85% (3, 4) and risk for ovarian cancer to 26% (BRCA1) and 10% (BRCA2) (5-8). Specific BRCA mutations are clustered among certain ethnic groups, such as Ashkenazi Jews (9-11), and in the Netherlands (12), Iceland (13, 14), and Sweden (15). Additional germline mutations associated with familial breast or ovarian cancer have been identified, and others are suspected (16, 17). 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 (19, 20). 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 (21-24). 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 (26, 27) provided by genetic counselors (28-30), nurse educators (31-33), 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 (34, 35). 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) (36-40). Table 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 (41-44), 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, 45, 46), 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). Methods The analytic framework in Figure 1 outlines the patient population, interventions, and health outcomes. This report focuses on the following key questions: Figure 1. Analytic framework. KQ BRCA BRCA BRCA BRCA1 BRCA2 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 riskno first-degree relatives and no more than 1 second-degree relative on each side of the family with breast or ovarian cancer; moderate risk1 first-degree relative or 2 second-degree relatives on the same side of the family with breast or ovarian cancer; and high riskat least 2 first-degree relatives with breast or ovarian cancer. On the basis of pooled data from more than 100000 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

Prenatal Screening for HIV: A Review of the Evidence for the U.S. Preventive Services Task Force

Women are the fastest-growing group of persons with new HIV diagnoses, accounting for 30% of new U.S. infections in 2001 (1, 2). An estimated 6000 to 7000 HIV-positive women give birth each year in the United States (3), and 280 to 370 HIV-infected infants were born in the United States annually between 1999 and 2001 (4). In 2000, 40% of HIV-infected infants were born to mothers not known to have HIV infection before delivery (5). As of 2003, about 5000 cumulative deaths from perinatally acquired AIDS had occurred in the United States (6). Mother-to-child transmission of HIV infection can occur during pregnancy (antepartum), during labor and delivery (intrapartum), and after delivery (postnatal). In the absence of breastfeeding, antepartum transmission is thought to account for 25% to 40% of cases of mother-to-child transmission; the remaining cases occur during labor and delivery (7). Pregnancy and labor management techniques that minimize contact between infected maternal blood and the fetus can decrease the risk for transmission (8). Breastfeeding is thought to be the only important mode for postnatal transmission (4, 9) and accounts for about 44% of infant cases in settings with high breastfeeding rates (10). Higher maternal viral loads and lower CD4 cell counts are associated with an increased risk for transmission (11-15). In the United States, combination antiretroviral regimens, in conjunction with avoidance of breastfeeding and cesarean section before labor and before rupture of membranes (elective cesarean section) in selected women, are the standard of care to reduce mother-to-child transmission of HIV (16, 17). To update its 1996 recommendations, the U.S. Preventive Services Task Force (USPSTF) commissioned a new systematic review of the risks and benefits of prenatal testing for anti-HIV antibodies in asymptomatic women (18). Methods The Figure summarizes the analytic framework and key questions for this review. Key question 1 addresses direct evidence on the effects of screening on clinical outcomes. The other key questions address the chain of evidence necessary to estimate the effects of screening on clinical outcomes if direct evidence is insufficient. Appendix A discusses the scope and the methods used for this review in more detail. Figure. Screening for HIVanalytic framework for pregnant women. KQ HIV ab Briefly, we identified relevant studies from MEDLINE (1983 through 30 June 2004) and the Cochrane Clinical Trials Registry (2004, issue 2), reference lists, hand searches of relevant journals, and suggestions from experts (Appendix B). We selected studies that provided evidence on the benefits and harms of screening, risk factor assessment, follow-up testing, interventions, and the acceptability of prenatal HIV testing. For interventions, we focused on studies of the safety and effectiveness of antiretroviral prophylaxis (17). We also reviewed studies on the safety and effectiveness of elective cesarean section (20) and avoidance of breastfeeding. A separate report (19) reviews other recommended interventions, such as vaccinations, prophylaxis against opportunistic infections, and routine monitoring and follow-up (7, 21-23). We assessed the internal validity and relevance of included studies using predefined criteria developed by the USPSTF (Appendix C) (24). We rated the overall body of evidence for each key question using the system developed by the USPSTF. We used the results of the evidence review to construct an outcomes table estimating the effects of one-time screening for HIV infection in hypothetical cohorts of pregnant women. We calculated numbers needed to screen (NNS) and treat (NNT) to prevent 1 case of mother-to-child transmission or to cause 1 complication from interventions. The point estimates and 95% CIs for NNS and NNT were based on Monte Carlo simulations. This research was funded by the Agency for Healthcare Research and Quality under a contract to support the work of the USPSTF. Agency staff and USPSTF members participated in the initial design of the study and reviewed interim analyses and the final report. Draft reports were distributed to 13 content experts for review. Agency approval was required before this manuscript could be submitted for publication, but the authors are solely responsible for the content and the decision to submit it for publication. Data Synthesis Does Screening for HIV in Pregnant Women Reduce Mother-to-Child Transmission or Premature Death and Disability? No studies compare clinical outcomes from screening or not screening pregnant women for HIV. Although the number of infants with perinatally acquired HIV transmission has markedly declined in the United States, this reduction is probably due to a combination of increased prenatal screening and increased effectiveness and uptake of therapies (3, 7). No studies estimated the relative impact of these factors. Can Clinical or Demographic Characteristics Identify Subgroups of Asymptomatic Pregnant Women at Increased Risk for HIV Infection Compared with the General Population of Pregnant Women? Risk factors for HIV infection appear similar in pregnant and nonpregnant women and include risky sexual behaviors, injection drug use, and transfusion between 1978 and 1985 (22, 25). Heterosexual transmission has become the most common route of HIV infection among U.S. women (26). The largest (n= 73472) study of U.S. women at prenatal or obstetrics clinics found that 0.6% were HIV positive (27). Smaller U.S. studies of pregnant women have reported prevalence rates ranging from 0.13% to 5% (28-30). In the United States, HIV prevalence varies by region, and minority women are more likely to be infected (26). Observational studies in the United States (all published before 1996) found that 8% to 57% of HIV-infected pregnant women had identifiable risk factors (31-35). Differences in the criteria used to define high-risk behaviors and varying stringency of risk factor assessment (31) could explain some of the variation in results. No study evaluated different targeted prenatal screening strategies to determine the proportion of infected women correctly identified. In 1995, the U.S. Public Health Service (36) and the American Academy of Pediatrics (37) recommended prenatal counseling and voluntary HIV testing. No U.S. studies since 1995 evaluated the yield of targeted compared with universal screening. In a 7-state observational study, however, the proportion of HIV-infected women given a diagnosis before delivery increased from 70% to 80% between 1993 and 1996 (38). In the United Kingdom, 1 observational study found an increased incidence of known HIV seropositivity after the implementation of universal prenatal testing (39), but another found that 50% of seropositive women (identified by anonymous testing) remained undiagnosed (40). What Are the Test Characteristics of HIV Antibody Test Strategies in Pregnant Women? The use of enzyme immunoassay followed by confirmatory Western blot or immunofluorescent assay remains the standard method for diagnosing HIV-1 infection. This method is associated with a sensitivity and specificity greater than 99% (41, 42). False-positive diagnoses are rare, even in low-risk settings (43). The diagnostic accuracy of standard HIV testing is thought to be similar for pregnant and nonpregnant persons, although indeterminate results may occur slightly more frequently in pregnancy (44). Rapid HIV antibody tests provide results in 10 to 30 minutes, compared with 1 to 2 weeks for standard testing (45). Patients should be notified of positive rapid test results before confirmation when doing so might benefit them, such as for women with unknown HIV status presenting in active labor (46). However, this could result in unnecessary exposure to antiretroviral therapy if the rapid test result is a false positive. Three good-quality (47-49) and 4 fair-quality (50-53) studies evaluated the diagnostic accuracy of rapid HIV testing during pregnancy using standard testing as the reference standard. The only study to evaluate a rapid HIV test currently in use in the United States was a good-quality prospective study of the OraQuick Advance test (OraSure Technologies, Inc., Bethlehem, Pennsylvania) on blood samples from 5744 women (prevalence, 0.59%) who presented in labor (47). The sensitivity was 100% (95% CI, 90% to 100%), the specificity was 99.9% (CI, 99.78% to 99.98%), the positive predictive value was 90% (CI, 75% to 97%), and the negative predictive value was 100%. In studies of nonpregnant persons, the sensitivities of currently available rapid HIV tests ranged from 96% to 100%, and the specificities were all greater than 99% (54-58). No studies have compared the diagnostic accuracy of prenatal HIV testing using home-based sampling kits or noninvasive (urine or oral) specimens with the accuracy of standard testing as the reference standard. Although 1 Indian study found a lower sensitivity with the OraQuick test on saliva than on plasma (75.0% vs. 86.4%), it did not use standard enzyme immunoassay plus Western blot as the reference standard, and local conditions may have affected saliva specimens (59). No clinical studies have evaluated the yield of repeated prenatal HIV testing, which would depend in part on the incidence of HIV infections during pregnancy (60). What Are the Harms Associated with Screening? In a recent U.S. study of rapid HIV testing during labor, 4 of 4849 women had a false-positive rapid test result and briefly received antiretroviral prophylaxis before negative confirmatory results (47). Other evidence on the frequency and harms from false-positive diagnoses in pregnant women is anecdotal (61) but could include elective pregnancy termination based on incorrect test results, anxiety, discrimination, or altered partner relationships. False-negative and true-negative test results could encourage continued risky behaviors. Data on rates and consequences (such as anxiety)

Screening and treatment for lipid disorders in children and adolescents: systematic evidence review for the US Preventive Services Task Force.

OBJECTIVE. This was a systematic evidence review for the US Preventive Services Task Force, intended to synthesize the published evidence regarding the effectiveness of selecting, testing, and managing children and adolescents with dyslipidemia in the course of routine primary care. METHODS. Literature searches were performed to identify published articles that addressed 10 key questions. The review focused on screening relevant to primary care of children without previously identified dyslipidemias, but included treatment trials of children with dyslipidemia because some drugs have only been tested in that population. RESULTS. Normal values for lipids for children and adolescents are defined according to population levels (percentiles). Age, gender, and racial differences and temporal trends may alter these statistical cut points. Approximately 40% to 55% of children with elevated total cholesterol and low-density lipoprotein levels will continue to have elevated lipid levels on follow-up. Current screening recommendations based on family history will fail to detect substantial numbers (30%–60%) of children with elevated lipid levels. Drug treatment for dyslipidemia in children has been studied and shown to be effective only for suspected or proven familial monogenic dyslipidemias. Intensive dietary counseling and follow-up can result in improvements in lipid levels, but these results have not been sustained after the cessation of the intervention. The few trials of exercise are of fair-to-poor quality and show little or no improvements in lipid levels for children without monogenic dyslipidemias. Although reported adverse effects were not serious, studies were generally small and not of sufficient duration to determine long-term effects of either short or extended use. CONCLUSIONS. Several key issues about screening and treatment of dyslipidemia in children and adolescents could not be addressed because of lack of studies, including effectiveness of screening on adult coronary heart disease or lipid outcomes, optimal ages and intervals for screening children, or effects of treatment of childhood lipid levels on adult coronary heart disease outcomes.