Beth N. Peshkin

Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.

PURPOSE Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.

Characterization of BRCA1 and BRCA2 Mutations in a Large United States Sample

PURPOSE An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families. METHODS We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family. RESULTS In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling. CONCLUSION The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.

Impact of BRCA1/BRCA2 Mutation Testing on Psychologic Distress in a Clinic-Based Sample

PURPOSE Despite the increasingly widespread availability of BRCA1 and BRCA2 genetic testing, little is known about the psychologic impact of such testing in the clinical setting. The objective of this study was to examine the long-term psychologic impact of receiving BRCA1/2 test results within a clinic-based testing program. PATIENTS AND METHODS The participants were 279 high-risk women who underwent genetic counseling and testing for alterations in the BRCA1/2 genes. At baseline (before genetic testing) and at 6 months after the disclosure of mutation status, we measured perceived risk for breast and ovarian cancer, cancer-specific distress, and general distress. We examined the impact of the test result on each of these outcomes at the 6-month follow-up. Analyses were conducted separately for probands and their relatives who were unaffected with cancer. RESULTS We found no effect of test result among affected probands. Among unaffected relatives, we found that participants who received definitive negative test results exhibited significant reductions in perceived risk and distress compared with participants who received positive test results. Importantly, relatives who received positive test results did not exhibit increased distress or perceived risk. CONCLUSION These results suggest that clinic-based BRCA1/2 testing can lead to psychologic benefits for individuals who receive negative test results. At 6 months after disclosure, those who receive positive or uninformative test results do not exhibit increased psychologic distress or perceived risk.

A brief assessment of concerns associated with genetic testing for cancer: the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire.

The Multidimensional Impact of Cancer Risk Assessment (MICRA) is a new tool to measure the specific impact of result disclosure after genetic testing. The authors compared its performance with that of questionnaires measuring general and cancer-specific distress. Participants (158 women) responded 1 month after they received genetic test results. The women were divided into 4 standard clinical test result groups: BRCA1/2 positive, BRCA1/2 negative, panel negative, and true negative. Factor analysis supported the formation of 3 subscales: Distress (6 items, alpha = .86), Uncertainty (9 items, alpha = .77), and Positive Experiences (4 items, alpha = .75). All 3 MICRA subscales differentiated participants who were BRCA1/2 positive from the other 3 groups. MICRA thus helps identify subgroups of vulnerable genetic testing participants.

Psychological distress in women seeking genetic counseling for breast-ovarian cancer risk: The contributions of personality and appraisal

The purpose of the present study was two-fold: (a) to characterize the psychological status of women with a family history of breast or ovarian cancer who self-refer for genetic counseling and BRCA1 testing; and (b) to identify specific demographic, personality, and appraisal factors that contribute to cancer-specific distress and general distress in this group of women. Participants were 256 women ages 18 and older who had at least one first-degree relative (FDR) with breast and/or ovarian cancer. Participants were recruited through breast cancer clinics and obstetrics/gynecology departments at two medical centers by responding to program information described in a brochure. The results revealed moderate distress levels in this population. The results of a hierarchical regression of general distress indicated that women with higher levels of general distress were less likely to be married, less optimistic, and had heightened breast cancer risk perceptions accompanied by feelings of low perceptions of control over the development of breast cancer (R2=.44, p=.0001). Women with higher levels of cancer-specific distress tended to be younger and non-White and had low perceptions of control over developing breast cancer (R2=.15, p=.0002). These findings suggest that self-referred genetic counseling participants may be psychologically vulnerable and may benefit from interventions designed to decrease distress and the perceived absence of control over developing breast cancer.

Bilateral Prophylactic Oophorectomy and Ovarian Cancer Screening Following BRCA1/BRCA2 Mutation Testing

PURPOSE Despite the widespread availability of genetic testing for BRCA1/BRCA2 mutations, little is known about the impact of testing on ovarian cancer prevention and screening. For mutation testing to effect cancer mortality, positive test results must be followed by appropriate behavior change. In this study, we prospectively examined the impact of BRCA1/2 testing on the utilization of prophylactic oophorectomy and ovarian cancer screening. PARTICIPANTS AND METHODS Participants were 289 high-risk women who underwent genetic counseling and testing for alterations in the BRCA1/2 genes. We measured self-reported receipt of bilateral prophylactic oophorectomy (BPO) and utilization of CA-125 and transvaginal ultrasound (TVU) in the year following testing, and examined the impact of test results on these outcomes. In addition, we examined the role of sociodemographic, medical, family history, and psychological variables on the receipt of BPO, CA-125, and TVU. RESULTS Twenty-seven percent of mutation carriers, 5% of uninformative patients, and 2% of noncarriers received a BPO in the year following testing. In addition to test results, perceived risk for ovarian cancer and family history of ovarian cancer independently predicted receipt of BPO. The receipt of a positive test result was associated with increased utilization of CA-125 and TVU. Additional predictors included perceived risk for ovarian cancer (both CA-125 and TVU) and state anxiety (CA-125). CONCLUSION These results demonstrate the significant behavioral impact of receiving a positive BRCA1/2 test result. The increased rate of oophorectomy among mutation carriers suggests that testing for BRCA1/2 mutations may ultimately impact ovarian cancer mortality.

What Would You Do? Specialists’ Perspectives on Cancer Genetic Testing, Prophylactic Surgery, and Insurance Discrimination

PURPOSE To examine what cancer genetics specialists predict they would do personally if they were at 50% risk of carrying a mutation that predisposes to hereditary breast/ovarian cancer (BRCA1/BRCA2) and hereditary nonpolyposis colon cancer (HNPCC). METHODS Questionnaire survey of the membership of the National Society of Genetic Counselors (NSGC) Special Interest Group (SIG) in Cancer. RESULTS Of the 296 active members of the NSGC Cancer-SIG surveyed, 163 (55%) responded. Eighty-five percent predicted that if they had a 50% risk of carrying a BRCA1/BRCA2 mutation, they would pursue genetic testing. If they tested positive for a mutation at age 35, 25% predicted they would pursue prophylactic bilateral mastectomies and 68%, prophylactic oophorectomy. Ninety-one percent of respondents believe they would pursue genetic testing for HNPCC, and 17% would elect prophylactic colectomy; 54%, prophylactic hysterectomy; and 52%, prophylactic oophorectomy if they tested positive for a mutation. The majority (68%) would not bill their insurance companies for genetic testing because of fear of discrimination, and 26% would use an alias when undergoing testing. Fifty-seven percent of counselors would seek professional psychologic support to help them cope with the results of testing. CONCLUSION A large percentage of cancer genetic counseling providers predicted they would opt for prophylactic surgery at a young age if they carried a BRCA or HNPCC mutation, and most would seek professional psychologic assistance when undergoing testing. More than half of respondents would not bill their insurance companies for genetic testing, largely because of fear of genetic discrimination. The vast majority of those providers most familiar with cancer genetic testing and its associated medical, psychologic, and legal implications would still pursue genetic testing.

Randomized Noninferiority Trial of Telephone Versus In-Person Genetic Counseling for Hereditary Breast and Ovarian Cancer

PURPOSE Although guidelines recommend in-person counseling before BRCA1/BRCA2 gene testing, genetic counseling is increasingly offered by telephone. As genomic testing becomes more common, evaluating alternative delivery approaches becomes increasingly salient. We tested whether telephone delivery of BRCA1/2 genetic counseling was noninferior to in-person delivery. PATIENTS AND METHODS Participants (women age 21 to 85 years who did not have newly diagnosed or metastatic cancer and lived within a study site catchment area) were randomly assigned to usual care (UC; n = 334) or telephone counseling (TC; n = 335). UC participants received in-person pre- and post-test counseling; TC participants completed all counseling by telephone. Primary outcomes were knowledge, satisfaction, decision conflict, distress, and quality of life; secondary outcomes were equivalence of BRCA1/2 test uptake and costs of delivering TC versus UC. RESULTS TC was noninferior to UC on all primary outcomes. At 2 weeks after pretest counseling, knowledge (d = 0.03; lower bound of 97.5% CI, -0.61), perceived stress (d = -0.12; upper bound of 97.5% CI, 0.21), and satisfaction (d = -0.16; lower bound of 97.5% CI, -0.70) had group differences and confidence intervals that did not cross their 1-point noninferiority limits. Decision conflict (d = 1.1; upper bound of 97.5% CI, 3.3) and cancer distress (d = -1.6; upper bound of 97.5% CI, 0.27) did not cross their 4-point noninferiority limit. Results were comparable at 3 months. TC was not equivalent to UC on BRCA1/2 test uptake (UC, 90.1%; TC, 84.2%). TC yielded cost savings of

Validity of Models for Predicting BRCA1 and BRCA2 Mutations

114 per patient. CONCLUSION Genetic counseling can be effectively and efficiently delivered via telephone to increase access and decrease costs.

Long-term outcomes of BRCA1/BRCA2 testing: risk reduction and surveillance.

Context A computer software program from the University of Texas Southwestern Medical Center (CaGene) has multiple prediction models to estimate BRCA1 and BRCA2 mutation probability, which guides decisions on whether to test for a mutation. A comprehensive quantitative evaluation of how well the prediction models discriminate between persons who carry the mutation and those who do not is lacking. Contribution The authors used 7 prediction models to estimate the probability of a BRCA1/BRCA2 mutation in 3342 families. All 7 models were able to discriminate between mutation-positive and mutation-negative people. Implications The probability that someone carries the BRCA1/BRCA2 mutation should not be considered in isolation when decisions are being made about genetic testing. Other factors should be discussed with the patient and factored into the decision-making process. The Editors Deleterious mutations of BRCA1 (MIM 113705) and BRCA2 (MIM 600185) increase the risk for breast and ovarian cancer (13). Whereas deleterious variants are relatively rare in the general population, they are common among families with multiple occurrences of breast or ovarian cancer (46). When counseling a woman facing decisions about genotyping for BRCA1 and BRCA2, it is important to accurately evaluate the probability that she carries a deleterious mutation (pretest mutation probability) and the probability that a mutation will be found if she is genotyped (which depends on the accuracy of mutation testing). Reliable, evidence-based, individualized counseling strategies can enhance informed decision making, both about whether to pursue BRCA1/BRCA2 testing and what to do with the results (79). The demand for assessment of complex family histories of cancer has led to widespread use of statistical models to estimate mutation probabilities (2, 1018). Model-based predictions are currently used in counseling about genetic testing, are included in materials distributed to women considering genetic testing (1821), are used for determining eligibility for screening and prevention studies (22), and are factored into coverage decisions by insurers (23). More than a dozen models exist. They use different statistical methods and source populations, pedigree features, and predicted outcomes. In clinical practice, different models applied to the same person can give a wide range of probabilities that a BRCA1/BRCA2 mutation is present. This degree of variability raises concerns about whether some models are more accurate than others and calls for a careful independent comparative evaluation of the predictive performance of existing models. We assessed the validity of commonly used models for estimating mutation probabilities of BRCA1 and BRCA2 in individuals identified through the Cancer Genetics Network. We assembled a large set of families with history of breast cancer, ovarian cancer, or both. We used standardized computational methods across contributing institutions to evaluate 7 models. Our main goal was to measure how well these models discriminated between mutation carriers and noncarriers. Methods Study Overview We conducted a cross-sectional, multicenter analysis. For each family in the study, we identified an individual (the counselee) for whom we collected genetic test results for BRCA1, BRCA2, or both; genotyping methods; pretest estimations of mutation probability using each model; and additional information about family history of cancer. We used genetic test results as the gold standard for judging the sensitivity and specificity of the various models. We evaluated all models on every counselee, except where noted. Data Collection Table 1 summarizes the salient data (2432). Sources include 3 population-based studies and 8 data sets of individuals seen in clinics for women at high risk for a BRCA mutation. In the population-based studies, the participants reflected the demographic characteristics of a defined subpopulation (for example, all breast cancer cases in Orange County in the University of California, Irvine [UCI], study [31]). In contrast, patients from high-risk clinics had been referred because of a family history of cancer or were self-referred because of an interest in genetic testing (inclusion criteria varied across clinics). Table 1. Demographic Characteristics of Counselees and Sample Size, by Center Each center calculated all of the model probabilities for its own families. We designated the first genotyped person in each family as the counselee and computed predictions by using the genetic counseling software CaGene (University of Texas Southwestern Medical Center, Dallas, Texas) (24). The software version was customized and distributed to participating sites to ensure uniform procedures across all sites. Data entry and computation of model predictions were performed at the sites. This decentralized approach for data entry and probability calculations allowed site investigators to use pedigree information that models required but that centers could not export to a central site because of privacy concerns. In addition to model predictions, a subset of centers also exported the data required for the models to the National Cancer Institutes (NCI) Cancer Genetics Network Data Coordinating Center. The study population includes 3342 families. The institutional review boards at each participating institution approved the study protocol. All included counselees gave consent for using their data for research according to local institutional review board requirements. The Cancer Genetics Network steering committee reviewed the study design. Genetic Testing Appendix Table 1 summarizes genotyping methods by center and provides a brief description of each method. Determining whether a person carries a deleterious mutation of BRCA1 or BRCA2 is technically demanding because of the large size of these genes, the wide spectrum of mutations, and the presence of mutations whose clinical significance is unknown (3335). Commercial testing uses sequencing to search for unknown mutations or to probe for mutations that are commonly found among Ashkenazi Jewish persons. Research settings, particularly in the time in which the study was conducted, have used less expensive and less sensitive techniques (Appendix Table 1). Although sequencing is the most sensitive of the techniques used in our study, recent evidence highlights how it can miss certain mutations, such as large deletions or intronic mutations (3, 36). Therefore, the set of individuals carrying a mutation (the carriers) is not the same as the set of individuals who test positive for a mutation (the positive cases). Thus, Table 1 underestimates the true number of carriers; the size of the error varies according to the method of genotyping. Appendix Table 1. Number of Counselees, by Genotyping Method for Each Gene and Center Models We studied 7 models: BRCAPRO, the family history assessment tool (FHAT), Finnish, Myriad, NCI, University of Pennsylvania (Penn), and Yale University (Yale). Appendix Table 2 summarizes the characteristics, input variables, and output of the models. Three broad categories of models have been proposed: empirical (Finnish, Myriad, NCI, and Penn), mendelian (BRCAPRO and Yale), and expert-based (FHAT). The first step in developing an empirical model is to summarize the salient aspects of a family history in some predictor variables. The second step is to apply statistical learning techniques, such as logistic regression, to describe the relationship between these variables and the genotyping results (the dependent variable). Mendelian models represent the known modes of inheritance of deleterious genetic variants by established mathematical relationships between phenotypes (in this case, cancer status of family members) and genotypes (14, 3741). The mendelian model inputs include cancer incidence curves (penetrance) for both carriers and noncarriers and the prevalence of deleterious variants. Expert-based models calculate scores that summarize degree of risk, using algorithms constructed on the basis of clinical judgment. For example, FHAT (16) uses a 17-question interview to produce a quantitative score (score range, 0 to 45) representing the severity of family history. Appendix Table 2. Input Variables and Features of Each Model Empirical models calculate the probability of a positive test result for a mutation in the counselee (that is, the result of genetic testing), whereas mendelian models directly estimate the probability of carrying a mutation (the true mutation status of the counselee) (37). The 2 types of predictions are therefore not directly comparable, a fact often overlooked in counseling practice. Because genotyping methods are highly specific for the BRCA1 and BRCA2 genes (that is, they have a very low false-positive rate), multiplying the genotype probability by the genotyping sensitivity gives the probability of finding a mutation. Therefore, to compare an empirical model probability of a BRCA mutation with a mendelian model probability, one must know the sensitivity of the genotyping method of the study used to develop the empirical model. Expert-based scores do not have a direct probabilistic interpretation. In our analyses, we rescaled the FHAT score by dividing by its maximum value of 45. The Penn model (11) estimates the probability of a positive BRCA1 test result in any family member. We adapted it to provide the probability of a positive test in the counselee. We assigned affected counselees the same mutation probability as the family. We assigned unaffected counselees one half the family probability if the closest affected relative of the counselee is a first-degree relative and one quarter of the family probability if the closest relative is a second-degree relative. We used a version of the BRCAPRO (13, 14) model based on the genetic variables described by Iversen and colleagues (42). We defined the Yale model by postulating a si