Mary S. Beattie

Risk-Reducing Salpingo-Oophorectomy in BRCA Mutation Carriers: Role of Serial Sectioning in the Detection of Occult Malignancy

PURPOSE Women who carry deleterious mutations of BRCA1 or BRCA2 genes have up to a 54% lifetime risk of developing ovarian cancer. After childbearing, women at high risk increasingly choose bilateral risk-reducing salpingo-oophorectomy (RRSO). Two recent studies of BRCA mutation carriers reported occult malignancy in 2.5% of women undergoing RRSO. This study aimed to increase this detection rate using a protocol. METHODS In 1996, the University of California San Francisco Gynecologic Oncology Program instituted a surgical-pathologic RRSO protocol that was composed of complete removal and serial sectioning of both ovaries and fallopian tubes, peritoneal and omental biopsies, and collection of peritoneal washings for cytology. We report the pathologic findings in 67 BRCA mutation carriers according to the degree of adherence to this protocol. RESULTS Of the 67 procedures, the protocol was followed completely or partially in 41 (61%). Seven occult malignancies were discovered, four in the fallopian tube and three in the ovaries. Six of these were microscopic, and all seven (17%) were found in specimens from complete or partial protocol procedures as opposed to standard procedures (P = .026). Other variables such as age, parity, BRCA1 or BRCA2 mutation, or type of surgery did not alter the strong effect of protocol procedure on the cancer detection rate. CONCLUSION A rigorous operative and pathologic protocol for RRSO increases the detection rate of occult ovarian malignancy in BRCA mutation carriers nearly seven-fold. If confirmed, this finding will alter postoperative management because additional staging, chemotherapy, and follow-up may be necessary in affected women.

Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer

CONTEXT Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. OBJECTIVE To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. DESIGN, SETTING, AND PARTICIPANTS A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). MAIN OUTCOME MEASURE Five-year overall mortality. RESULTS The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). CONCLUSION Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.

Fecal incontinence in females older than aged 40 years: who is at risk?

Purpose: This study was designed to estimate the prevalence of, and identify risk factors associated with, fecal incontinence in racially diverse females older than aged 40 years. Methods: The Reproductive Risks for Incontinence Study at Kaiser is a population‐based study of 2,109 randomly selected middle‐aged and older females (average age, 56 years). Fecal incontinence, determined by self‐report, was categorized by frequency. Females reported the level of bother of fecal incontinence and their general quality of life. Potential risk factors were assessed by self‐report, interview, physical examination, and record review. Multivariate logistic regression analysis was used to determine the independent association between selected risk factors and the primary outcome of any reported fecal incontinence in the past year. Results: Fecal incontinence in the past year was reported by 24 percent of females (3.4 percent monthly, 1.9 percent weekly, and 0.2 percent daily). Greater frequency of fecal incontinence was associated with decreased quality of life (Medical Outcome Short Form‐36 Mental Component Scale score, P = 0.01), and increased bother (P < 0.001) with 45 percent of females with fecal incontinence in the past year and 100 percent of females with daily fecal incontinence reporting moderate or great bother. In multivariate analysis, the prevalence of fecal incontinence in the past year increased significantly [odds ratio per 5 kg/m2 (95 percent confidence interval)] with obesity [1.2 (1.1‐1.3)], chronic obstructive pulmonary disease [1.9 (1.3‐2.9)], irritable bowel syndrome [2.4 (1.7‐3.4)], urinary incontinence [2.1 (1.7‐2.6)], and colectomy [1.9 (1.1‐3.1)]. Latina females were less likely to report fecal incontinence than white females [0.6 (0.4‐0.9)]. Conclusions: Fecal incontinence, a common problem for females, is associated with substantial adverse affects on quality of life. Several of the identified risk factors are preventable or modifiable, and may direct future research in fecal incontinence therapy.

Prevalence and Type of BRCA Mutations in Hispanics Undergoing Genetic Cancer Risk Assessment in the Southwestern United States: A Report From the Clinical Cancer Genetics Community Research Network

PURPOSE To determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA). PATIENTS AND METHODS Hispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board-approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement. RESULTS Deleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States. CONCLUSION BRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.

Uptake, Time Course, and Predictors of Risk-Reducing Surgeries in BRCA Carriers

INTRODUCTION AND AIMS For women who carry BRCA mutations, risk-reducing surgeries are an option to decrease breast and ovarian cancer risk. This study aims to determine the uptake, time course, and predictors of risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) in BRCA carriers. RESULTS In 272 female carriers, followed for a median of 3.7 years, 23% of those eligible chose RRM, and 51% percent chose RRSO. Among BRCA carriers who chose these procedures, median time to both RRM and RRSO was approximately 4 months after learning of BRCA-positive results. Predictors of RRM were as follows: age below 60 years (hazard ratio 1.8, p=0.04), prior breast cancer (hazard ratio 2.4, p=0.0004), and RRSO (hazard ratio 7.2, p<0.0001). Predictors of RRSO were as follows: age below 60 years (hazard ratio 3.6, p=0.006), prior breast cancer (hazard ratio 1.8, p=0.002), and RRM (hazard ratio 5.4, p<0.0001). CONCLUSIONS Many women who undergo BRCA testing use these results to make clinical decisions; those who choose risk-reducing surgeries typically do so within months of receiving BRCA-positive results. Predictors of risk-reducing surgery uptake include the following: age below 60 years, prior breast cancer, and utilization of another risk-reducing surgery. Future research directions include examining other preventive and screening options in BRCA carriers as well as studying motivations for choosing or declining risk-reducing surgeries.

Comparison of age at natural menopause in BRCA1/2 mutation carriers with a non-clinic-based sample of women in northern California.

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) are related to an increased lifetime risk of developing breast and ovarian cancer. Although risk‐reducing salpingo‐oophorectomy reduces the risk of both cancers, loss of fertility is a major concern. A recent study suggested an association between BRCA1 mutation and occult primary ovarian insufficiency. The objective of the current study was to determine whether BRCA1/2 mutation carriers have an earlier onset of natural menopause compared with unaffected women.

Communication of BRCA Results and Family Testing in 1,103 High-Risk Women

Background: Genetic testing for hereditary cancer risk has implications for individuals and families. This study of women at risk of hereditary breast and ovarian cancer examines communication of BRCA results and subsequent genetic testing in the family. Methods: We surveyed 1,103 female BRCA testers at two hospitals, querying for communication of results and testing in relatives. Results: Ninety-seven percent of participants communicated BRCA results with at least one relative. Communication was negatively associated with older age [odds ratio (OR), 0.66 per decade; 95% confidence interval, (95% CI), 0.4–0.9], Asian race (OR, 0.18; 95% CI, 0.06–0.5), and testing at the public hospital versus the cancer center (OR, 0.19; 95% CI, 0.07–0.5). Communication was positively associated with increased knowledge of hereditary breast and ovarian cancer screening and risk reduction recommendations (OR, 1.9; 95% CI, 1.1–3.4) and increased satisfaction with the decision to BRCA test (OR, 2.6; 95% CI, 1.6–4.0). Seventy-five percent of BRCA-positive participants reported that at least one relative pursued genetic testing. Family testing was negatively associated with Asian race (OR, 0.15; 95% CI, 0.02–0.8) and positively associated with increased socioeconomic status (OR, 1.4; 95% CI, 1.1–1.7) and increased satisfaction with decision (OR, 2.1; 95% CI, 1.1–4.1). Conclusion: Despite high overall rates of communicating BRCA results, underserved and some minority women seem less likely to inform relatives of their BRCA status or have relatives test for a known family mutation. Satisfaction with the decision to BRCA test is positively associated with both outcomes. Impact: This study identified several novel predictors of family communication and family genetic testing in a large population of high-risk women. This work can inform clinicians interested in improving family communication regarding cancer predisposition testing. Cancer Epidemiol Biomarkers Prev; 19(9); 2211–9. ©2010 AACR.

Classifying Variants of Undetermined Significance in BRCA2 with Protein Likelihood Ratios

Background Missense (amino-acid changing) variants found in cancer predisposition genes often create difficulties when clinically interpreting genetic testing results. Although bioinformatics has developed approaches to predicting the impact of these variants, many of these approaches have not been readily applicable in the clinical setting. Bioinformatics approaches for predicting the impact of these variants have not yet found their footing in clinical practice because 1) interpreting the medical relevance of predictive scores is difficult; 2) the relationship between bioinformatics “predictors” (sequence conservation, protein structure) and cancer susceptibility is not understood. Methodology/Principal Findings We present a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function. We apply the method to a tumor suppressor gene, BRCA2, whose loss of function is important to cancer susceptibility. Protein likelihood ratios are computed for 229 unclassified variants found in individuals from high-risk breast/ovarian cancer families. We map the variants onto a protein structure model, and suggest that a cluster of predicted deleterious variants in the BRCA2 OB1 domain may destabilize BRCA2 and a protein binding partner, the small acidic protein DSS1. We compare our predictions with variant “re-classifications” provided by Myriad Genetics, a biotechnology company that holds the patent on BRCA2 genetic testing in the U.S., and with classifications made by an established medical genetics model [1]. Our approach uses bioinformatics data that is independent of these genetics-based classifications and yet shows significant agreement with them. Preliminary results indicate that our method is less likely to make false positive errors than other bioinformatics methods, which were designed to predict the impact of missense mutations in general. Conclusions/Significance Missense mutations are the most common disease-producing genetic variants. We present a fast, scalable bioinformatics method that integrates information about protein sequence, conservation, and structure in a likelihood ratio that can be integrated with medical genetics likelihood ratios. The protein likelihood ratio, together with medical genetics likelihood ratios, can be used by clinicians and counselors to communicate the relevance of a VUS to the individual who has that VUS. The approach described here is generalizable to regions of any tumor suppressor gene that have been structurally determined by X-ray crystallography or for which a protein homology model can be built.

Eligibility criteria in private and public coverage policies for BRCA genetic testing and genetic counseling

Purpose: Coverage policies for genetic services for hereditary cancers are of interest because the services influence cancer risk reduction for both persons with cancer and their family members. We compared coverage policies for BRCA genetic testing and genetic counseling among selected payers in the United States to illuminate eligibility criteria variation that may explain differential access by insurance type. We compared these policies with policies for breast cancer screening with magnetic resonance imaging to consider whether payers apply a unique policy approach to genetic services.Methods: We conducted a case study of large private and public payers selected on number of covered lives. We examined coverage policies for BRCA genetic testing, genetic counseling, and screening with magnetic resonance imaging and the eligibility criteria for each. We compared eligibility criteria against National Comprehensive Cancer Network guidelines.Results: Eligibility criteria for BRCA testing were related to personal history and family history of cancer. Although private payers covered BRCA testing for persons with and without cancer, the local Medicare carrier in our study only covered testing for persons with cancer. In contrast, Arizonas Medicaid program did not cover BRCA testing. Few payers had detailed eligibility criteria for genetic counseling. Private payers have more detailed coverage policies for both genetic services and screening with magnetic resonance imaging in comparison with public payers.Conclusion: Despite clinical guidelines establishing standards for BRCA testing, we found differences in coverage policies particularly between private and public payers. Future research and policy discussions can consider how differences in private and public payer policies influence access to genetic technologies and health outcomes.

Pre-counseling Education for Low Literacy Women at Risk of Hereditary Breast and Ovarian Cancer (HBOC): Patient Experiences Using the Cancer Risk Education Intervention Tool (CREdIT)

The Cancer Risk Education Intervention Tool (CREdIT) is a computer-based (non-interactive) slide presentation designed to educate low-literacy, and ethnically and racially diverse public hospital patients at risk of Hereditary Breast and Ovarian Cancer (HBOC) about genetics. To qualitatively evaluate participants’ experience with and perceptions of a genetic education program as an adjunct to genetic counseling, we conducted direct observations of the intervention, semi-structured in person interviews with 11 women who viewed CREdIT, and post-counseling questionnaires with the two participating genetic counselors. Five themes emerged from the analysis of interviews: (1) genetic counseling and testing for breast/ovarian cancer was a new concept; (2) CREdIT’s story format was particularly appealing; (3) changes in participants’ perceived risk for breast cancer varied; (4) some misunderstandings about individual risk and heredity persisted after CREdIT and counseling; (5) the context for viewing CREdIT shaped responses to the presentation. Observations demonstrated ways to make the information provided in CREdIT and by genetic counselors more consistent. In a post-session counselor questionnaire, counselors’ rating of the patient’s preparedness before the session was significantly higher for patients who viewed CREdIT prior to their appointments than for other patients. This novel educational tool fills a gap in HBOC education by tailoring information to women of lower literacy and diverse ethnic/racial backgrounds. The tool was well received by interview participants and counselors alike. Further study is needed to examine the varied effects of CREdIT on risk perception. In addition, the implementation of CREdIT in diverse clinical settings and the cultural adaptation of CREdIT to specific populations reflect important areas for future work.