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Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3).Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.

Introduction In 2010, the cutoff for HR positivity in breast cancer was established as ≥1% of cells staining HR+, previously having varied from 1% to 10%. The impact of this change on treatment patterns and outcomes is poorly understood. SystHERs is a prospective, observational cohort registry of patients (pts) with HER2+ metastatic breast cancer (MBC) that commenced enrollment in 2012. To our knowledge, SystHERs is the largest registry to collect and analyze data for the HER2+ subgroup. We report baseline characteristics, treatment patterns, and early outcomes by %HR+ (1–9% vs 10–100%). Methods SystHERs enrolled pts aged ≥18 years and within 6 months of HER2+ MBC diagnosis. For pts with locally-determined HR+ disease, defined as HR+ in primary or metastatic tissue, %HR+ is the highest percentage of ER+ or PR+ tissue in early breast cancer or MBC. The percentage of ER+ or PR+ cells was not reported for pts considered HR– by the investigator. Median overall survival (OS; Kaplan–Meier) and hazard ratios (Cox regression) were estimated. Results As of Feb 1, 2016, data were available for 872 eligible pts with known HR status, of whom 608 (70%) had HR+ disease. Of the 608 pts, 53 (9%) had 1–9%HR+ and 496 (82%) had 10–100%HR+; %HR+ was not reported for 59 pts. Baseline characteristics were similar between %HR+ subgroups (Table 1). As shown in Table 2, the 1–9%HR+ subgroup was less likely to receive first-line hormonal therapy (26%) than the 10–100%HR+ subgroup (56%). 87% and 79% of pts received chemotherapy, respectively. Median time from MBC diagnosis was 16.5 months (range, 0.4–49.4 months). Median OS was not reached at the data cutoff. The number of deaths was 13 (25%) in the 1–9%HR+ subgroup, and 68 (14%) in the 10–100%HR+ subgroup (log-rank P=0.025). The OS hazard ratio (0.514, 95% CI 0.283–0.931) favored the 10–100%HR+ subgroup. OS did not differ significantly between pts with 1–9%HR+ vs HR– disease (log-rank P=0.582, hazard ratio 1.185, 95% CI 0.647–2.169). Table 1. Baseline characteristics 1-9%HR+ (n=53)10-100%HR+ (n=496)HR– (n=264)Age at MBC diagnosis, median yrs (range)54 (30–86)57 (21–86)55 (28–88)Race, % White838372Black151320Premenopausal, %282522ECOG performance status, % 04654441463942≥2878MBC diagnosis type, % De novo404958Recurrent605142Visceral, %*686275*Non-hepatic abdominal, ascites, CNS, liver, lung, or pleural effusion sites of metastasis Table 2. First-line treatment 1-9%HR+ (n=53)10-100%HR+ (n=496)HR– (n=264)HER2-targeted therapy, %969391Chemotherapy, %877989Hormonal therapy, %26564 Conclusions These preliminary observational data suggest potential differences in treatment patterns and survival outcomes in low vs moderate/high HR+ expressers, with the former being less likely to receive hormonal therapy (26% vs 56%). Furthermore, low HR positivity was associated with poorer OS and was similar to OS observed in pts with HR– disease. Citation Format: Jahanzeb M, Tripathy D, Rugo H, Swain S, Kaufman PA, Mayer M, Hurvitz S, O'Shaughnessy J, Mason G, Yardley DA, Brufsky A, Chu L, Antao V, Beattie M, Yoo B, Cobleigh M. Treatment patterns and clinical outcomes in patients with hormone receptor (HR)+ HER2+ metastatic breast cancer and low vs high levels of HR positivity from the SystHERs Registry [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-27.

Introduction HR+ metastatic breast cancer (MBC) generally has a more indolent course than HR– MBC. Less is known about differences in BL characteristics and disease outcomes by HR status in HER2+ MBC in the modern tx setting where patients (pts) may recur after adjuvant therapy. SystHERs is an ongoing, prospective, observational cohort study of HER2+ MBC pts. Here we describe BL characteristics, tx patterns, and outcomes by HR status and MBC diagnosis type. Methods SystHERs enrolled pts aged ≥18 years and within 6 months of MBC diagnosis. Locally-determined HR status was captured at initial diagnosis and/or disease recurrence; HR+ was defined as ER+ and/or PR+ disease in primary (early BC) or MBC. Tx data are shown for pts ≥9 months from MBC diagnosis to capture the completion of chemotherapy and the addition of hormonal therapy during maintenance tx. Median overall survival (OS; Kaplan-Meier) and the hazard ratio (Cox regression) were estimated. Results As of Feb 2016, data were available for 872 eligible pts with known HR status; 70% had HR+ disease and 50% had de novo MBC. Median follow-up from MBC diagnosis was 16.5 months (range, 0.4–49.4 months). Clinically important BL demographics and disease characteristics with noticeable differences are presented in Table 1. More black (vs white) pts were observed to be HR–. More recurrent (vs de novo) pts were observed to be HR+. MBC tx choices may be influenced by adjuvant tx. Table 2 shows the most common first-line tx regimens in de novo vs recurrent pts with HR+ HER2+ disease and ≥9 months from MBC diagnosis. Among these pts, 60% de novo and 56% recurrent pts received any hormonal therapy. The most common first-line tx regimen for pts with HR– disease was chemotherapy + HER2-targeted therapy (92%). There were 88 (15%) and 55 (21%) deaths in the HR+ and HR– groups, respectively. Median OS was not reached for either group, but the hazard ratio favored pts with HR+ disease (log-rank P=0.026; hazard ratio 0.683; 95% CI 0.488–0.957). Table 1. BL characteristics HR+ HER2+ (n=608)HR– HER2+ (n=264)Race, % White8272Black1321MBC diagnosis type, % De novo4758Recurrent*5342Visceral disease, %6375No significant differences in other characteristics by HR status (eg, sex, ethnicity, education, menopausal status, performance status, number of metastatic sites at diagnosis). *Pts with prior adjuvant therapy: HR+, 89%; HR–, 83%. Table 2. Most common first-line tx regimens in pts with HR+ HER2+ disease and ≥9 months from MBC diagnosis De novo (n=227)Recurrent (n=235)Chemotherapy + HER2-targeted therapy + hormonal therapy, %4938Chemotherapy + HER2-targeted therapy only, %3741HER2-targeted + hormonal therapy only, %1014 Conclusions In SystHERs, 70% of pts with HER2+ MBC had HR+ disease. A higher percentage of recurrent pts had HR+ disease vs de novo pts, perhaps suggesting selective elimination of HR– clones during adjuvant tx. While black pts are known to be more likely to develop HR– HER2– BC, our results show that HR– HER2+ disease is also more common in black pts, suggesting a proclivity for this population to develop HR– MBC regardless of HER2 status. In these early results, survival was higher in pts with HR+ HER2+ MBC. Citation Format: Cobleigh M, Yardley DA, Brufsky A, Rugo H, Swain S, Kaufman PA, Tripathy D, Mayer M, Hurvitz S, O'Shaughnessy J, Mason G, Chu L, Antao V, Beattie M, Yoo B, Jahanzeb M. Baseline (BL) characteristics, treatment (tx) patterns, and outcomes in patients with hormone receptor (HR)+ vs HR– HER2+ disease from the SystHERs registry [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-08.

Introduction HER2+ MBC patients with CNS metastases are often excluded from clinical trials. The Systemic Therapies for HER2+ Metastatic Breast Cancer Registry (SystHERs), a real-world, prospective registry study, is uniquely positioned to evaluate this understudied population over time. Here we describe the clinical characteristics, HER2-targeted treatments, and survival outcomes of patients with and without CNS metastases at MBC diagnosis. Methods SystHERs is enrolling patients with HER2+ MBC who are >18 years of age and within 6 months of MBC diagnosis. Patients with CNS metastases are identified by their physicians according to local clinical practice. Patient-reported outcomes are obtained at enrollment and throughout the study. Median PFS and OS were estimated using the Kaplan-Meier method and Cox regressions were used to estimate hazard ratios (HRs). Results As of February 2, 2015, data are available for 579 eligible patients, of whom 53 (9%) had CNS metastases at MBC diagnosis (median time from diagnosis to enrollment was 2.3 months). Clinical characteristics and patient-reported functioning in patients with and without CNS metastases at MBC diagnosis are shown in Table 1. Table 1. CNS (n=53)Non-CNS (n=526)Median age (range)57 (36-86)56 (21-88)De novo MBCa, n (%)15 (28)275 (52)Hispanic or Latina, n (%)7 (13)52 (10)White, n (%)46 (87)407 (77)BMI (range)29 (17-43)28 (9-60)ECOG PS (0-1), n (%)36 (68)471 (90)Hormone receptor status, n (%) ER+,PR+21 (40)247 (47)ER+,PR-11 (21)106 (20)ER-,PR+010 (2)ER-, PR-21 (40)153 (29)FACT-Bb,c, median (IQR)(n=42)(n=422) 93 (78-110)102 (85-118)Rotterdam Symptom Checklistb,d, median (IQR)(n=43)(n=429) 75 (54-88)88 (67-100)General HRQOLb,d, median (IQR)(n=43)(n=434) 60 (50-80)80 (61-90)aMetastases confirmed within approximately 90 days of diagnosis. bHigher scores indicate better functioning. cScale range 0-144. dScale range 0-100. First-line MBC treatment data are available for 502 patients, of whom 488 (97%) reported first-line HER2-targeted therapy at the time of data cutoff (Table 2). Table 2.First-line HER2-targeted therapy, n (%)CNS (n=40)Non-CNS (n=448)Any trastuzumab + pertuzumab22 (55)313 (70)Any trastuzumab, no pertuzumab11 (28)117 (26)Any lapatinib14 (35)14 (3)Any T-DM15 (13)29 (6) At a median follow-up time of 12.9 months, median first PFS was 8 months in patients with CNS metastases, and 11.9 months in those without (HR = 0.442; 95% CI 0.304 – 0.641). Median OS was 22 months in patients with CNS metastases, and was not reached in patients without CNS metastases (HR = 0.299; 95% CI 0.174 – 0.514). Conclusions Patients with CNS metastases at MBC diagnosis represent 9% of this registry population. Poor baseline function and an increased risk of progression and death characterized these patients compared to those without baseline CNS metastases. Treatments administered to these patients differ from ASCO consensus recommendations (Ramakrishna, 2014). Further studies are needed to determine the associations between treatments and both clinical and patient-reported outcomes. At the time of presentation, detailed treatment data and additional patient-reported data will be available. Citation Format: Cobleigh M, Hurvitz S, O'Shaughnessy J, Mason G, Yardley D, Jahanzeb M, Brufsky A, Rugo H, Swain S, Kaufman P, Tripathy D, Mayer M, Ogale S, Yoo B, Beattie M. Central nervous system metastases at diagnosis in patients with HER2+ MBC: Baseline characteristics, HER2-targeted treatments and clinical outcomes from the SystHERs registry. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-17-01.

BACKGROUND: 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. METHODS: White carriers of the BRCA1/2 gene (n = 382) were identified within the Breast Cancer Risk Program Registry at the University of California at San Francisco and compared with non–clinic-based white women in northern California (n = 765). The 2 groups were compared with regard to median age at the time of natural menopause before and after adjustment for known risk factors, and the role of smoking within each group was examined using the Kaplan-Meier approach for unadjusted analyses and Cox proportional hazards regression analyses for adjusted analyses. RESULTS: The median age at the time of natural menopause in the BRCA1/2 carriers was significantly younger than among the unaffected sample (50 years vs 53 years; P < .001). The unadjusted hazard ratio for natural menopause when comparing BRCA1/2 carriers with unaffected women was 4.06 (95% confidence interval, 3.03-5.45) and was 3.98 (95% confidence interval, 2.87-5.53) after adjusting for smoking, parity, and oral contraceptive use. For BRCA1/2 carriers who were current heavy smokers (smoking ≥ 20 cigarettes/day), the median age at natural menopause was 46 years versus 49 years for nonsmokers (P = .027). CONCLUSIONS: The BRCA1/2 mutation was associated with a significantly earlier age at natural menopause, and heavy smoking compounded this risk. Because the relationship between menopause and the end of natural fertility is considered to be fixed, these findings suggest the risk of earlier infertility among BRCA1/2 carriers. Cancer 2013. © 2012 American Cancer Society.

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.

Outcomes aft er genetic testing for Hereditary Breast and Ovarian Cancer (HBOC) Syndrome have not been well studied in underserved populations. We surveyed 1,123 BRCA testers from a genetic counseling program serving an academic cancer center (n=1,045) and a public county hospital (n=78) a median of 3.7 years aft er testing for mutations in BRCA1 and BRCA2 (breast cancer susceptibility genes). We compared genetic counseling outcomes, cancer screening rates, and self- reported general health. We found no differences in genetic counseling outcomes between hospitals. Breast cancer screening rates were similarly high at both hospitals, which are warranted in this high- risk population. Screening rates for ovarian, colon, and skin cancer were significantly lower in participants from the public hospital. BRCA results were not a predictor of general health at either hospital. When creating a genetic counseling program that serves women in different hospital settings, providers should emphasize guidelines- based screening recommendations for all patients. © Meharry Medical College.

Tamoxifen decreases breast cancer recurrence, mortality, and breast cancer risk in high-risk women. Despite these proven benefits, tamoxifen use is often limited due to side effects. We identified predictors of tamoxifen-induced side effects based on clinical variables and serum tamoxifen metabolite biomarkers in a cross-sectional study of patients taking tamoxifen. We enrolled 241 women and collected data on demographics, tamoxifen use and side effects, as well as potential clinical and serum predictors. We used logistic regression models and adjusted for age, body mass index, ethnicity, education, prior post-menopausal hormone therapy, tamoxifen duration, and endoxifen levels to identify factors associated with side effects. Common tamoxifen attributed side effects were hot flashes (64%), vaginal dryness (35%), sleep problems (36%), weight gain (6%), and depression, irritability or mood swings (6%). In multi-variate models, tamoxifen duration, age, prior post-menopausal hormone therapy, and endoxifen levels all predicted side effects. Women who had been on tamoxifen for >12 months were less likely to report side effects (OR 0.15, 95% CI, 0.04–0.58) or severe side effects (OR 0.05, 95% CI, 0.005–0.58) compared to women on tamoxifen for

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.

A growing body of research describes cancers other than breast and ovarian in families with BRCA1/2 mutations, but the prevalence and characteristics of pancreatic cancer in these families has not been well described. This study was designed to: (1) estimate the prevalence of pancreatic cancer in BRCA1/2 positive families; (2) ascertain age of onset and gender distribution of pancreatic cancer in this cohort; and (3) compare age and gender characteristics of pancreatic cancer in BRCA1/2 positive families with those of the general population. Within the UCSF Cancer Risk Program cohort, 24/219 (11.0%) BRCA1 and 17/156 (10.9%) BRCA2 families had at least 1 individual with pancreatic cancer. In the 24 BRCA1 families, median age of diagnosis was 59 (range 45-80) in males, and 68 (range 38-87) in females (male:female ratio = 2.00). In the 17 BRCA2 families, median age of diagnosis was 67 (range 39-78) in males and 59 (range 46-81) in females (male:female ratio = 1.11). The SEER database, which describes cancer characteristics in a representative sample of the US population, reports a median age of 70 in males and 74 in females (male:female ratio = 0.96) over the same time period. Additionally, mean ages of diagnosis of pancreatic cancer in BRCA1/2 families differ significantly from the SEER mean (P = 0.0014 for BRCA1 and P = 0.011 for BRCA2 by unpaired t-test). Our findings suggest that families with early onset pancreatic cancer and features of hereditary breast and ovarian cancer should be considered for BRCA1/2 testing.

BackgroundMissense (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 FindingsWe 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/SignificanceMissense 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.

Genetic counseling for BRCA1 and BRCA2 mutations involves teaching about hereditary cancer, genetics and risk, subjects that are difficult to grasp and are routinely misunderstood. Supported by a grant from the Avon Foundation, the UCSF Cancer Risk Program started the first genetic testing and counseling service for a population of traditionally underserved women of varied ethnic and social backgrounds at the San Francisco General Hospital (SFGH). Informed by educational theory and clinical experience, we devised and piloted two simplified explanations of heredity and genetic risk, with the aim of uncovering how to best communicate genetics and risk to this underserved population. A "conventional" version comprised pictures of genes, pedigrees, and quantitative representations of risk. A "colloquial" pictorial version used an analogy of the "information book" of genes, family stories and vignettes, and visual representations of risk, without using scientific words such as genes or chromosomes. A verbal narrative accompanied each picture. We presented these modules to four focus groups of five to eight women recruited from the SFGH Family Practice Clinic. Overall, women preferred a picture-based approach and commented that additional text would have been distracting. The majority of women preferred the colloquial version because it was easier to understand and better conveyed a sense of comfort and hope. We conclude that simplicity, analogies, and familiarity support comprehension while vignettes, family stories, and photos of real people provide comfort and hope. These elements may promote understanding of complex scientific topics in healthcare, particularly when communicating with patients who come from disadvantaged backgrounds.

Objectives The purpose of this work was to determine the prognostic value of normal exercise myocardial perfusion imaging (MPI) tests and exercise echocardiography tests, and to determine the prognostic value of these imaging modalities in women and men. Background Exercise MPI and exercise echocardiography provide prognostic information that is useful in the risk stratification of patients with suspected coronary artery disease (CAD). Methods We searched the PubMed, Cochrane, and DARE databases between January 1990 and May 2005, and reviewed bibliographies of articles obtained. We included prospective cohort studies of subjects who underwent exercise MPI or exercise echocardiography for known or suspected CAD, and provided data on primary outcomes of myocardial infarction (MI) and cardiac death with at least 3 months of follow-up. Secondary outcomes (unstable angina, revascularization procedures) were abstracted if provided. Studies performed exclusively in patients with CAD were excluded. Results The negative predictive value (NPV) for MI and cardiac death was 98.8% (95% confidence interval [CI] 98.5 to 99.0) over 36 months of follow-up for MPI, and 98.4% (95% CI 97.9 to 98.9) over 33 months for echocardiography. The corresponding annualized event rates were 0.45% per year for MPI and 0.54% per year for echocardiography. In subgroup analyses, annualized event rates were Conclusions Both exercise MPI and exercise echocardiography have high NPVs for primary and secondary cardiac events. The prognostic utility of both modalities is similar for both men and women.

Diese Studie wurde durchgefuhrt, um bei ethnisch unterschiedlichen Frauen uber 40 Jahren die Pravalenz von Stuhlinkontinenz zu untersuchen sowie mit Stuhlinkontinenz assoziierte Risikofaktoren zu bestimmen. Die Studie „Reproductive Risks for Incontinence Study at Kaiser“ ist eine bevolkerungsbasierte Untersuchung von 2 109 willkurlich ausgewahlten Frauen mittleren Alters und alter (Durchschnittsalter 56 Jahre). Die Stuhlinkontinenz wurde mittels Patientenaussage festgestellt und nach der Haufigkeit ihres Auftretens eingestuft. Die Frauen berichteten uber den Grad der Belastung durch die Stuhlinkontinenz sowie ihre allgemeine Lebensqualitat. Potenzielle Risikofaktoren wurden durch Selbstbeurteilung, Befragung, eine korperliche Untersuchung und Prufung der Krankenakte beurteilt. Zur Feststellung der Unabhangigkeit von ausgesuchten Risikofaktoren und dem wesentlichen Ergebnis von jeder berichteten Stuhlinkontinenz im zuruckliegenden Jahr wurde die multivariate logistische Regressionsanalyse eingesetzt. 24% der Frauen gaben eine Stuhlinkontinenz in den letzten zwolf Monaten an (3,4% monatlich, 1,9% wochentlich, und 0,2% taglich). Eine grosere Haufigkeit von Stuhlinkontinenz war mit verringerter Lebensqualitat (Medical Outcome Short Form-36 Mental Component Scale Score, p = 0,01) sowie mit gestiegener Belastung (p < 0,001) assoziiert: so klagten 45% der Frauen mit Stuhlinkontinenz in den letzten zwolf Monaten und 100% der Frauen mit taglicher Stuhlinkontinenz uber eine masige oder grose Belastung. Bei der multivarianten Analyse stieg die Pravalenz von Stuhlinkontinenz im zuruckliegenden Jahr in Verbindung mit Adipositas [1,2 (1,1– 1,3)], chronisch obstruktiver Lungenerkrankung [1,9 (1,3–2,9)], Reizdarmsyndrom [2,4 (1,7–3,4)], Harninkontinenz [2,1 (1,7–2,6)] und Kolektomie [1,9 (1,1–3,1)] significoloproctology kant an [Odds Ratio per 5 kg/m2 (95% Konfidenzintervall)]. Latina-Frauen hatten eine geringere Wahrscheinlichkeit fur Stuhlinkontinenz als weise Frauen [0,6 (0,4– 0,9)]. Stuhlinkontinenz, ein alltagliches Frauenproblem, ist mit wesentlichen negativen Auswirkungen auf die Lebensqualitat verbunden. Einige der festgestellten Risikofaktoren sind vermeidbar oder modifizierbar und konnen den Verlauf der weiteren Forschung bei der Therapie der Stuhlinkontinenz beeinflussen.

Accurate measurement of low serum estradiol (E(2)30 pg/ml or110 pmol/liter) is needed to study relationships between endogenous E(2) and risks of diseases in older women.The objective of this study was to determine whether an extraction-based (indirect) assay or a non-extraction-based (direct) assay correlates better with mass spectrometry and body mass index (BMI).In a pilot study of 40 postmenopausal women, endogenous E(2) measurements from three indirect and four direct assay methods and gas chromatography-tandem mass spectrometry (GC-MS/MS) were compared. A confirmatory study compared an indirect and a direct assay, selected among those in the pilot study, to GC-MS/MS; this study was conducted in 374 postmenopausal women not taking hormone therapy from the Ultra Low-dose TRansdermal estrogen Assessment (ULTRA) trial.Pearson correlation coefficients among E(2) measurements by assay methods and BMI, and their confidence intervals, by bias-corrected bootstrap method, were used.In the pilot study, E(2) by three indirect assays correlated better (P0.03) with GC-MS/MS and with BMI than measurements by four direct assays. In the confirmatory study, the indirect assay correlated better (P0.01) with GC-MS/MS and BMI than the direct assay. Measurements by the indirect and direct assays were overestimated, but deviations in direct assay measurements were less precise. Mean E(2) by the indirect and direct assays were higher (by 14 and 68%, respectively) and less reproducible than by GC-MS/MS.Until mass spectrometry is practical for wide use, extraction-based indirect assays may be preferable for measuring low postmenopausal serum E(2).

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.

For both primary and secondary prevention of coronary heart disease (CHD), it is prudent to use strategies that are of proven benefit and that do not harm patients. In all women, these strategies include lifestyle approaches such as smoking avoidance, proper nutrition, and regular exercise. Lipid-lowering and blood pressure control with pharmacotherapy are indicated in women who do not meet target lipid or blood pressure levels with lifestyle interventions. For women with CHD, aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors should be considered. Widespread under-use of established preventive therapies has been documented in women. These interventions should be emphasized in clinical practice. For secondary prevention of CHD in women, the American Heart Association (AHA) recommends against initiating hormone replacement therapy (HRT) based on studies that have shown no benefit and early harm. For patients with CHD already on HRT, the decision to continue or stop HRT should be based on established noncoronary benefits and risks and patient preference. There are insufficient data to suggest that HRT should be initiated for the sole purpose of primary prevention of CHD. Because the new AHA guidelines recommend placing significant weight on the noncardiac benefits and risks of HRT, it is important to become familiar with these noncardiac effects. It is also important to understand the evidence supporting the AHA’s decision to recommend placing relatively less weight on the cardiac effects of HRT.

Background For women at potentially increased risk for ovarian cancer, data regarding screening and risk reduction are limited. Previous studies have reported on the behaviors of BRCA mutation carriers, but less is known about the behaviors of non- BRCA carriers. We surveyed a large cohort of women after BRCA testing to identify the prevalence and posttest predictors of risk-reducing and screening interventions. Methods A median of 3.7 years after BRCA testing, 1447 women who received genetic counseling and BRCA testing at 2 hospital sites were surveyed, with a 77.6% response rate. We analyzed data from 1077 survey respondents. We performed univariate and multivariate logistic regression analyses to identify predictors of risk-reducing salpingo-oophorectomy (RRSO), screening transvaginal ultrasonography (TVUS), and screening serum cancer antigen 125 (CA-125). Results Among the respondents, 201 women (18.7%) received positive test results for a deleterious mutation, 103 women (9.6%) received true-negative results, and 773 women (71.8%) received uninformative results. Overall, 19.1% of eligible women underwent RRSO and 39.6% used screening procedures. A positive BRCA result predicted RRSO (odds ratio [OR], 28.1; 95% CI, 16.2-48.6), TVUS (9.5 [4.3-21.0]), and serum CA-125 (13.0 [5.5-29.0]). Similarly, a true-negative BRCA result reduced the OR for RRSO (0.1 [0.0-0.6]), TVUS (0.2 [0.1-0.5]), and serum CA-125 (0.3 [0.1-0.7]). Of the 71.8% of women who received uninformative results after BRCA testing, 12.3% subsequently underwent RRSO, 33.8% reported ever having undergone screening serum CA-125 since BRCA testing, and 37.3% reported ever having undergone screening TVUS since BRCA testing. Conclusions Results of BRCA testing strongly predict RRSO and ovarian cancer screening. Use of RRSO and ovarian screening was reported in a sizable percentage of non- BRCA carriers despite insufficient data to determine the effectiveness of these interventions.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., Author Summary BRCA1 mutation carriers have increased and variable risks of breast and ovarian cancer. To identify modifiers of breast and ovarian cancer risk in this population, a multi-stage GWAS of 14,351 BRCA1 mutation carriers was performed. Loci 1q32 and TCF7L2 at 10q25.3 were associated with breast cancer risk, and two loci at 4q32.2 and 17q21.31 were associated with ovarian cancer risk. The 4q32.3 ovarian cancer locus was not associated with ovarian cancer risk in the general population or in BRCA2 carriers and is the first indication of a BRCA1-specific risk locus for either breast or ovarian cancer. Furthermore, modeling the influence of these modifiers on cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers for the first time showed that a wide range of individual absolute risks of each cancer can be estimated. These differences suggest that genetic risk modifiers may be incorporated into the clinical management of BRCA1 mutation carriers.

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.To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.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).Five-year overall mortality.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).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.

New prognostic tests, such as gene-expression profiling (GEP) of breast tumors, are expected to prolong survival and improve the quality of life for many breast cancer patients. In this article, we argue that GEP has not been adequately validated in minority populations, and that both biological and social factors might affect the broad utility of these tests in diverse populations. We suggest that the widespread use of this technology could potentially lead to suboptimal treatment for black women, resulting in a further increase in black–white patient disparities in treatment response, morbidity and mortality rates. We argue for the need to build a large and diverse evidence base for GEP and other emerging technologies in personalized medicine.

Purpose: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. Results: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95–1.10), serous EOC (OR = 1.08, 95% CI: 0.98–1.18), familial EOC (OR = 1.09, 95% CI: 0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88–1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99–1.22), among serous cases (HR = 1.12, 95% CI = 0.99–1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93–1.52). Conclusions: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted. Clin Cancer Res; 17(11); 3742–50. ©2011 AACR.

[Background]: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. [Methods]: We genotyped rs3814113 in 10 029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. [Results]: The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. [Conclusion]: Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation., Spanish National Cancer Center (CNIO) and the Spanish Consortium: Partially supported by Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, and the Spanish Ministry of Science and Innovation (FIS PI08 1120).

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. © National Society of Genetic Counselors, Inc. 2010.

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

630 Background: HER2 amplifications and activating mutations are an emerging drug target in the treatment of colorectal cancer (CRC). Ongoing studies, such as MyPathway (Clinicaltrials.gov NCT02091141), include basket trials of targeted therapies for multiple solid tumor types. The frequency of HER2 mutations in GI cancers and a drug resistance mechanism to the HER2 kinase inhibitor, afatinib, are presented here. Methods: The Foundation Medicine database of 53,126 cases was searched and clinical data from patients with GI tumors enrolled in the HER2 basket of MyPathway was included. Results: 10,358 patients with GI cancers and FoundationOne (FO) testing were identified and compared to the HER2 mutation frequency reported by The Cancer Genome Atlas (TCGA). In MyPathway, 28 GI tumors with HER2 alterations are enrolled: CRC (n = 13, all amplified), liver/biliary (n = 5), pancreatic (n =4), small intestine (n = 3), and esophageal (n = 2). Several CRC patients demonstrated responses to trastuzumab/pertuzumab (reported separately). The HER2 mutant CRC cell lines, CW-2 and CCK-81, are highly sensitive to afatinib (IC50=7-20 nM). Addition of the HER3 ligand, neuregulin1 caused afatinib resistance, but pertuzumab prevented HER3/HER2 activation and reversed this drug resistance. Conclusions: HER2 mutations or amplifications are commonly found in a wide range of GI cancers. Pre-clinical data provide rationale for inclusion of pertuzumab in the treatment strategy for these cancers. The MyPathway Trial is testing this approach. [Table: see text]

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)] zwith 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.

Background Prospective studies have shown an association between increased serum levels of estradiol and testosterone and breast cancer risk in postmenopausal women. Raloxifene has been shown to reduce breast cancer risk more in women with high estradiol levels than in those with lower levels. The purpose of this study was to determine whether sex hormone levels were associated with breast cancer risk and with response to tamoxifen in a high-risk population. Methods Using a case-cohort design, we studied 135 women with postmenopausal breast cancer and 275 postmenopausal women without breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project Cancer Prevention Trial (P-1) and who had been treated with tamoxifen or placebo for 69 months. We measured estradiol, testosterone, and sex hormone-binding globulin by using radioimmunoassay in baseline plasma samples. Relative risks (RRs) and 95% confidence intervals (CIs) for invasive breast cancer were estimated for each quartile of sex hormone level using Cox proportional hazards models. All statistical tests were two-sided. Results Median plasma levels of estradiol, testosterone, and sex hormone-binding globulin were similar between the case and cohort groups. The relative risk of breast cancer for women in the placebo group was not associated with sex hormone levels (risk of estrogen receptor-positive breast cancer in women by quartile of estradiol: Q1 [lowest], RR = 1.0; Q2, RR = 1.16, 95% CI = 0.49 to 2.7; Q3, RR = 1.08, 95% CI = 0.45 to 2.61; and Q4, RR = 1.29, 95% CI = 0.59 to 2.82). The reduced risk of invasive breast cancer in tamoxifen-treated women compared with placebo-treated women was not associated with sex hormone levels. Conclusions These data do not support the use of endogenous sex hormone levels to identify women who are at particularly high risk of breast cancer and who are most likely to benefit from chemoprevention with tamoxifen.

Genetic counseling and testing for heritable susceptibility to breast cancer caused by mutations in BRCA genes are largely unavailable to underserved women in the United States. Starting in 2002 the UCSF Cancer Risk Program offered this service free of charge to poor and medically indigent women at San Francisco General Hospital (SFGH). One recruitment strategy was a single-page questionnaire in four languages administered to women waiting for mammograms at SFGH. This report analyzes our first 3 years of experience with the recruitment questionnaire and compares the patient demographics and BRCA test results at SFGH with a more typical population undergoing genetic counseling and testing at UCSF's Mt. Zion Hospital (MZH). To our knowledge this is the first comprehensive clinical service for hereditary breast cancer in a U.S. public hospital. The ethnic mix of all 350 patients counseled was Caucasian 49% (approximately 20% of Caucasians reported Ashkenazi Jewish ancestry), Latina, 26%; African American, 13%; and Asian/other, 12%. Compared to the MZH population, SFGH patients were more ethnically diverse, less educated and more likely to be unemployed. Of 72 patients tested for BRCA mutations, 51 (71%) were negative, 5 were BRCA1 positive, and 12 were BRCA2 positive. Four (1 Caucasian, 1 Latina, 2 African American) had a total of 13 BRCA variants of unknown significance (VUS). The ratio of BRCA1/BRCA2 positive SFGH patients (5/12) was reversed compared to MZH (119/91). We evaluated 4573 recruitment questionnaires and 280 (6%) were judged to represent a high risk of heritable cancer. After additional screening and referral negotiation, 74 were scheduled for counseling. We judged the recruitment questionnaire to be a feasible, efficient, and reasonably cost-effective way to identify women at high risk of hereditary cancer in a traditionally underserved population. Underserved populations present special challenges for genetic counselors because of large, geographically dispersed families, cultural taboos about cancer diagnoses, and social marginalization. Despite these complexities, the clinical service at SFGH has been well accepted by patients and staff. Our successful venture can serve as a model for other public hospitals contemplating this clinical service.

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, 0.640.84; 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 inBRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.

Background: Underserved families at risk of Hereditary Breast and Ovarian Cancer (HBOC) have decreased access to genetic cancer risk assessment (GCRA). Neither the process nor outcomes of GCRA have been carefully studied in large and diverse underserved populations. The Consortium of Underserved BRCA testers (CUB), formed in 2010 among three county hospitals, aims to rigorously study GCRA and patient outcomes at each site. Methods: CUB's founding members are: San Francisco General Hospital (SF), Stroger Hospital of Cook County (Chicago), and Grady Memorial Hospital (Atlanta). Underserved patients are defined as low-income, low literacy, uninsured, and/or members of ethnic, racial and linguistic minority groups. Together we developed a common clinical and research protocol, with standardized intake forms, questionnaires, follow-up protocols, and research instrument delivery. Using mixed methods, we examined and compared referral patterns, demographics, and BRCA test results between sites. We used chart reviews and common data collection instruments to gather and pool data. Using descriptive and comparative statistics, we examined similarities and differences between Consortium sites. Results: The GCRA programs in SF, Chicago, and Atlanta began 9, 6, and 3 years ago, respectively. Medicaid funding for BRCA testing has been available in SF since 2011, in Chicago since 2009, and is not yet available in Atlanta. Each site has a unique referral process for GRCA, including specialty and primary care clinics, mammography, and family members. Chi-squared analysis demonstrated significantly different referral patterns between each site (p The ratio of women referred to women tested for a BRCA mutation is 4.0:1 in SF, 2.40:1 in Chicago, and 1.5:1 in Atlanta. Differences in these ratios relate to referral and outreach sources, as well as funding for BRCA testing. The percentage of women found to have BRCA mutations was similar at each site: 18% in SF, 16% in Chicago, and 13% in Atlanta. There were significant differences, however, in the ethnic and racial composition of the population tested between sites. In SF, 9% were African American, 21% were Asian, 41% were Caucasian, and 25% were Hispanic. In Chicago, 38% were African American, 7% were Asian, 25% were Caucasian, and 26% were Hispanic. In Atlanta, 67% were African American, 2% were Asian, 13% were Caucasian, and 5% were Hispanic. Conclusions: Despite significant differences in referral patterns and Medicaid funding for BRCA testing, underserved women at all 3 public hospitals demonstrated similar BRCA positive rates, which are similar to positive rates at tertiary cancer centers and University hospitals. To our knowledge, this cohort of 636 BRCA testers is among the largest, most diverse population of its kind. In the future, CUB hopes to serve as a valuable resource to share best practices and investigate outcomes for underserved families at risk of HBOC. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A39.

1514 Background: Little is known about prevalence or ancestral origins of BRCA1and BRCA2 (BRCA) mutations among high-risk Hispanics, the fastest growing relatively underserved population in the U.S...

Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in roughly 5 percent of ovarian cancer patients. Both genes play key roles in DNA damage repair but appear to have distinct, although often complementary, functions. The risks of breast and ovarian cancer have been shown to differ between BRCA1 and BRCA2 carriers, and mutation-specific effects have also been suggested for both groups. Published reports comparing the survival of ovarian cancer patients with and without BRCA1/2 mutations generally show a survival advantage among mutation carriers. This is thought to be related to an improved response of carriers to platinum-based therapies. Since it is not known whether BRCA1 and BRCA2 carriers show similar survival patterns, we have performed a large, multicenter study to investigate the impact of germline BRCA1 and BRCA2 mutations on ovarian cancer survival. 3,531 invasive epithelial ovarian cancer cases (1,178 BRCA1, 367 BRCA2 and 1,986 BRCA-negative) with survival time data from twenty-four studies in the U.S.A, Europe, Israel and Asia were included. In our main analysis, we excluded patients who were known or who were likely to have not received platinum-based therapy. Compared to non-carriers, BRCA1 and BRCA2 carriers were more likely to present with advanced stage (BRCA1; p=2×10−4, BRCA2; p=4×10−6), high grade (BRCA1; p=4×10−9, BRCA2; p=1×10−4), serous disease (BRCA1; p=3×10−6, BRCA2; p=0.003). BRCA1 carriers were younger at diagnosis (p=2×10−9) and BRCA2 slightly older at diagnosis (p=0.002) than non-carriers. BRCA1 and BRCA2 carriers did not differ in terms of tumor stage, grade or histology but did show differences in the age at diagnosis (p=2×10−14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from non-carriers in overall survival (BRCA1: HR=1.02, p=0.77, BRCA2: HR=0.89, p=0.36). After adjusting for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest, non-significant, survival advantage (HR=0.84, p=0.12) while BRCA2 carriers showed a marked improvement (HR=0.57, p=6×10−4) compared to non-carriers. This survival advantage was also seen when comparing BRCA2 carriers to BRCA1 carriers after adjustment for age at diagnosis (HR=0.69, p=5×10−4). Similar results were obtained when we restricted the analysis to high grade, advanced stage, serous cases. The survival differences we observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemo-sensitivity. Additional analyses investigating the later will be presented in addition to mutation-specific effects within BRCA1 and BRCA2. In this study, we provide strong evidence for genetic heterogeneity of survival effects in ovarian cancer patients with BRCA mutations. This could be applied to both clinical prediction and to aid our understanding of the complex biology of BRCA mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2752. doi:10.1158/1538-7445.AM2011-2752

Background Pharmacogenetic testing holds major promise in allowing physicians to tailor therapy to patients based on genotype. However, there is little data on the impact of pharmacogenetic test results on patient and clinician choice of therapy. CYP2D6 testing among tamoxifen users offers a potential test case of the use of pharmacogenetic testing in the clinic. We evaluated the effect of CYP2D6 testing in clinical practice to determine whether genotype results affected choice of hormone therapy in a prospective cohort study. Methods Women planning to take or currently taking tamoxifen were considered eligible. Participants were enrolled in an informational session that reviewed the results of studies of CYP2D6 genotype on breast cancer recurrence. CYP2D6 genotyping was offered to participants using the AmpliChip CYP450 Test. Women were classified as either poor, intermediate, extensive or ultra-rapid metabolizers. Results were provided to clinicians without specific treatment recommendations. Follow-up was performed with a structured phone interview 3 to 6 months after testing to evaluate changes in medication. Results A total of 245 women were tested and 235 completed the follow-up survey. Six of 13 (46%) women classified as poor metabolizers reported changing treatment compared with 11 of 218 (5%) classified as intermediate, extensive or ultra-rapid metabolizers (P < 0.001). There was no difference in treatment choices between women classified as intermediate and extensive metabolizers. In multi-variate models that adjusted for age, race/ethnicity, educational status, method of referral into the study, prior knowledge of CYP2D6 testing, the patients' CYP2D6 genotype was the only significant factor that predicted a change in therapy (odds ratio 22.8; 95% confidence interval 5.2 to 98.8). Genetic testing did not affect use of co-medications that interact with CYP2D6. Conclusions CYP2D6 genotype testing led to changes in therapy among poor metabolizers, even in the absence of definitive data that an alternative medicine improved outcomes. Pharmacogenetic testing can affect choice of therapy, even in the absence of definitive data on clinical impact.

Purpose: With the support of the Avon Foundation, genetic counseling is available to underserved populations at the San Francisco General Hospital. One of the major challenges in providing genetic counseling for hereditary breast and ovarian cancer among these women is the lack of culturally appropriate educational tools.The purpose of this study is to evaluate the use of a Cancer Risk Educational Intervention (CREdIT), a novel audio-visual PowerPoint-based tool as an adjunct to genetic counseling. Methods: CREdIT took on average 15 minutes to view and was available in English and Spanish. It employed non-scientific images and language specifically designed for use by our target population. Participant questionnaires evaluating patient satisfaction, risk perception, knowledge of cancer genetics, and anxiety were administered before and after the intervention and at 1 year follow-up. For each of the continuous outcomes, differences from pre- to post-intervention were assessed with analyses of variance, while chi-squared tests were used to examine the differences among categorical variables. Results: A total of 52 women of diverse backgrounds who were on average 47 years old (range 27-69) took part in the study. Of these, 15% reported previous history of cancer, 58% were non-white and 59% had a below college education. Twenty-one percent viewed the presentation in Spanish. Following the presentation of CREdIT, we found an increase in the knowledge of BRCA inheritance and associated risk of malignancy, and options for risk reduction (all p < .05). However, participants' perceived risk perception did not change from baseline to post-CREdIT (p=.73). Virtually all participants (98%) reported that CREdIT helped them learn more about cancer risk. Although patient anxiety decreased post-CREdIT (p=.02), 29% patients reported that CREdIT made them worry more about cancer. Among 32 participants who were interviewed at the long-term follow-up, we found that, compared to post-CREdIT, knowledge changed for only two of the seven questions (p< .05). There were also no changes in anxiety or cancer worry compared to baseline (both p< .05). Conclusions: These interim findings suggest that our intervention was successful at increasing knowledge regarding breast cancer genetics without increasing anxiety or cancer worry. Our long-term goal is to perform a large-scale evaluation among underserved women at risk of hereditary cancer across the Avon Foundation-supported clinics nationwide. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4074.

Abstract #2101 Introduction: In underserved, lower literacy and multiethnic women at risk of Hereditary Breast and Ovarian Cancer (HBOC), there is a need for culturally appropriate educational tools. The purpose of this Phase I study is to evaluate the use of a Cancer Risk Educational Intervention Tool (CREdIT) as an adjunct to genetic counseling for HBOC for underserved women at San Francisco General Hospital (SFGH). Methods: CREdIT is a 15 minute audio-visual powerpoint story presentation (available in English and Spanish) which employs non-scientific images and language specifically designed for use by our target population. Participant questionnaires, administered before and after the intervention, evaluate patient satisfaction, risk perception, knowledge of cancer genetics, and anxiety. Genetic counselor questionnaires address counselor satisfaction and time-flow. Results: To date, we have recruited 23 women of diverse backgrounds (mean age of 46, range: 26 to 63). Of these, seven (30%) are first-generation immigrants and four (17%) have less than a high school diploma. Eight (35%) have had cancer, and eighteen (78%) reported that cancer runs in their families. We have found an increase in knowledge following the CREdIT presentation, specifically vis-à-vis BRCA inheritance, BRCA-associated cancer risk, and risk-reducing options (all p < 0.05). These improvements occur without an increase in patient anxiety (p > 0.05). All participants believed that the presentation helped them learn more about cancer risk, and genetic counselors reported increased patient preparedness and counselor satisfaction as a result of CREdIT use (p < 0.05). Mean genetic counselor consultation time decreased by 5.5 minutes after CREdIT use. Conclusions: CREdIT appears to increase knowledge and improve understanding of BRCA-associated risks without raising anxiety in underserved women at risk of HBOC. Genetic counselors report increased satisfaction and patient preparedness, and decreased counseling time with CREdIT. Future work will involve examining long-term outcomes of CREdIT use; subgroup analyses to identify patient populations most likely to benefit from CREdIT; further evaluation using clinical trial methodology; and strategies for its dissemination to other settings working with underserved, multiethnic populations. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2101.

9667 Background: Genetic counseling and BRCA testing are largely unavailable to underserved women attending public hospitals because of cost and availability. A gift from Avon Foundation in 2001 en...

INTRODUCTION The aim of this clinical update is to summarize articles and guidelines published in the last year with the potential to change current clinical practice as it relates to women’s health.

Background Individuals who carry deleterious BRCA mutations face significantly elevated risks of breast, ovarian, and other cancers. These individuals are also responsible for informing relatives of their increased risk for carrying the family BRCA mutation. Few interventions have been developed to facilitate this family communication process. Methods We developed the Sharing Risk Information Tool (ShaRIT), a personalized educational intervention, to support BRCA carriers as they discuss BRCA positive results and their implications with relatives. We conducted a pilot study of 19 BRCA carriers identified through the University of California San Francisco Cancer Risk Program. Our study had two aims: 1) to assess the feasibility and acceptability of ShaRIT, and 2) describe characteristics associated with increased family communication and BRCA testing. Participants in our study were divided into two groups: those who had not received ShaRIT as part of their genetic counseling protocol (control group, n = 10) and those who received ShaRIT (n = 9). Results All 9 women who received ShaRIT reported that it was a useful resource. Characteristics associated with increased sharing and testing included: female gender, degree of relationship, and frequency of communication. Increased pedigree knowledge showed a trend toward higher rates of sharing. Conclusions Both participants and genetic counselors considered ShaRIT a well-received, comprehensive tool for disseminating individual risk information and clinical care guidelines to Hereditary Breast and Ovarian Cancer Syndrome families. Because of this, ShaRIT has been incorporated as standard of care at our institution. In the future we hope to evaluate the effects of ShaRIT on family communication and family testing in larger populations of BRCA positive families.