A germline mutation in the BRCA1 3'UTR predicts Stage IV breast cancer.

BACKGROUND: A germline, variant in the BRCA1 3'UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3'UTR mutations in cancer. METHODS: The impact of the BRCA1-3'UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3'UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont. RESULTS: Luciferase reporters with the BRCA1-3'UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3'UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3'UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR=1.4, 95% CI 1.1-1.8, p=0.033). More importantly, patients with the BRCA1-3'UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p=0.018, OR=3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3'UTR-variant had significantly less dense breasts (p=0.0398) in the Vermont cohort. CONCLUSION: A variant in the 3'UTR of BRCA1 is functional, leading to decreased BRCA1 expression, modest increased breast cancer risk, and most importantly, presentation with stage IV breast cancer, likely due to aggressive tumor biology.

The Impact of Incentives on Weight Control in Men: A Randomized Controlled Trial.

Overweight and obese men were recruited to a 6-month, randomized controlled weight loss trial, which compared the Gutbusters weight loss program alone to the Gutbusters program with incentives for successful weight loss. The intervention was delivered primarily online, with weekly in-person weight collections. Gutbusters was designed using a template from the REFIT intervention and encouraged participants (N = 102, 47.0 ± 12.3 years, 32.5 kg/m2) to make six 100-calorie changes to their typical daily diet for a total of 42 changes per week. Weight loss was significantly greater in the Gutbusters+Incentive group compared to the Gutbusters alone group at both 12 and 24 weeks (p's = < .01). The Gutbusters+Incentive group's a mean weight loss was 9.9 pounds at 12 weeks (95% CI: 6.9, 12.9) and 8.4 pounds at 24 weeks (95% CI: 3.9, 13.0). The Gutbusters alone group mean weight loss was 3.7 pounds at 12 weeks (95% CI: -.06, 7.5) and 3.4 pounds at 24 weeks (95% CI: -2.2, 9.0). This study adds to the literature of behavioral weight programs that are designed for men. Unlike the majority of previous male weight loss interventions, which were designed with an intervention comparison to a no treatment or waitlist control, Gutbusters was implemented as a comparative effectiveness trial, which will help bolster the evidence base for real-world application.

Enrollment Challenges: Recruiting Men to Weight Loss Interventions.

Obese men are at an increased risk of chronic disease and are far less likely than women to attempt weight loss. There is a need to successfully recruit men to weight loss clinical trials. Overweight and obese men were recruited to a 6-month, randomized, controlled weight loss trial. Initial recruitment efforts were aimed at men in the workplace with less than or equal to 2 years of college education. After unsatisfactory interest from men and businesses alike, recruitment strategy shifted to enroll men outside the workplace with any educational background. Recruitment methods included word of mouth, email and website advertisements, printed posters in local businesses and doctors' offices, Facebook ads, and a 1-week newspaper ad campaign. Initial interest and enrollment was negligible with only 35 men enrolled in the first 7 months. The launch of a 1-week newspaper advertisement was the most useful recruitment technique and 102 overweight/obese men were successfully enrolled. Study retention remained high throughout the Gutbusters program, indicating targeted, effective recruitment, and not weight loss interest, may be the largest barrier to trial participation for overweight and obese men.

A crowdsourcing approach to understand weight and weight loss in men.

•Crowdsourcing can be used to detect unexpected barriers to male weight loss.•Some unique behaviors related to high BMI were revealed including watching others play video games.•Novel behaviors to target: less watching video games and more organized physical activity.

Multi-institutional Evaluation of Women at High Risk of Developing Breast Cancer.

INTRODUCTION: We performed the present study to better understand the practices and preferences of women with an elevated risk of breast cancer by merging the registries from 2 separate institutions and comparing the clinical characteristics and outcomes. MATERIALS AND METHODS: The data from women enrolled in institutional review board-approved registries from 2003 to 2015 at the New York University Langone Medical Center and University of Vermont Medical Center were evaluated. We compared patient characteristics, risk factors, uptake of prevention methods, and cancer rates between the 2 registries. RESULTS: A total of 1035 women were included in the present analysis. We found a 99% concordance of variables collected between the 2 registries. Significant differences were found in age, risk characteristics, uptake of prevention methods, and cancer rates between the 2 registries. The uptake of chemoprevention was low (8% for all women), with greater uptake among women with atypia found on biopsy examination (66%) than among those with a strong family history or BRCA mutations. Women with BRCA mutations accounted for 76% of those undergoing risk-reducing surgery. Of the 1035 women, 43 (4%) developed breast cancer. Of these, 86% were diagnosed with American Joint Committee on Cancer stage 0 or 1 disease, 95% with tumors < 2 cm, and 70% with poor to moderately differentiated pathologic features. Only 1 of the women who developed breast cancer had been undergoing chemoprevention, and none had undergone previous prophylactic surgery. CONCLUSION: We found a high degree of concordance between registries, suggesting no barriers exist to multi-institutional collaboration. Overall, a low uptake of prevention opportunities was found in this high-risk population. Women developing breast cancer had predominantly low-stage but higher grade disease, which might suggest a benefit to participation in surveillance (or high-risk) programs.

The Effect of Atorvastatin on Breast Cancer Biomarkers in High-Risk Women.

Statins have the potential to reduce breast cancer incidence and recurrence as shown in both epidemiologic and laboratory studies. The purpose of this study was to evaluate the effect of a lipophilic statin, atorvastatin, on breast cancer biomarkers of risk [mammographic density (MD) and insulin growth factor 1 (IGF-1)] in high-risk premenopausal women.Premenopausal women at increased risk for breast cancer received either 40 mg of atorvastatin or placebo for 1 year. Biomarker assessment was performed prior to initiation and at completion of study medication. MD was determined using both Breast Imaging Reporting and Data System and the visual analogue scale. Serum IGF-1 was determined by ELISA assay at the end of the study.Sixty-three women were enrolled between December 2005 and May 2010. Sixteen (25%) women withdrew. The mean age of participants was 43 (range, 35-50), 100% were white, and the average body mass index (BMI) was 26.4. The statin group demonstrated a significant decrease in cholesterol and low-density lipoprotein (LDL), suggesting compliance with study medication. After accounting for BMI, there was no difference in change in MD between groups. There was a significant increase in serum IGF-1 in the statin group.In this multi-institutional randomized prospective clinical trial of premenopausal women at increased risk for breast cancer, we did not see an effect of atorvastatin on MD. Further investigation of statins may be warranted; however, design of prior trials and potential mechanism of action of the agent need to be considered in the design of future trials. Cancer Prev Res; 9(5); 379-84. ©2016 AACR.

Comparison of false positive rates for screening breast magnetic resonance imaging (MRI) in high risk women performed on stacked versus alternating schedules.

PURPOSE: Breast MRI added to mammography increases screening sensitivity for high-risk women but false-positive (FP) rates are higher and the optimal screening schedule for coordination with mammography is unclear. We compare rates of FP MRI when studies were performed on two different schedules. PATIENTS AND METHODS: High-risk women at the University of Vermont who had at least 1 MRI and 1 mammogram performed within one year between 2004-2012 were eligible for inclusion in this study. Screening was considered stacked if both studies were performed within 90 days and alternating if studies were 4-8 months apart. False positive was defined in one of three ways. RESULTS: 137 women had screening which met inclusion criteria and 371 MRIs were reviewed. The FP rates were similar for the two schedules when considering BI-RAD 4, 5, 0 or biopsy as a positive test. FP rates were significantly higher for the stacked schedule (18.2 vs. 10.2%, p = 0.026) when considering BI-RADS 3-4-5-0 as positive test, due to the elevated rate of BI-RADS 3 assessments among stacked exams. CONCLUSION: False positive rates differ based on the type of exam (baseline or subsequent) and definition of positive but do not differ based on imaging schedule (stacked or alternating); suggesting that women and their providers may choose the imaging schedule they prefer. This is significant as a randomized clinical trial comparing the two schedules is not likely to be performed, given the high cost and large number of women needed for such a study.