Abstract 1904: Randomized clinical trial testing the efficacy of the combination of omega-3-fatty acids (n-3FA) and the antiestrogen raloxifene in reducing breast density (BD) in postmenopausal women
Authors: Sandhu Narinder , Schetter Susann E. , Liao Jason , Hartman Terryl J. , Richie John P. , El-Bayoumy Karam , Prokopczyk Bogdan , DuBrock Cindy , Signori Carina , Hamilton Christopher , Demers Laurence M. , Manni Andrea 
Published: August 2015

Abstract
Our preclinical data indicate that n-3FA potentiate the chemopreventive effects of the antiestrogen (AE) Tamoxifen against mammary tumorigenesis induced by 1-methyl-1-nitrosourea in female Sprague Dawley rats.(A. Manni et al. Int. J. of Cancer 2014; 134:1549).To test the clinical impact of this approach we conducted a randomized clinical trial in healthy postmenopausal women at increased risk of breast cancer based on BD ≥ 25% detected at their routine annual screening mammogram. Out of 784 eligible subjects, 266 women were randomly assigned to one of the following groups 1) Control 2) The AE Raloxifene 60mg 3) Raloxifene 30mg 4) Lovaza 4g (the FDA approved n-3FA formulation containing EPA + DHA), 5) Lovaza 4gm plus Raloxifene 30mg. The rationale for choosing a dose of Raloxifene half the conventional dose of 60mg to be tested in combination was in the attempt to reduce toxicity while preserving antitumor action as supported by our preclinical studies with Tamoxifen (A. Manni et al. Canc. Prev. Res 2010; 3:322). The groups were comparable with regard to baseline demographics including age, BMI, parity, age at first child birth, family history of breast cancer, and history of prior breast biopsies. The duration of the intervention was 2 years and the change in breast density at year one and two was the primary endpoint. Breast density, a well established biomarker of breast cancer risk, was measured by the volumetric method using the Volpara software. Two hundred and fourteen women (∼80%) completed the trial. Compliance was excellent as assessed by pill counts (&gt;95%) and plasma fatty acid analysis using gas chromatography-flame ionization (GC-FID) detection which showed the expected rise in n-3FA levels in the groups receiving Lovaza. Toxicity was minimal with vasomotor symptoms being more frequent in the groups receiving Raloxifene (13.2% with 30mg and 22.6% with 60mg) and gastrointestinal events more frequent in the combination group. No subject experienced thromboembolic events. The combination group exhibited the most beneficial changes in lipid panel with reduction in LDL (low density lipoprotein) cholesterol, triglyceride and increase in HDL (high density lipoprotein) cholesterol. Compared to control, none of the interventions significantly affected percent or absolute breast density at either year one or two. Our results indicate that in this group of healthy postmenopausal women the combination of Lovaza and Raloxifene at less than the conventional dose (e.g. 30mg), while feasible and well tolerated did not reduce breast cancer risk as assessed by a decrease in breast density. (This work has been funded by Susan G. Komen for the Cure, KG081632).
Citation Format: Narinder Sandhu, Susann E. Schetter, Jason Liao, Terryl J. Hartman, John P. Richie, Karam El-Bayoumy, Bogdan Prokopczyk, Cindy DuBrock, Carina Signori, Christopher Hamilton, Laurence M. Demers, Andrea Manni. Randomized clinical trial testing the efficacy of the combination of omega-3-fatty acids (n-3FA) and the antiestrogen raloxifene in reducing breast density (BD) in postmenopausal women. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1904. doi:10.1158/1538-7445.AM2015-1904