Abstract PD3-09: Sulindac reduces breast density and alters collagen alignment in patients on aromatase inhibitors
Authors: Thompson Patricia , Huang Chuan , Wertheim Betsy , Preece Christina , Yang Jie , Martinez Jessica , Roe Denise , Chalasani Pavani , Stopeck Alison 
Published: March 2020

Abstract
Background. Preclinical and observational evidence supports cancer prevention activity of non-steroidal anti-inflammatory drugs (NSAIDs) in the breast via suppression of prostaglandin E2 (PGE2) synthesis by cyclooxygenase-2 (COX2). Evidence includes linking of PGE2 to aromatase activity and estrogen synthesis in breast adipose tissue, as well as effects on collagen and breast density (BD). Methods. In an open-label trial, we evaluated the effect of the non-selective NSAID sulindac at 150 mg bid for 12 months on BD in 52 postmenopausal women taking adjuvant aromatase inhibitors (AIs) for breast cancer. BD was measured using a fat-water decomposition MRI based BD measure (MRD) previously shown to be more quantitative than mammographic density. A non-randomized observation cohort of 46 postmenopausal women on AI without NSAID use was conducted in parallel to assess the effect of AI on MRD over 12 months. Eligible participants were recruited at two study sites and included women with an intact, unaffected contralateral breast and BI-RADS ≥ 2. Each subject’s MRI_BD measures at baseline and at 6 and 12 months were included in linear mixed models for longitudinal data. Log-transformation was applied to the outcome of BD. Covariates included log-transformed baseline BD, time on AI, and baseline body mass index (BMI) and change in BMI. Breast tissue collagen fiber alignment for 30 women with paired breast biopsies, before and after 6 months on sulindac, was examined using Second-Harmonic Generation (SHG) microscopy and analysis of the distribution (histogram) of ‘straight’ fibers in three randomly selected areas of breast tissue. Straightness of individual fibers was calculated as the linear length of a fiber divided by the distance along the fiber. Results. Participants on sulindac intervention had a significant change in BD relative to baseline BD at 6 (p=0.05) and 12 months (p&lt;0.001). After adjusting for time on AI, baseline BMI and BMI change, the relative change in BD at 12 months from baseline BD was 10% lower (95% CI; -14.4, -5.4%) for women on sulindac. For the AI only group, no significant change from baseline BD was observed at 6 (p=0.50) or 12 months (p=0.17). The relative change in BD for the AI only group at 12 months was -3.5% (95% CI; -8.3, +1.6%). For women with baseline MRD_BD of ≥ 25%, the relative decrease in BD from baseline in the sulindac group was greater, at -16.3% (95% CI, -25.4, -6.2%). In contrast, there was no evidence for baseline BD effect on change in BD at 12 months in the AI only group whose baseline BD was ≥25% [-3.3% change at 12 mo (95% CI; -12.7, +7.1%)]. Exploratory analyses of collagen fiber alignment in the sulindac group at 6 months showed a significant decrease in straight collagen fibers (p=0.01). The decrease in collagen straightness correlated with a decrease in BD (rho=0.66, p=0.01). Conclusions. Twice daily 150 mg sulindac for 12 months in postmenopausal women on AIs was associated with a significant decrease in BD using MRD that was slightly higher for women with higher baseline BD. At the tissue level, the decrease in BD was associated with change in collagen straightness. No decrease in BD was observed in a non-randomized population of postmenopausal women on AI only therapy. These results suggest that sulindac decreases BD and may do so through effects on collagen alignment. Further investigation of sulindac for effects on BD, including synergy with AIs, for breast cancer prevention is indicated.
Citation Format: Patricia Thompson, Chuan Huang, Betsy Wertheim, Christina Preece, Jie Yang, Jessica Martinez, Denise Roe, Pavani Chalasani, Alison Stopeck. Sulindac reduces breast density and alters collagen alignment in patients on aromatase inhibitors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-09.