Abstract P1-09-16: Randomized study of COX2 inhibition on systemic inflammation in obese and non-obese subjects

Abstract

Introduction: Obesity is associated with poor breast cancer outcomes in postmenopausal women. Our prior retrospective studies have shown that use of nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with reduced recurrence in obese breast cancer patients and a doubling of time to recurrence. Because it was recently determined that CD163+ M2 macrophages were clinically associated with fast proliferation, poor differentiation, estrogen receptor negativity and histological duct type in human primary breast tumors, the mechanism proposed was a decrease in prostaglandin E2 (PGE2) and aromatase locally in the breast with a concomitant decrease in circulating M2-activated tumor associated macrophages (TAMs). Methods: Postmenopausal women of varying body habitus were recruited at the CTRC in San Antonio and underwent randomized assignment to 1 of 3 arms: Aspirin (ASA) at 81mg daily, 1500mg of docosahexaenoic acid (DHA) and 2500mg eicosapentaenoic acid (EPA) given daily, or combined ASA and DHA/EPA. Sera were collected prior to and following 28 days of exposure, and cytokines including prostaglandin E2 were assessed via enzyme ­linked immunosorbent assay (ELISA). 28 circulating cytokines/chemokines were assessed by Luminex array using Millipore Milliplex MAP to look for associations between cytokine array profiles, PGE2 production and macrophage activation. Circulating class M-1 activated and M-2 activated macrophages were enumerated by flow cytometry to assess how PGE2 modulation influences macrophage phenotype and function. Investigators were blinded to randomization until analysis was complete. Results: A total of 122 patients were randomized with 2 drop outs and 115 completing the 28 days of intervention as planned. The median BMI was 31.4, with 12.8% normal (BMI <25.0), 27.3% overweight (25.0-29.9), and 59.9% obese (>29.9). Patients had a median age of 63 (47-76), 91% white, and 46.0 % Hispanic. A positive correlation was observed between BMI and baseline PGE2 levels. The most consistent impact on PGE2 was observed with ASA with 81% obtaining a decrease from baseline (median change -28%); by comparison 55.1% (-1%) and 65.6% (-22%) of subjects showed decrease in the DHA/EPA and combined groups respectively. As of today, full cytokine profiling was performed on a subset of 38 patients and revealed a positive correlation with change in PGE2 and cytokines: EGF, Eotaxin, GM-CSF, IL1Ra, IL5, IL8, MIP1b, and TNFa. Conclusion: Aspirin alone most consistently impacted patient circulating PGE2 levels, and will be used in planned studies as an adjunct to adjuvant endocrine therapy in obese hormone receptor positive post-menopausal patients. Full cytokine and macrophage activation status will be reported. Citation Format: Brenner AJ, Lengfelder L, Quach DK, Cavazos DA, Ramirez RJ, Gruslova A, Kist K, Lathrup K, Kaklamani V, Beeram M, deGraffenried LA. Randomized study of COX2 inhibition on systemic inflammation in obese and non-obese subjects [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 P1-09-16.