Abstract P3-14-12: Phase 0 study evaluating COX2 inhibition on circulating PGE2 levels from obese subjects

Abstract

Introduction: Obesity is associated with poor breast cancer outcomes in postmenopausal women in response to aromatase inhibitor therapy. Our prior studies have shown an association between reduced recurrence rate and use of cyclooxygenase-2 (COX-2) inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) in obese breast cancer patients. The mechanism proposed was a decrease in prostaglandin E2 (PGE2) and reduced activation of the aromatase promote locally in the breast. Methods: Postmenopausal women of varying body habitus were recruited at the CTRC in San Antonio and underwent randomized assignment to 1 of 3 arms: ASA 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 immunosorbant assay (ELISA). Conditioned media was generated by exposing macrophages to patient sera in order to see if the patient sera induced PGE2 concentration in vitro. Results: Thirty of the planned 120 subjects have completed assessment. No toxicity has been noted. In 71% of the patients, serum PGE2 levels decreased, but only 60% demonstrated concurrent decrease in serum PGE2 levels as well as macrophage PGE2 production, while almost all (88%) of the patients whose serum did not demonstrate a decrease in PGE2 levels also demonstrated no decrease in induced levels. Conclusion: NSAIDs appear to effectively decrease circulating levels of PGE2 in most obese women. However, one third of the subjects did not demonstrate concurrent suppression of induced PGE2 from macrophages. These data suggest that circulating levels of PGE2 may not be reflective of local tumor microenvironment levels, and other pro-inflammatory circulating factors may be responsible for regulating local inflammatory responses. Final analysis will be completed and presented at the SABCS meeting. Citation Format: Lengfelder L, Brenner A, Bowers L, Apte S, Galván G, Kist K, deGraffenried L. Phase 0 study evaluating COX2 inhibition on circulating PGE2 levels from obese subjects. [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 P3-14-12.