Abstract P6-17-03: The importance of the ultimate ratio of Omega-6 to Omega-3 fatty acids in the efficacy of fish oil supplements in suppressing inflammation in obese postmenopausal women

Abstract

Over the last decade, a large body of evidence has established that obesity is associated with a worse breast cancer prognosis for both pre- and postmenopausal women. There are several mechanisms which have been proposed for promoting this effect, including stage of diagnosis and co-morbidities, but more recent evidence suggests that the obese state is associated with changes in the biology of the disease, promoting a more aggressive phenotype. Our recently published in vitro and retrospective studies suggest that this is due, at least in part, through cyclooxygenase 2 (COX-2)-derived prostaglandin E2 (PGE2), and that interventions that suppress COX-2 PGE2 production may provide significant benefit for the obese ER+ patient in preventing many of the cancer-promoting effects associated with obesity. Omega-3 fatty acids have demonstrated anti-cancer benefit through multiple mechanisms, including suppression of inflammation-related signaling. DHA and EPA (omega-3 PUFAs found in fish oil) modulate inflammatory responses through COX-2 dependent and independent mechanisms. However, previous studies investigating the potential anti-cancer benefit of omega-3 PUFA and fish oil supplementation have produced mixed results, and none have focused specifically on the obese patient population. To determine if supplementation with non-steroidal anti-inflammatory drugs (NSAIDs), including omega-3 fatty acids, can effectively suppress PGE2 production in the obese postmenopausal patient, we conducted a double-blind, prospective Phase 0, comparative, 30 day, non-interventional study with correlative biomarker endpoints. One hundred twenty (120) postmenopausal women without breast cancer were randomized to three arms 1. ASA 81mg po daily, 2. 1500mg of docosahexaoic acid (DHA) and 2500mg eicosapentanoic acid (EPA) given daily and 3. Combined ASA and DHA/EPA at above doses. Serum samples were collected prior to and on day 29 of taking the supplements. PGE2 levels in the pre- and post-supplement serum samples were analyzed in triplicate by ELISA and presented as the percentage of change between post- and pre-supplement levels. Of the women in Arm 2 (DHA + EPA only), only 55% demonstrated a significant suppression of PGE2 levels after 30 day of supplements, compared to those in Arm 1 (ASA), in which 80% demonstrated a significant response. We anticipate that the omega-3 fatty acid supplements were not as effective in as large a population as the aspirin due to a failure to reach a critical ratio between circulating levels omega-6 and omega-3 fatty acids, which has been shown by our own group and others to be a key determinant of cellular response. Studies are on-going to analyze the PUFA levels in both the pre and post supplement serum samples, and pre-clinical studies are being conducted to determine if the ratio of omega-6 to omega-3 PUFAs modulates PGE2 production in several different cell types, including macrophages, adipocytes and the breast cell itself. These results will be critical for moving clinical studies utilizing these agents forward, both in terms of elucidating the mechanism mediating an effect, and also in identifying an accurate biomarker for monitoring compliance and response. Citation Format: Quach D, Lengfelder L, Winnika L, Harlow B, Galvan G, Jolly C, Brenner A, deGraffenried L. The importance of the ultimate ratio of Omega-6 to Omega-3 fatty acids in the efficacy of fish oil supplements in suppressing inflammation in obese postmenopausal women [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 P6-17-03.