The Impact of Omega-3 Fatty Acid Supplementation on Obesity-induced Inflammatory Signaling within in the Breast Tumor Microenvironnment. Obesity is associated with a worsened prognosis in breast cancer. This is in part due to the role of prostaglandin E2 (PGE2) in the obesity-inflammation-aromatase axis. Omega-3 polyunsaturated fatty acids (PUFAs) have demonstrated anti-cancer effects through multiple pathways, including suppression of the pro-inflammatory COX2-PGE2 pathway. In order to determine if supplementation with omega-3 fatty acids can effectively suppress PGE2 production in obese postmenopausal women, we conducted a 30 day non-interventional study with correlative biomarker endpoints. Forty (40) postmenopausal women were provided oral daily supplements of 1500mg of docosahexaoic acid (DHA) and 2500mg eicosapentanoic acid (EPA). Serum samples were collected prior to and on day 29 of taking the supplement and analyzed for PGE2 levels. Fifty-five percent (55%) of the subjects demonstrated a significant suppression of PGE2 levels. To test if response could be based upon the ratio of omega-6 to omega-3 fatty acids on inflammatory signaling within the breast, pre-clinical studies were performed on different cell types found in the tumor microenvironment. Macrophages, breast cancer epithelial cells and pre-adipocytes were exposed to omega-6 and omega-3 fatty acids at ratios of 46:1, 20:1, 10:1 and 1.3:1 for 24 hours. While breast cancer epithelial cells demonstrated limited response to PUFA concentrations, the macrophage and adipocyte cells produced high levels of PGE2 when exposed to higher ratios of omega-6 fatty acids, which was effectively suppressed in a dose-dependent manner with increasing levels of omega-3 fatty acids. These data suggest that obese breast cancer patients may have a particular benefit to omega-3 fatty acid supplementation. Ongoing studies will assess how PUFA-modulated changes in inflammatory signaling from different cells within the microenvironment impact breast cancer cell proliferation, therapeutic resistance, and migration as measures of breast cancer progression. These mechanistic studies, in combination with our on-going NCI-funded prospective clinical study in newly diagnosed breast cancer patients, will significantly contribute to understanding how ratios of omega-6 to omega-3 fatty acids can modulate inflammatory signaling within the tumor microenvironment, and if this can be used to improve therapeutic response in the obese breast cancer population. Citation Format: Duan K. Quach, Brittany Harlow, Laura Winikka, Andrew Brenner, Murali Beeram, Stefano Tiziani, Lucy Lengfelder, Gloria Galvan, Christopher Jolly, Linda deGraffenried. The impact of omega-3 fatty acid supplementation on obesity-induced inflammatory signaling within the breast tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 233. doi:10.1158/1538-7445.AM2017-233
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.
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.
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.
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