Abstract P3-10-02: Differential response of inflammatory cytokines to omega-3 fatty acid supplementation based on menopausal status

Background: High dose marine omega-3 fatty acid supplementation is currently undergoing assessment in early phase primary prevention trials. A potential mechanism of action is thought to be inflammation resolution. Since post-menopausal women may have higher systemic levels of pro-inflammatory cytokines, and hormones may affect response to fatty acids, we conducted two parallel pilot trials of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as Lovaza® supplementation in women at high risk for development of breast cancer. This post-hoc analysis examines whether five cytokines involved in inflammatory processes (HGF, MCP-1, NGF, PAI-1, TNF-alpha) are impacted by menopausal status. Methods: Separate trials were conducted in pre-menopausal (N=36) or post-menopausal (N=35) women. Blood (fasting) and benign breast tissue (non-fasting, sampled by random periareolar fine needle aspiration) was acquired before and after intervention with 4 g Lovaza® daily for 6 months. In addition to standard risk and response biomarkers, panels of cytokines associated with inflammatory processes were assayed by Luminex® technology: HGF, insulin, MCP-1, NGF, PAI-1, resistin, TNF-alpha. For breast tissue, values were normalized to protein content. Results: Thirty-four women in each trial completed the intervention and provided pre-study and post-study specimens. At baseline, higher values for post-menopausal compared to pre-menopausal women were observed for serum levels of MCP-1 (p=0.002, non-parametric Mann-Whitney test), PAI-1 (p=0.001), and TNF-alpha (p=0.019). The same was observed for off-study specimens. There was no statistically significant (non-parametric Wilcoxon signed rank test) effect of the intervention in either cohort for MCP-1 or PAI-1. However, for TNF-alpha, while there was no modulation observed in pre-menopausal women, there was a modest decrease (medians of 3.7 to 3.4 pg/ml; p=0.016) for post-menopausal women. An effect on TNF-alpha would not have been detected if the two cohorts had been combined. For breast tissue, higher values for post-menopausal women at baseline were observed for HGF (p=0.029), MCP-1 (p=0.013), NGF (p=0.001), and TNF-alpha (p=0.001), but not PAI-1 (p=0.79). Off-study values were also typically higher in post-menopausal women. As with serum levels, there was a significant decrease in TNF-alpha values over the course of the study (p=0.042) in post-menopausal women but not pre-menopausal women. A decrease was also observed for HGF (p=0.002) and MCP-1 (p=0.001) for post-menopausal women but not pre-menopausal women. Conclusion: This post-analysis suggests caution when admixing pre-menopausal and post-menopausal women in small clinical trials of omega-3 fatty acid supplementation, especially when assessing biomarkers of inflammatory processes. For trials with both, sufficient subjects should be enrolled that stratification prior to randomization is possible. Citation Format: Kimler BF, Fabian CJ. Differential response of inflammatory cytokines to omega-3 fatty acid supplementation based on menopausal status. [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 P3-10-02.