Inflammatory oxylipins and aromatase inhibitor toxicity in breast cancer

点击翻译按钮获取中文摘要

PROJECT SUMMARY Treatment with an aromatase inhibitor (AI), which significantly decreases circulating estrogen concentrations, for 5-10 years reduces 10 year breast cancer mortality by about 40%. However, AI-associated musculoskeletal symptoms (AIMSS) affect up to half of treated patients, cause poor adherence and compliance with therapy, and can increase breast cancer recurrence and mortality. Few effective management options have been identified. The etiology of AIMSS remains poorly understood, although it is thought to be due, at least in part, to estrogen deprivation and inflammation. The oxylipin lipid mediators, which are derived from omega-3 and omega-6 fatty acids, are pro- or anti- inflammatory, and have been implicated in inflammation-related pain. In addition, estrogens are known to influence the metabolism of fatty acids. Preliminary data from an untargeted lipidomics study of AI-treated patients identified quantitative differences in polyunsaturated fatty acids (PUFA) in patients who did and did not develop AIMSS. Based on these data, the central hypothesis is oxylipins, which are metabolites of PUFA, may play a role in the development of AIMSS, through an estrogen deprivation-induced shift in oxylipins to pro- inflammatory omega-6 fatty acid-derived metabolites. In addition, genetic predisposition to altered activity of the key enzymes involved in oxylipin metabolism could further influence the risk of developing AIMSS in individual patients. This hypothesis will be tested by analyzing samples and data from a previously conducted clinical trial of women starting AI therapy. Plasma samples, germline DNA, and patient-reported outcomes will be used to investigate the following Specific Aims: (1) to investigate the effect of estrogen deprivation with AI therapy on oxylipin profiles, (2) to examine associations between change in oxylipins with AI therapy and development of AIMSS, and (3) to evaluate associations between genetic alterations related to metabolism of oxylipins and patterns of oxylipin metabolites in AI-treated patients. Through this mechanistic study we will learn the impact of AI therapy and estrogen deprivation on inflammatory lipid mediators, namely oxylipins, and their role in the development of AIMSS, and may identify predictors of development of AIMSS. These important insights into the etiology of AIMSS can potentially lead to mechanism- based interventions designed to prevent or treat this treatment-emergent toxicity. Preventing the development of AIMSS can improve quality of life for breast cancer survivors, and could increase compliance with AI therapy and reduce breast cancer recurrence and mortality.