Inflammatory oxylipins and aromatase inhibitor toxicity in breast cancer

项目摘要 芳香化酶抑制剂（AI）治疗可显著降低循环雌激素浓度， 5-10 10年乳腺癌死亡率降低约40%。然而，AI相关的肌肉骨骼 症状（AIMSS）影响多达一半的治疗患者，导致对治疗的依从性和依从性差， 会增加乳腺癌的复发率和死亡率。已确定的有效管理备选办法很少。 AIMSS的病因仍然知之甚少，尽管它被认为是由于，至少部分是由于雌激素 剥夺和炎症。 氧脂素脂质介质，来源于ω-3和ω-6脂肪酸，是促或抗- 炎性的，并且已经涉及炎症相关的疼痛。此外，已知雌激素 影响脂肪酸的代谢。来自AI治疗的非靶向脂质组学研究的初步数据 患者确定了多不饱和脂肪酸（PUFA）的定量差异， 发展AIMSS。基于这些数据，中心假设是作为PUFA代谢物的氧脂素， 在AIMSS的发展中发挥作用，通过雌激素剥夺诱导的氧化脂素向促氧化脂素的转变， 炎症性ω-6脂肪酸衍生代谢物。此外，遗传易感性改变活动的 参与氧脂素代谢的关键酶可能进一步影响个体发生AIMSS的风险。 患者这一假设将通过分析先前进行的临床试验的样本和数据进行检验 开始人工智能治疗的女性血浆样本、生殖系DNA和患者报告的结局将用于 研究以下具体目的：（1）研究雌激素剥夺联合AI治疗对 氧脂素谱，（2）检查AI治疗的氧脂素变化与 AIMSS，以及（3）评估与氧脂代谢相关的遗传改变和 AI治疗患者中的氧脂平代谢物模式。 通过这项机制研究，我们将了解AI治疗和雌激素剥夺对炎症反应的影响。 脂质介质，即氧脂素，及其在AIMSS发展中的作用，并可能确定AIMSS的预测因子。 AIMSS的发展。这些对AIMSS病因学的重要见解可能会导致机制- 旨在预防或治疗这种治疗后出现的毒性的干预措施。防止发展 AIMSS可以改善乳腺癌幸存者的生活质量，并可以提高AI治疗的依从性 降低乳腺癌复发率和死亡率。

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.