Estrogen Deprivation and Aromatase Inhibitor associated Arthralgia

描述（由研究者提供）：这项题为“雌激素剥夺和芳香酶抑制剂相关的关节痛”的申请，旨在应用药物遗传流行病学、适当的生物标志物和经过验证的患者报告的结果，以确定雌激素剥夺在接受芳香酶抑制剂（AIs）作为早期乳腺癌辅助治疗的绝经后妇女关节痛（关节痛）发生、严重程度和功能干扰中的作用。AIs是一类阻断雄激素向雌激素转化的药物，抑制芳香化酶，从而导致雌激素明显耗竭。近50%服用ai的乳腺癌患者报告ai相关关节痛（AIAA）。AIAA损害功能状态和生活质量，导致10- 20%的患者过早停药。AIAA的潜在机制尚不清楚，因此难以确定有出现此类症状风险的个体，并妨碍了制定有效干预措施的努力。AIAA的病因可能是复杂的。根据基础科学文献、临床经验和我们的初步结果，我们假设AIs诱导的雌激素戒断可能导致疼痛敏感性增加，从而导致AIAA的主观体验。最近，我们发现CYP19A1（编码芳香化酶）的多态性与患者报告的AIAA发生相关，表明编码雌激素途径某些酶的基因的遗传变异可能预测AIAA的风险。为了扩展这项工作，我们将汇集一个由疼痛和症状管理、遗传流行病学和生物统计学、生殖内分泌学、乳腺肿瘤学和护理学方面的研究人员和临床医生组成的多学科团队，以实现以下目标：具体目标1：确定与雌激素途径相关的遗传变异与患者报告的AIAA发生之间的关联。我们将对1000名目前接受人工智能治疗的I-III期乳腺癌幸存者进行一项横断面研究，以确定特定基因变异与患者报告的关节痛结局之间的关系。特异性目的2：确定雌激素水平是否介导CYP19A1基因多态性与AIAA之间的关系。为了回答这个问题，我们将在450名即将开始人工智能治疗的乳腺癌患者中进行一项前瞻性队列研究；我们将在人工智能治疗开始前（基线）以及人工智能治疗开始后的1个月、3个月和6个月对他们进行跟踪。探索目的：探讨人工智能相关雌激素剥夺在疼痛敏感性中的作用。为了回答这个问题，我们将从上述前瞻性队列中选取符合条件且同意的参与者（N=100）进行多模态感官测试。这项拟议的研究将增加我们对AIAA潜在机制的理解。这种加深的了解将有助于开发和转化新的治疗方法和预防策略，以解决这一影响数十万乳腺癌患者的重要问题。

DESCRIPTION (provided by Investigator): This application entitled, "Estrogen deprivation and Aromatase Inhibitor associated Arthralgia," seeks to apply pharmacogenetic epidemiology, appropriate biomarkers, and validated patient-reported outcomes to define the role of estrogen deprivation in arthralgia (joint pain) occurrence, severity, and functional interference among postmenopausal women receiving aromatase inhibitors (AIs) as adjuvant therapy for early stage breast cancer. AIs are a class of medications that block the conversion of androgens to estrogens inhibiting aromatase enzyme, thereby resulting in significant estrogen depletion. Nearly 50 percent of breast cancer patients taking AIs report AI-associated arthralgia (AIAA). AIAA impairs functional status and quality of life, leading to premature medication discontinuation in 10-20percent of patients. The mechanisms underlying AIAA are not well understood, making it difficult to identify individuals at risk for developing such symptoms and hampering efforts to devise effective interventions. The etiology of AIAA is likely to be complex. Based upon basic science literature, clinical experience, and our preliminary results, we hypothesize that estrogen withdrawal induced by AIs may result in an increase in pain sensitivity, leading to the subjective experience of AIAA. Recently, we have identified polymorphisms in CYP19A1 (encoding the aromatase enzyme) that were associated with patient-reported AIAA occurrence, demonstrating that genetic variations in the genes encoding certain enzymes of the estrogen pathways may predict the risk of AIAA. To extend this work, we will bring together a multidisciplinary team of researchers and clinicians in pain and symptom management, genetic epidemiology and biostatistics, reproductive endocrinology, breast oncology, and nursing to address the following aims: Specific Aim 1: To determine the associations between genetic variants related to estrogen pathways and patient-reported AIAA occurrence. We will conduct a cross-sectional study of 1,000 stage I-III breast cancer survivors currently receiving AIs to determine relationships between specific genetic variants and patient-reported outcomes of arthralgia. Specific Aim 2: To determine whether estrogen levels mediate the association between CYP19A1 genetic polymorphism and AIAA. To answer this aim, we will conduct a prospective cohort study among 450 breast cancer patients who are due to initiate AIs; we will follow them before AIs (Baseline), and at one, three, and six months after initiation of AI therapy. Exploratory Aim: To explore the role of AI-related estrogen deprivation in pain sensitivity. To answer this aim, we will perform multimodal sensory testing in a subset of eligible and consenting participants from the above prospective cohort (N=100). The proposed study will increase our understanding of the mechanisms underlying AIAA. This increased understanding will facilitate the development and translation of new therapeutics and preventative strategies for this important problem affecting hundreds of thousands of breast cancer patients.