Estrogen Deprivation and Aromatase Inhibitor associated Arthralgia

描述（研究者提供）：本申请题为“雌激素缺乏和芳香化酶抑制剂相关的关节痛”，旨在应用药物遗传学流行病学、适当的生物标志物和经验证的患者报告结果来定义雌激素缺乏在关节痛中的作用（关节疼痛）发生率、严重程度，以及接受芳香化酶抑制剂（AIs）作为早期乳腺癌辅助治疗的绝经后妇女的功能干扰。AI是一类阻断雄激素转化为雌激素抑制芳香酶的药物，从而导致显著的雌激素耗竭。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的基本机制尚不清楚，因此很难确定有可能出现此类症状的个人，并阻碍了制定有效干预措施的努力。AIAA的病因可能很复杂。基于基础科学文献、临床经验和我们的初步结果，我们假设AI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CYP 19 A1（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，我们将汇集一个多学科团队的研究人员和临床医生在疼痛和症状管理，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，以解决以下目标：具体目标1：确定与雌激素途径和患者报告的AIAA发生相关的遗传变异之间的关联。我们将对1,000名目前接受AI的I-III期乳腺癌幸存者进行横断面研究，以确定特定遗传变异与患者报告的关节痛结局之间的关系。具体目标2：确定雌激素水平是否介导CYP 19 A1基因多态性和AIAA之间的关联。为了实现这一目标，我们将在450名即将开始AI的乳腺癌患者中进行一项前瞻性队列研究;我们将在AI前（基线）以及AI治疗开始后1个月、3个月和6个月对他们进行随访。探索性目的：探索人工智能相关的雌激素剥夺在疼痛敏感性中的作用。为了实现这一目标，我们将在上述前瞻性队列（N=100）的合格和知情同意的参与者子集中进行多模式感觉测试。这项研究将增加我们对AIAA机制的理解。这种增加的理解将促进新的治疗和预防策略的开发和翻译，以解决影响数十万乳腺癌患者的这一重要问题。

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.