Estrogen Deprivation and Aromatase Inhibitor associated Arthralgia

描述(由Investigator提供)：这项名为“雌激素剥夺和芳香酶抑制剂相关的关节痛”的申请寻求应用药物遗传学流行病学、适当的生物标记物和患者报告的有效结果来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)的发生、严重程度和功能干预中的作用。AIS是一类阻止雄激素转化为雌激素的药物，它抑制芳香酶，从而导致显著的雌激素消耗。接受人工智能治疗的乳腺癌患者中，近50%报告了人工智能相关关节痛(AIAA)。AIAA损害功能状态和生活质量，导致10%-20%的患者过早停止用药。AIAA的潜在机制尚不清楚，这使得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。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引起的雌激素停用可能导致疼痛敏感性的增加，从而导致AIAA的主观体验。最近，我们发现CYP19A1(编码芳香酶)的多态与患者报告的AIAA的发生有关，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、乳腺肿瘤学和护理领域的研究人员和临床医生组成的多学科团队，以解决以下目标：具体目标1：确定与雌激素途径相关的基因变异与患者报告的AIAA发生之间的关联。我们将对目前接受人工授精治疗的1,000名I-III期乳腺癌幸存者进行横断面研究，以确定特定基因变异与患者报告的关节痛结果之间的关系。具体目的2：确定雌激素水平是否介导了CYP19A1基因多态与AIAA之间的关联。为了回答这一目标，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前瞻性队列研究；我们将在人工智能治疗之前(基线)以及人工智能治疗开始后一个月、三个月和六个月跟踪他们。探索性目的：探讨AI相关雌激素剥夺在疼痛敏感性中的作用。为了实现这一目标，我们将在上述预期队列(N=100)中符合条件且同意的参与者中进行多模式感觉测试。这项拟议的研究将增加我们对AIAA潜在机制的理解。这种认识的增加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.