Estrogen Deprivation and Aromatase Inhibitor associated Arthralgia

雌激素剥夺和芳香酶抑制剂相关的关节痛

• 批准号: 8660047
• 负责人: JUN J MAO
• 金额: $ 45.79万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660047
• 关键词: Address; Adherence; Adjuvant Therapy; Affect; Androgens; Aromatase; Aromatase Inhibitors; Arthralgia; Basic Science; Biological Markers; Biometry; Breast; CYP19A1 gene; Cancer Patient; Cancer Survivor; Clinical; Cohort Studies; Complex; Consent; Cross-Sectional Studies; Development; Diagnosis; Early Diagnosis; Enzymes; Epidemiology; Estrogens; Etiology; Frequencies; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Grant; Individual; Intervention; Knowledge; Lead; Literature; Measurement; Measures; Mechanical Stimulation; Mediating; Menopause; Modeling; Oncologic Nursing; Oncology Nurse; Pain; Pain Research; Pain management; Participant; Pathway interactions; Patient Outcomes Assessments; Patients; Perception; Pharmaceutical Preparations; Pharmacogenetics; Postmenopause; Process; Publishing; Quality of life; Reporting; Reproductive Endocrinology; Research Personnel; Risk; Role; Sensory; Severities; Staging; Symptoms; Testing; Translations; United States; Withdrawal; Woman; Work; base; cohort; deprivation; effective intervention; effective therapy; experience; functional status; genetic epidemiology; genetic variant; malignant breast neoplasm; multidisciplinary; novel therapeutics; premature; prospective; public health relevance; symptom management

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.

描述（由研究者提供）：本申请题为“雌激素剥夺和芳香酶抑制剂相关关节痛”，旨在应用药物遗传学流行病学、适当的生物标志物和经过验证的患者报告结果来定义雌激素剥夺在关节痛（关节痛）发生中的作用接受芳香酶抑制剂（AI）作为早期辅助治疗的绝经后妇女的症状、严重程度和功能干扰 乳腺癌。 AI 是一类阻止雄激素转化为雌激素并抑制芳香酶的药物，从而导致雌激素显着消耗。近 50% 服用 AI 的乳腺癌患者报告有 AI 相关关节痛 (AIAA)。 AIAA 会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，因此很难识别有出现此类症状风险的个人，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 AI 引起的雌激素戒断可能会导致疼痛敏感性增加，从而导致 AIAA 的主观体验。最近，我们发现了 CYP19A1（编码芳香酶）的多态性与患者报告的 AIAA 发生相关，证明编码雌激素途径某些酶的基因的遗传变异可以预测 AIAA 的风险。为了扩展这项工作，我们将汇集疼痛和症状管理、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多学科研究人员和临床医生团队，以实现以下目标： 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。我们将对 1,000 名目前正在接受 AI 的 I-III 期乳腺癌幸存者进行一项横断面研究，以确定特定遗传变异与患者报告的关节痛结果之间的关系。具体目标 2：确定雌激素水平是否介导 CYP19A1 基因多态性与 AIAA 之间的关联。为了实现这一目标，我们将对 450 名即将开始 AI 的乳腺癌患者进行一项前瞻性队列研究；我们将在 AI 之前（基线）以及开始 AI 治疗后 1、3 和 6 个月进行跟踪。探索性目标：探讨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，我们将对来自上述前瞻性队列（N=100）的合格且同意的参与者子集进行多模式感官测试。拟议的研究将增加我们对 AIAA 背后机制的理解。这种了解的加深将有助于针对影响数十万乳腺癌患者的这一重要问题开发和转化新的治疗方法和预防策略。