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; 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（调查人员提供）：此申请标题为“雌激素剥夺和芳香酶抑制剂相关的关节痛”，试图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的结果来定义雌激素剥夺在Arthralgia（关节疼痛）中的er症的作用，并且在Arthralgia（关节疼痛）中发生了性，并且在Arthralgia（关节疼痛）中发生了性，这是造成的。抑制剂（AIS）作为早期乳腺癌的辅助治疗。 AIS是一类药物，可阻止雄激素向雌激素酶的雌激素的转化，从而导致明显的雌激素消耗。服用AIS的乳腺癌患者中，有将近50％的患者报告了AI相关的关节痛（AIAA）。 AIAA会损害功能状况和生活质量，从而导致10-20％患者中性药物停用过早。 AIAA背后的机制尚不清楚，因此很难确定有可能出现此类症状的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AIS引起的雌激素戒断可能会导致疼痛敏感性的增加，从而导致AIAA的主观经验。最近，我们已经确定了与患者报告的AIAA发生有关的CYP19A1（编码芳香酶）中的多态性，这表明编码雌激素途径某些酶的基因的遗传变异可能会预测AIAA风险。为了扩展这项工作，我们将召集一个多学科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，乳房肿瘤学和护理方面的综合团队，以解决以下目的：特定目的1：确定与雌激素途径与患者相关的遗传变体与患者相关的遗传变体和遗传变体之间的关联。我们将对目前接受AIS的1,000阶段I-III乳腺癌幸存者进行横断面研究，以确定特定遗传变异和患者报告的亚氏痛结局之间的关系。具体目的2：确定雌激素水平是否介导了CYP19A1遗传多态性和AIAA之间的关联。为了回答这一目标，我们将对启动AIS的450名乳腺癌患者进行一项前瞻性队列研究。我们将在AI（基线）之前以及AI治疗开始后的一个，三个月和六个月之前跟随它们。探索目的：探索与AI相关的雌激素缺乏在疼痛敏感性中的作用。为了回答这个目标，我们将在上述前瞻性队列的合格和同意参与者的子集中进行多模式的感觉测试（n = 100）。拟议的研究将提高我们对AIAA基础机制的理解。这种提高的理解将促进新的治疗剂和预防策略的发展和翻译，以影响数十万乳腺癌患者的这一重要问题。