AROMATASE INHIBITORS: SKELETAL EFFECTS AND THE ROLE OF CYP19 GENE POLYMORPHISMS

芳香酶抑制剂：骨骼效应和 CYP19 基因多态性的作用

基本信息

批准号：
7267973
负责人：
REINA C VILLAREAL
金额：
$ 16.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7267973
关键词：
Acute Address Adjuvant Therapy Adrenal Glands Adverse effects Age-Related Bone Loss Alleles Anabolism Androgens Androstenedione Aromatase Aromatase Inhibition Aromatase Inhibitors Bone Density Breast Cancer Prevention CYP19A1 gene Chronic Class Coagulation Process Code Conflict (Psychology)Data Development Diagnosis Disease Disease-Free Survival Endometrial Carcinoma Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Estradiol Estrogen receptor negative Estrogen receptor positive Estrogens Estrone Ethnic group Exemestane Exhibits Failure Fracture Generations Genes Genetic Polymorphism Genetic Variation Genotype Goals Hand High Prevalence Incidence Lead Letrozole Longitudinal Studies Marketing Measurement Menopause Neck Normal tissue morphology Numbers Osteoporosis Ovarian Ovariectomy Pathway interactions Patients Pharmaceutical Preparations Pilot Projects Postmenopause Predisposition Production Rate Rattus Reporting Research Research Personnel Risk Role Route Serum Skeletal system Source Staging System Tamoxifen Testing Thromboembolism Time Total Estrogen Blockade Uterus Variant Woman anastrozole base bone health bone loss bone metabolism bone turnover clinically significant design enzyme activity experience follow-up hormone therapy improved malignant breast neoplasm prevent programs response sex trend

项目摘要

DESCRIPTION (provided by applicant): The use of tamoxifen as the first line agent for endocrine therapy of estrogen receptor positive (ER+) breast cancer has recently been challenged by a newer class drugs, the aromatase inhibitors, which are found to have superior efficacy over tamoxifen with better side-effect profile. On the other hand, because of it's mechanism of action, bone loss is understandably a concern among these women. Reports of an increased incidence of fractures in women on aromatase inhibitors, a few were significant and some not, came from studies that were not designed to investigate the skeletal effects of the drug. No data on bone mineral density (BMD) were available from these studies, thus, bone loss was not adequately addressed. Previous studies have identified certain polymorhisms of the CYP19 gene (the gene that codes for the aromatase enzyme) to be associated with differences in enzymatic activity and BMD. Whether these polymorphisms influence the skeletal response to aromatase inhibition remains undetermined. We hypothesize that the use of aromatase inhibitors is associated with significant bone loss, and the degree of bone loss will be determined by polymorphisms of the CYP19 gene. To test this hypothesis we propose to do a one-year longitudinal study of postmenopausal women from different ethnic groups who will be initiated on aromatase inhibitors for breast cancer. Women with breast cancer but will not be put on aromatase inhibitors will serve as controls. We will obtain BMD measurements and markers bone turnover at baseline and on follow-up. We will also genotype these women for CYP19 gene polymorphisms associated with differences BMD. We will compare the rates of bone loss in women on aromatase inhibitors versus those not taking the drug, and also among the different variants of the different polymorphisms examined. We anticipate that significant bone loss is associated with aromatase inhibitor therapy and but certain variants of the CYP19 gene are especially more sensitive to inhibition, thus, will be experiencing more bone loss than others. The data generated from this proposed study will be used to develop a full-scale proposal with the goal of establishing the appropriate approach to maintaining bone health in women given aromatase inhibitors. As more patients are surviving breast cancer, more will be expected to experience osteoporotic complications from endocrine therapies intended to improve survival, thus, this issue needs to be addressed.

描述（由申请人提供）：他莫昔芬用作雌激素受体阳性（ER+）乳腺癌内分泌治疗的第一线药物最近受到了一种较新的类药物，即芳香酶抑制剂的挑战，芳香酶抑制剂，发现与副效率更好的副氧化剂相比具有优于他莫昔芬的功效。另一方面，由于行动机制，骨质流失是可以理解的，这些女性是一个关注的问题。关于芳香酶抑制剂女性骨折发病率增加的报道，其中一些是重要的，有些不是来自旨在研究该药物的骨骼作用的研究。这些研究没有提供有关骨矿物质密度（BMD）的数据，因此，骨质流失没有充分解决。先前的研究已经确定了CYP19基因（编码芳香酶酶的基因）的某些多词与酶活性和BMD的差异相关。这些多态性是否影响对芳香酶抑制的骨骼反应仍然不确定。我们假设使用芳香酶抑制剂与明显的骨质流失有关，骨质流失程度将由CYP19基因的多态性确定。为了检验这一假设，我们建议对来自不同种族的绝经后妇女进行一年的纵向研究，这些妇女将以用于乳腺癌的芳香酶抑制剂开始。患有乳腺癌的妇女，但不会将其放在芳香酶抑制剂上。我们将在基线和随访时获得BMD测量值，并标记骨转换。我们还将基因型这些女性用于与BMD差异相关的CYP19基因多态性。我们将比较女性在芳香酶抑制剂上的骨质流失率与未服用药物的骨骼抑制剂的率，以及所检查的不同多态性的不同变体中的骨质流失率。我们预计明显的骨质流失与芳香酶抑制剂疗法有关，但是CYP19基因的某些变体对抑制特别敏感，因此，骨质流失将比其他抑制更大。这项拟议的研究产生的数据将用于制定一项全尺度建议，目的是建立适当的方法来维持芳香酶抑制剂的女性骨骼健康。随着越来越多的患者生存的乳腺癌，预计旨在提高生存率的内分泌疗法会经历骨质疏松并发症，因此，需要解决此问题。