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

描述（由申请人提供）：使用他莫昔芬作为雌激素受体阳性（ER+）乳腺癌内分泌治疗的一线药物最近受到一类新药的挑战，芳香酶抑制剂被发现具有优于他莫昔芬的疗效，但副作用更小。另一方面，由于它的作用机制，骨质流失在这些女性中是一个可以理解的问题。关于芳香化酶抑制剂的女性骨折发生率增加的报道，有些是显著的，有些不是，这些研究不是为了调查药物对骨骼的影响而设计的。这些研究没有关于骨矿物质密度（BMD）的数据，因此，骨质流失没有得到充分的解决。先前的研究已经发现CYP19基因（编码芳香酶的基因）的某些多态性与酶活性和骨密度的差异有关。这些多态性是否影响骨骼对芳香酶抑制的反应仍未确定。我们假设芳香酶抑制剂的使用与显著的骨质流失有关，而骨质流失的程度将由CYP19基因的多态性决定。为了验证这一假设，我们建议对来自不同种族的绝经后妇女进行为期一年的纵向研究，这些妇女将开始使用芳香酶抑制剂治疗乳腺癌。患有乳腺癌但不服用芳香酶抑制剂的妇女将作为对照。我们将在基线和随访时获得骨密度测量和骨转换标记。我们还将对这些女性进行与骨密度差异相关的CYP19基因多态性的基因分型。我们将比较服用芳香化酶抑制剂的妇女与未服用该药的妇女的骨质流失率，以及所检查的不同多态性的不同变体。我们预计显著的骨质流失与芳香酶抑制剂治疗有关，但CYP19基因的某些变体对抑制尤其敏感，因此，将比其他变体经历更多的骨质流失。这项拟议研究的数据将用于制定全面的建议，目标是建立适当的方法来维持给予芳香酶抑制剂的妇女的骨骼健康。随着越来越多的乳腺癌患者存活下来，更多的人将会因旨在提高生存率的内分泌治疗而出现骨质疏松症并发症，因此，这一问题需要得到解决。

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.