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

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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.