This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Based on the results of recently reported, prospective randomized clinical trials, aromatase inhibitors (AI) are being increasingly used in the adjuvant setting for patients with newly diagnosed breast cancer (1),(2),(3). Although all of these agents inhibit aromatase activity, they differ fundamentally in their chemical structure and mechanism of enzymatic activity. Specifically, exemestane is a steroidal, 'suicide' inhibitor, while letrozole and anastrozole are nonsteroidal imidazole and triazole inhibitors. Therefore, one might postulate that these agents might differ in both their anti-cancer effect and in their toxicities. Since the benefits of the studied aromatase inhibitors over tamoxifen appear modest, decisions about which class of drugs to use in the treatment of post-menopausal women with breast cancer would benefit from predictive information about either class of drugs or individual agents. In 2000, we developed a consortium, funded by the National Institutes of Health, to study the pharmacogenomics of tamoxifen therapy for breast cancer. This consortium, made up of investigators from the Indiana University School of Medicine, Johns Hopkins/Sidney Kimmel Comprehensive Cancer Center, and the University of Michigan Comprehensive Cancer Center, has prospectively enrolled over 200 women who are starting adjuvant tamoxifen therapy to a pharmacogenetics study with multiple endpoints. These women have agreed to pharmacogenetic testing, serial pharmacokinetic analysis, and monitoring for estrogenic and anti-estrogenic endpoints, such as hot flashes, serum lipid profiles, and bone density. These studies have resulted in the identification of an important anti-estrogenic tamoxifen metabolite, endoxifen, which is present in 5 fold higher abundance than the known anti-estrogenic metabolite, 4-hydroxy tamoxifen (4). We have shown that endoxifen concentration is dependent on cytochrome P450 2D6 (CYP2D6) genotype, and is reduced by co-administration of potent CYP2D6 inhibitors, such as paroxetine and fluoxetine but not by selective serotonin reuptake inhibitors (SSRI) antidepressants that are weak inhibitors of CYP2D6, such as sertraline and venlafaxine (5). In addition, studies of the relationship between serum lipid profiles and estrogen receptor genotype have allowed us to identify a pattern of genetic variants that identify a group of women most likely to experience improved lipid profiles benefit during tamoxifen treatment. We now propose to perform similar studies of women who will take an aromatase inhibitor in the adjuvant setting. We will conduct a prospective clinical trial in which women for whom an AI is appropriate ('up-front', or after 2-5 years of tamoxifen) will be randomly assigned to letrozole or exemestane. Baseline pharmacogenetic testing will be performed, and then detailed, serial evaluation of drug concentrations, estrogen metabolite concentrations, hot flashes, serum lipid levels, and breast density and bone density levels will be monitored over 2 years. Breast cancer outcome will not be the primary objective of this study. Rather, estimates of estrogenic activity and other potential toxicities will be correlated with pharmacogenomic and pharmacokinetic results. This study will follow our current model, in which we perform intense genetic and phenotypic characterization of a relatively small group of patients, with the eventual goal of extending these studies to the larger trials in which breast cancer recurrence is the primary outcome measure, carried out by the multi-institutional cooperative groups.
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