METABOLIC PROFILE OF TAMOXIFEN WITH PHARMACOGENETIC PREDICTORS & CLINICAL EFFECT

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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. Tamoxifen is a selective estrogen receptor modulator (SERM) prescribed to many women worldwide. Tamoxifen is used for the treatment of metastatic breast cancer and, more often, as adjuvant therapy for primary breast cancer. In addition, the drug has been recently approved by the FDA for reduction of breast cancer incidence in women whoa re at a high risk for developing the disease. It is known that women who are treated with tamoxifen experience other benefits that include potential improvement in bone mineral density and lipid profile. Changes in coagulation factor profile are also noted. Adverse effects of Tamoxifen therapy include hot flashes and a small increase in the incidence of endometrial cancer. The pathophysiology of hot flashes is not well understood. Due to a global change in the thermoregulatory set point in the hypothalamus. Then, as a result of a trigger, a woman may suffer hot flashes. However, the relationship between a decrease in estrogen, other hormones, and neurotransmitters, is poorly understood. In addition, factors that predispose individual women to hot flashes are only partially established. Tamoxifen is extensively metabolized by the liver via cytochrome P450 enzyme system. It is known that genetic polymorphisms in drug metabolizing enzymes are associated with different responses to drugs. The purpose of this trial is to correlate genetically distinct metabolic profiles of tamoxifen with pharmacogenetic predictors and clinical effects that include lipid concentration, bone mineral density, bone turnover metabolites, coagulation factors, and hot flashes. Our hypothesis is that women who are poor tamoxifen metabolizers will experience less benefit and potentially less toxicity. We will evaluate changes in lipid profile, bone mineral density, and bone turnover metabolites, and coagulation factors brought about by tamoxifen therapy, and correlate the findings with genetically distinct metabolic profiles of tamoxifen and genotypes for important candidate genes involved in the action of tamoxifen.