The successful application of pharmacogenetics requires a full understanding of the expression of genotype as phenotype. A large number of genes code for proteins that mediate response to medicines, and while it is clear that variations in one gene can alter the clinical response to a medicine significantly, this is rare. We propose to study multiple genetic influences on the clinical pharmacology of an important drug: tamoxifen. Our goal is to define multiple genetic influences on the action of this drug as a model for many other drugs, where multiple genetic variations are likely to alter pharmacologic responses. An interdisciplinary group of investigators will use a pharmacogenetic and analytical core laboratory and the resources of the Lombardi Cancer Center to study genetic influences on the metabolism, pharmacokinetics, efficacy and toxicity of tamoxifen. While tamoxifen has been shown to be metabolized by genetically polymorphic cytochrome P450 enzymes in human liver microsomes in vitro, the hypothesis that mutations in the genes coding for these enzymes might alter the drug's metabolism, effects or toxicity has never been tested in vivo, either in normal volunteers or in women with breast cancer. We have the following specific goals: 1) Determine the variability in the contributions of three genetically polymorphic enzymes (CYP2C9, CYP2D6 and CYP3A) to tamoxifen metabolism in human liver microsomes and in isolated human hepatocytes; 2) Test the hypothesis that CYP2D6, CYP3A or CYP2C9 genetics alter the pharmacokinetics of tamoxifen and its metabolites in a clinical trial in patients being prescribed tamoxifen as an adjuvant; 3) Test the hypothesis that metabolic pharmacogenetics influence the efficacy of tamoxifen through analysis of tamoxifen concentrations and metabolic genotypes in patients enrolled in the NSABP-P1 trial: a comparison of the preventive efficacy of tamoxifen and placebo; and 4) Test the hypothesis that genetics alter the toxicity of tamoxifen by A) testing the hypothesis that genetic polymorphisms that influence the metabolism of tamoxifen change the incidence of hot flashes that occur after administration of the drug., and B) testing whether the adverse effects of tamoxifen on cardiac QT interval are influenced by genetic polymorphisms in metabolism and/or ion channels. The multiple pharmacogenetic influences on these measures of tamoxifen effect will be analyzed to determine the pharmacogenetic profile of subjects most likely to experience efficacy, or to experience adverse effects from tamoxifen.
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