COBRA Abstract, 2000

Specific Estrogen Receptor Modulator Pharmacogenetics

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 class of drugs: the Selective Estrogen Receptor Modulators (SERMs), for which is the prototype is tamoxifen. Our goal is to define multiple genetic influences on the action of this drug as a model for other drugs in the class, where multiple genetic variations are likely to alter pharmacologic responses. An interdisciplinary group of investigators will use established pharmacogenetics and analytical core laboratories and the resources of the Indiana University School of Medicine and University of Michigan Cancer Centers 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:

• 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;
• Based on our preliminary data that has demonstrated changes in an active metabolite of tamoxifen that are predicted by CYP2D6 genotype, we will test the hypothesis that pharmacogenetic variants influence the efficacy and toxicity of tamoxifen through analysis of tamoxifen concentrations and metabolic genotypes in patients enrolled in a prospective trial. This trial includes the measurement of lipid, coagulation and bone parameters in 300 patients prescribed tamoxifen to treat or prevent breast cancer who will be genotyped for variants in CYP isoforms, as well as both estrogen receptors, endothelial NO synthase, aromatase, and a number of other, specific candidate genes. To address the problem of using multiple variables as predictors, we have developed and proposed specific statistical methodology involving the use of variable selection and the false discovery rate, to allow us to determine the best pattern of predictive genotypes;
• Test the hypothesis that genetics alter the toxicity of tamoxifen by 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.

While these studies are focused on tamoxifen, all other SERMs, including estrogen itself alter bone, lipid, coagulation and mitotic parameters to varying degrees, and these data have considerable relevance to the current controversies surrounding
the use of estrogen as hormone replacement therapy. The multiple pharmacogenetic influences on these measures of individual effect will be analyzed to determine the pharmacogenetic profile of subjects most likely to experience efficacy, or to experience adverse effects from this important class of medicines: drugs that are used to treat a wide variety of the most common diseases affecting women.