Metabolizing Enzyme Genotype Versus Exemestane Metabolism Profiles

Aromatase inhibitors (AIs) are widely used as adjuvant treatment for estrogen-receptor positive breast cancer in post-menopausal women. AIs have been demonstrated to have equal to or greater efficacy and less toxicity than tamoxifen (TAM), the drug of choice for many years. Exemestane (EXE) is a 3rd-generation AI that has demonstrated efficacy in the treatment of breast cancer patients, and as with TAM and other AIs, there has been considerable inter-individual variability in overall response to EXE and in the occurrence of toxicities, but the causes of this variability have not been elucidated. Differences in drug metabolism can be a source of variability between patients. Genetic variations occur in several of the enzymes involved in phase I and II metabolic reactions and many of these can lead to alterations in enzyme activity which in turn can alter therapeutic response to drugs. EXE is extensively metabolized as unchanged EXE and is found at less than 1% in urine and 10% in plasma. EXE pharmacokinetics will be established in a series of 20 subjects taking EXE. EXE metabolites will then be measured at an optimal time post-EXE dose in the urine of 200 breast cancer patients being treated with EXE to establish whether metabolizing enzyme genotype-EXE metabolism phenotype correlations exist in vivo.