Breast cancer: Role of pharmacogenetics in tamoxifen therapy

<p><span>The role of pharmacogenetics in the personalization of tamoxifen therapy has relevance in the management of breast cancer. Since Tamoxifen is a pro-drug, genetic polymorphism in Phase I and Phase II drug metabolizing enzymes involved in the bioconversion of tamoxifen to therapeutically active metabolites is critical in determining therapeutic efficacy and adverse drug reactions of the therapy in breast cancer patients. In this review, the role of pharmacogenetics in the personalization of tamoxifen therapy has been discussed. Since, metabolism of tamoxifen by Cytochrome P450 2D6 is significant in determining the therapeutic efficacy of the drug, most of the clinical evidence on tamoxifen pharmacogenetics have been correlated with cytochrome p450 2D6 genetic polymorphism. However, there is discordance in the clinical data, and one of the reasons is the incomplete analysis of all the alleles of cytochrome p450 2D6. International Tamoxifen Pharmacogenomics Consortium has been formed to assess   the discordance. There are also clinical evidences associating genetic polymorphism in cytochrome P450 3A, 2C9, 2C19, Uridine diphosphate –glucuronosyltransferases and Sulfotransferases with clinical outcome of tamoxifen therapy. However, associations of genetic polymorphism in cytochrome P450 3A, 2C9, 2C19, Uridine diphosphate –glucuronosyltransferases and Sulfotransferases with clinical outcome in populations of different ethnicity are unexplored. Evidences on  the association of genetic polymorphisms and the clinical outcome have been summarized in the Table.  Since cost, statistically significant sample population size, labor and ethical issues are the major concerns of a pharmacogenetic investigation; the significance of bottom-up approach in pharmacogenetics has been discussed.</span></p>