Pharmacogenomics of endocrine therapy in breast cancer

The treatment of breast cancer with selective estrogen receptor modulators such as tamoxifen and with aromatase inhibitors represents a major advance in cancer chemotherapy. However, there are large variations among patients in both the therapeutic efficacy and side effects of these drugs. Pharmacogenomics is the study of the role of inheritance in this variation and genetic variation in tamoxifen response represents one of the most striking examples of the potential clinical importance of pharmacogenomics. Tamoxifen requires "metabolic activation" catalyzed by cytochrome P450 2D6 (CYP2D6) to form hydroxylated metabolites-4-hydroxytamoxifen and endoxifen (N-desmethyl-4-hydroxytamoxifen)- both of which are much more potent than is the parent drug. However, CYP2D6 is genetically polymorphic. Approximately 5-8% of Caucasian subjects are CYP2D6 "poor metabolizers" on a genetic basis and, as a result, are relatively unable to catalyze tamoxifen hydroxylation. These same subjects appear to have poorer outcomes when treated with tamoxifen than do CYP2D6 "extensive metabolizers". These data led the US Food and Drug Administration (FDA) to hold public hearings in 2006 on the inclusion of this pharmacogenomic information in tamoxifen labeling. However, a series of important questions still remains to be addressed with regard to tamoxifen pharmacogenomics. There have also been preliminary attempts to study the pharmacogenomics of aromatase inhibitors, including the application of a genotype-to-phenotype research strategy designed to explore the nature and extent of common DNA sequence variation in the CYP19 gene that encodes aromatase. Those results-together with our current level of understanding of tamoxifen pharmacogenomics-will be reviewed in this chapter and both will be placed within the context of the overall development of pharmacogenomics.