Tamoxifen Pharmacogenetics: CYP2D6 and Other Variables Influencing Tamoxifen and Tamoxifen Metabolite Exposure
- Author(s): Tchu, Simone Ming
- Advisor(s): Wu, Alan HB
- et al.
Tamoxifen is a selective estrogen receptor modulator (SERM) that is used for the treatment of estrogen receptor positive (ER+) breast cancer, most commonly as an adjuvant for the prevention of disease recurrence. Several retrospective studies suggest that functional CYP2D6 polymorphisms are associated with the clinical outcome of tamoxifen adjuvant therapy; variants that confer reduced enzymatic activity are associated with poorer outcomes. The biological basis for this association is that tamoxifen is a pro-drug and CYP2D6 metabolism is important for the formation of the potent anti-estrogenic metabolite, endoxifen. The general goal of this work was to investigate the effect of CYP2D6 polymorphisms and other variables on tamoxifen and tamoxifen metabolite exposure in order to clarify the best use of clinical tamoxfien pharmacogenetic test data.
An LC-MS/MS assay was developed and validated for the quantitation of tamoxifen, N-desmethyltamoxifen, and endoxifen in human serum. The assay was found to be robust for the measurement of these analytes at physiologically relevant concentrations. In collaboration with the Women's Healthy Eating and Living (WHEL) study group, serum endoxifen concentrations were shown to be associated with the clinical outcome of tamoxifen adjuvant therapy, and a sub-therapeutic endoxifen risk group was defined. Extensive CYP2D6 genotypes were determined for WHEL study subjects using the Roche P450 AmpliChip, and an analysis was performed to determine the extent to which genotype cutoffs define the sub-therapeutic endoxifen risk group among Caucasian subjects. Of subjects who carried two null CYP2D6 alleles, approximately 72% fell into the sub-therapeutic endoxifen risk group, but this accounted for less than a quarter of all subjects within the risk group. Poor metabolizer phenocopies were present in all genotype groups. In addition, inter-ethnic differences in serum tamoxifen and tamoxifen metabolites were determined between Caucasian, Asian, Hispanic, and African American subjects within the WHEL cohort, with Asians and Hispanics exhibiting higher median endoxifen concentrations. Finally, an association study was performed in order to determine if variants in candidate genes (UGT2B7, ABCC2, CYP2C19) influence serum endoxifen concentrations in Caucasian subjects. Statistically significant associations were determined, but are unlikely to be clinically relevant due to small effect.