Pharmacogenetics of Tamoxifen in Asian Breast Cancer Patients

Abstract

The current project evaluated the effects of candidate genes along the tamoxifen biochemical pathway on the variations in steady state plasma levels of tamoxifen and its metabolites in Asian breast cancer patients. The plasma concentrations of Z-endoxifen (Z-END) and N-desmethyl-tamoxifen (NDM) were found to be lower and higher respectively among Asian patients carrying the defective variant CYP2D6*5 (CYP2D6del) and *10 (100C>T, rs1065852) alleles. Correspondingly, the MRZ-END/NDM, was lower among patients carrying the variant genotypes CYP2D6*5/*10 or CYP2D6*10/*10 compared to patients who were wild-type, indicating lower relative formation of (Z)-endoxifen from NDM. Although these CYP2D6 variant alleles were found to influence the MRZ-4-OHT/TAM, no association with the plasma concentrations of the respective metabolites was observed. The second phase of analyses which involved investigating the impact of major hepatic phase II conjugating enzymes identified UGT1A4 but not UGT2B7, UGT2B15 and SULT1A1 to be a determinant tamoxifen disposition. UGT1A4*3 (142T>G, rs2011425) and the associated haplotype were associated with higher tamoxifen-N-glucuronide concentrations and MRTAM-N-GLUC/TAM. Thus, CYP2D6 and UGT1A4 polymorphisms were identified as significant factors influencing the plasma levels of tamoxifen and metabolites in Asian patients.