Abstract
In addition to the effect of cytochrome P450 ( CYP ) 2D6 genetic polymorphisms, the metabolism of tamoxifen may be impacted by other factors with possible consequences on therapeutic outcome (efficacy and toxicity). This analysis focused on the pharmacokinetic (PK)‐pharmacogenetic evaluation of tamoxifen in 730 patients with adjuvant breast cancer included in a prospective multicenter study. Plasma concentrations of tamoxifen and six major metabolites, the genotype for 63 single‐nucleotide polymorphisms, and comedications were obtained 6 months after treatment initiation. Plasma concentrations of endoxifen were significantly associated with CYP 2D6 diplotype ( P < 0.0001), CYP 3A4*22 genotype ( P = 0.0003), and concomitant intake of potent CYP 2D6 inhibitors ( P < 0.001). Comparison of endoxifen levels showed that the CYP 2D6 phenotype classification could be improved by grouping intermediate metabolizer ( IM )/ IM and IM /poor metabolizer diplotype into IM phenotype for future use in tamoxifen therapy optimization. Finally, the multivariable regression analysis showed that formation of tamoxifen metabolites was independently impacted by CYP 2D6 diplotype and CYP 3A4*22 , CYP 2C19*2 , and CYP 2B6*6 genetic polymorphisms.