Factors affecting tamoxifen metabolism in breast cancer patients; preliminary results of the French PHACS study (NCT01127295).

In addition to the effect of CYP2D6 genetic polymorphisms, the metabolism of tamoxifen may be impacted by other factors with possible consequences on therapeutic outcome (efficacy, toxicity). This analysis focused on the pharmacokinetic-pharmacogenetic evaluation of tamoxifen in 730 adjuvant breast cancer patients included in a prospective multicenter study. Plasma concentrations of tamoxifen and six major metabolites, the genotype for 63 single nucleotide polymorphisms and co-medications were obtained 6 months after treatment initiation. Plasma concentrations of endoxifen were significantly associated with CYP2D6 diplotype (p < 0.0001), CYP3A4*22 genotype (p = 0.0003) and concomitant intake of potent CYP2D6 inhibitors (p < 0.001). Comparison of endoxifen levels showed that the CYP2D6 phenotype classification could be improved by grouping IM/IM and IM/PM diplotype into intermediate metaboliser (IM) phenotype for future use in tamoxifen therapy optimisation. Finally, the multivariable regression analysis showed that formation of tamoxifen metabolites was independently impacted by CYP2D6 diplotype and CYP3A4*22, CYP2C19*2 and CYP2B6*6 genetic polymorphisms. This article is protected by copyright. All rights reserved.