Tamoxifen and CYP2D6 polymorphism in the treatment of hormone receptor-positive breast cancer

Abstract

Tamoxifen is a prodrug that requires metabolic activation to endoxifen and 4-hydroxy-tamoxifen. The cytochrome P450 (CYP) 2D6 is a key enzyme for the generation of these active metabolites and has genetic polymorphism. The plasma concentration of endoxifen was reportedly lower in patients with variant-type alleles of CYP2D6 compared with patients with wild-type alleles. However, inconsistencies among results of retrospective studies have been observed and a conclusion regarding the association of genetic CYP2D6 enzyme activity with tamoxifen efficacy for treating breast cancer has not been reached. We reported that the patients carrying variant-type alleles of CYP2D6 had significantly shorter recurrence free survival compared with patients carrying homozygous wild-type alleles in adjuvant tamoxifen therapy for breast cancer, and showed that the plasma concentrations of endoxifen were significant lower in patients with variant-type alleles than in those with wild-type alleles (Kiyotani et al., J Clin Oncol, 2010). We also demonstrated that the increase of tamoxifen dosing based on the individual CYP2D6 genotypes was able to reach therapeutic level of plasma endoxifen (Kiyotani et al., Breast Cancer Res Treat, 2012). Based on these results, we are conducting a randomized phase II study of CYP2D6 genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer at 51 institutions in Japan (TARGET-1 study, UMIN000009155). The US Eastern Cooperative Oncology Group (ECOG) is also conducting a phase II prospective study to clarify whether CYP2D6 genotype influence the efficacy of tamoxifen in patients with metastatic breast cancer (E-3108 study). Our goal is to reveal a correlation between tamoxifen efficacy and CYP2D6 genotype, and to develop a personalized medicine for tamoxifen therapy according to CYP2D6 genotype.