CYP2D6 Genotype Should Not Be Used to Determine Endocrine Therapy in Postmenopausal Breast Cancer Patients

Abstract

The antiestrogen tamoxifen is an effective treatment for all stages of estrogen receptor (ER)-positive breast cancer.1 Tamoxifen blocks estrogen-dependent breast cancer growth by competing with estrogen for binding to its receptor. Tamoxifen itself has antiestrogenic properties, but it is metabolized by a number of cytochrome P450 enzymes into many different metabolites that have varying degrees of antiestrogenic activity. Studies have consistently shown that cytochrome P450 2D6 (CYP2D6), a highly polymorphic drug-metabolizing enzyme, is the enzyme primarily responsible for the production of one of the most potent metabolites, endoxifen (4-hydroxy-N-desmethyl-tamoxifen). Preclinical studies of estrogen-dependent breast cancer have shown that endoxifen is an approximately 100-fold more potent antiestrogen than tamoxifen or the major tamoxifen metabolite, N-desmethyl-tamoxifen. Patients who are homozygous for two null CYP2D6 alleles, and are therefore poor metabolizers (PMs), as well as patients who are taking medications that are CYP2D6 inhibitors, have lower serum endoxifen concentrations as compared with patients who have one or more wild-type CYP2D6 alleles (intermediate metabolizers (IMs) and extensive metabolizers (EMs), respectively) (reviewed by Hertz et al.2).