Clinical Pharmacology & Therapeutics - CYP2D6 Genotype Should Not Be Used to Determine Endocrine Therapy in Postmenopausal Breast Cancer Patients

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Clinical Pharmacology & Therapeutics - CYP2D6 Genotype Should Not Be Used to Determine Endocrine Therapy in Postmenopausal Breast Cancer Patients

Clinical Pharmacology & Therapeutics (2013); 94 2, 183–185. doi:10.1038/clpt.2013.102

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

J M Rae^1,2

1. ¹Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA
2. ²Departments of Internal Medicine and Pharmacology, University of Michigan, Ann Arbor, Michigan, USA

Correspondence: JM Rae, (jimmyrae@umich.edu)

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).

These data led to the hypothesis that CYP2D6 PMs may not respond to tamoxifen therapy and that they may experience fewer side effects, compared with EMs, because they have lower circulating endoxifen levels. In an initial study testing this hypothesis, the relapse-free time and disease-free survival were lower in CYP2D6 PMs than in EMs.³ This report spurred subsequent, highly heterogeneous studies of patients treated with tamoxifen. To date, the studies have produced very contradictory results, with some studies showing the hypothesized positive association between CYP2D6 genotype and tamoxifen response, others showing no association, and some even suggesting an inverse association.² Most of these reports come from studies of convenience, representing quite low levels of evidence, and only a few of the studies utilized specimens collected and archived from prospectively conducted clinical trials, the gold standard for studies with a high level of evidence.