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Tamoxifen and CYP2D6: A Contradiction of Data

2012; AlphaMed Press; Volume: 17; Issue: 5 Linguagem: Inglês

10.1634/theoncologist.2011-0418

1549-490X

Daniel L. Hertz, Howard L. McLeod, William Irvin,

Receptor Mechanisms and Signaling

Abstract Learning Objectives: After completing this course, the reader will be able to: Describe the significant heterogeneity among the published studies on the link between CYP2D6 genotype and tamoxifen treatment efficacy.Explain the role of CYP2D6 metabolism in the conversion of tamoxifen to its active metabolite, endoxifen, and the potential importance of CYP2D6 polymorphisms to this process.Discuss the role that insufficient genotyping, CYP2D6 inhibition, and tamoxifen combination treatment may have had in the inconsistent findings of past pharmacogenetic studies. CME This article is available for continuing medical education credit at CME.TheOncologist.com Tamoxifen is an effective antiestrogen used in the treatment of hormone receptor–positive breast cancer. Bioconversion of tamoxifen to endoxifen, its most abundant active metabolite, is primarily dependent on the activity of cytochrome P450 2D6 (CYP2D6), which is highly polymorphic. Over 20 published studies have reported on the potential association between CYP2D6 polymorphism and tamoxifen treatment outcome, with highly inconsistent results. The purpose of this review is to explore differences among 17 independent studies to identify factors that may have contributed to the discrepant findings. This report discusses six putative factors that are grouped into two categories: (a) clinical management criteria: hormone receptor classification, menopausal status, and tamoxifen combination therapy; (b) pharmacologic criteria: genotyping comprehensiveness, CYP2D6 inhibitor coadministration, and tamoxifen adherence. Comparison of these factors between the positive and negative studies suggests that tamoxifen combination therapy, genotyping comprehensiveness, and CYP2D6 inhibitor coadministration may account for some of the contradictory results. Future association studies on the link between CYP2D6 genotype and tamoxifen treatment efficacy should account for combination therapy and CYP2D6 inhibition, and interrogate as many CYP2D6 alleles as possible.