title: Tamoxifen and CYP2D6: a contradiction of data.
abstract: 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.
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hertz
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: William J
authors.initials: WJ
authors.lastname: Irvin
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D013629:Tamoxifen / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6