UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Oncologist. 2012;17(5):620-30. doi: 10.1634/theoncologist.2011-0418. Epub 2012 Apr 24.
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.
他莫昔芬是一种有效的抗雌激素药物，用于治疗激素受体阳性乳腺癌。他莫昔芬转化为其最丰富的活性代谢物(endoxifen)主要依赖于细胞色素 P450 2D6（CYP2D6）的活性，CYP2D6 高度多态性。有 20 多项已发表的研究报告了 CYP2D6 多态性与他莫昔芬治疗结果之间的潜在关联，结果高度不一致。本综述的目的是探讨 17 项独立研究之间的差异，以确定可能导致研究结果不一致的因素。本报告讨论了六个假定因素，分为两类：（a）临床管理标准：激素受体分类、绝经状态和他莫昔芬联合治疗；（b）药理标准：基因分型全面性、CYP2D6 抑制剂联合用药和他莫昔芬依从性。对阳性和阴性研究中这些因素的比较表明，他莫昔芬联合治疗、基因分型全面性和 CYP2D6 抑制剂联合用药可能是一些矛盾结果的原因。未来关于 CYP2D6 基因型与他莫昔芬治疗疗效之间联系的关联研究应考虑联合治疗和 CYP2D6 抑制，并尽可能检测更多的 CYP2D6 等位基因。
