Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
Cancer Treat Rev. 2016 Nov;50:9-22. doi: 10.1016/j.ctrv.2016.08.001. Epub 2016 Aug 10.
Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) and approved for treatment of various malignancies. Hereditary genetic variants may affect a drug's pharmacokinetics or pharmacodynamics and account for differences in treatment response and adverse events among patients. In this review we present the current knowledge on genetic variants, commonly single-nucleotide polymorphisms (SNPs), tested in cohorts of cancer patients and possibly useful for prediction of capecitabine efficacy or toxicity. Capecitabine is activated to 5-FU by CES, CDA and TYMP, of which SNPs in CDA and CES2 were found to be associated with efficacy and toxicity. In addition, variants in genes of the 5-FU metabolic pathway, including TYMS, MTHFR and DPYD also influenced capecitabine efficacy and toxicity. In particular, well-known SNPs in TYMS and DPYD as well as putative DPYD SNPs had an association with clinical outcome as well as adverse events. Inconsistent findings may be attributable to factors related to ethnic differences, sample size, study design, study endpoints, dosing schedule and the use of multiple agents. Of the SNPs described in this review, dose reduction of fluoropyrimidines based on the presence of DPYD variants 2A (rs3918290), 13 (rs55886062), -2846A>T (rs67376798) and -1236G>A/HapB3 (rs56038477) has already been recommended. Other variants merit further validation to establish their definite role in explanation of interindividual differences in the outcome of capecitabine-based therapy.
卡培他滨是 5-氟尿嘧啶（5-FU）的口服前体药物，已被批准用于治疗各种恶性肿瘤。遗传变异可能会影响药物的药代动力学或药效学，并导致患者之间的治疗反应和不良事件存在差异。在这篇综述中，我们介绍了目前关于遗传变异（通常为单核苷酸多态性[SNP]）的知识，这些变异在癌症患者队列中进行了测试，并且可能有助于预测卡培他滨的疗效或毒性。卡培他滨被 CES、CDA 和 TYMP 激活为 5-FU，其中 CDA 和 CES2 的 SNP 与疗效和毒性相关。此外，5-FU 代谢途径中的基因变异，包括 TYMS、MTHFR 和 DPYD，也影响卡培他滨的疗效和毒性。特别是，TYMS 和 DPYD 中的知名 SNP 以及假定的 DPYD SNP 与临床结局以及不良事件相关。不一致的发现可能归因于与种族差异、样本量、研究设计、研究终点、给药方案和多种药物使用相关的因素。在本综述中描述的 SNP 中，基于 DPYD 变异 2A（rs3918290）、13（rs55886062）、-2846A>T（rs67376798）和-1236G>A/HapB3（rs56038477）的存在，已经推荐减少氟嘧啶类药物的剂量。其他变异值得进一步验证，以确定它们在解释卡培他滨治疗结果的个体差异方面的明确作用。
