Lunenburg Carin A T C, Henricks Linda M, van Kuilenburg André B P, Mathijssen Ron H J, Schellens Jan H M, Gelderblom Hans, Guchelaar Henk-Jan, Swen Jesse J
Department of Medical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Genes (Basel). 2018 Nov 28;9(12):585. doi: 10.3390/genes9120585.
genotyping prior to fluoropyrimidine treatment is increasingly implemented in clinical care. Without phasing information (i.e., allelic location of variants), current genotype-based dosing guidelines cannot be applied to patients carrying multiple variants. The primary aim of this study is to examine diagnostic and therapeutic strategies for fluoropyrimidine treatment of patients carrying multiple variants. A case series of patients carrying multiple variants is presented. Different genotyping techniques were used to determine phasing information. Phenotyping was performed by dihydropyrimidine dehydrogenase (DPD) enzyme activity measurements. Publicly available databases were queried to explore the frequency and phasing of variants of patients carrying multiple variants. Four out of seven patients carrying multiple variants received a full dose of fluoropyrimidines and experienced severe toxicity. Phasing information could be retrieved for four patients. In three patients, variants were located on two different alleles, i.e., in . Recommended dose reductions based on the phased genotype differed from the phenotype-derived dose reductions in three out of four cases. Data from publicly available databases show that the frequency of patients carrying multiple variants is low (< 0.2%), but higher than the frequency of the commonly tested *13 variant (0.1%). Patients carrying multiple variants are at high risk of developing severe toxicity. Additional analyses are required to determine the correct dose of fluoropyrimidine treatment. In patients carrying multiple variants, we recommend that a DPD phenotyping assay be carried out to determine a safe starting dose.
在氟嘧啶治疗前进行基因分型在临床护理中越来越普遍。在没有相位信息（即变异的等位基因位置）的情况下，当前基于基因型的给药指南无法应用于携带多个变异的患者。本研究的主要目的是探讨携带多个变异的患者接受氟嘧啶治疗的诊断和治疗策略。本文介绍了一系列携带多个变异的患者病例。使用不同的基因分型技术来确定相位信息。通过二氢嘧啶脱氢酶（DPD）酶活性测量进行表型分析。查询公开可用的数据库以探索携带多个变异的患者变异的频率和相位。七名携带多个变异的患者中有四名接受了全剂量的氟嘧啶并出现了严重毒性。可以为四名患者检索到相位信息。在三名患者中，变异位于两个不同的等位基因上，即在……基于相位基因型推荐的剂量减少与表型推导的剂量减少在四分之三的病例中有所不同。公开可用数据库的数据表明，携带多个变异的患者频率较低（<0.2%），但高于常见检测的*13变异的频率（0.1%）。携带多个变异的患者发生严重毒性的风险很高。需要进行额外的分析来确定氟嘧啶治疗的正确剂量。对于携带多个变异的患者，我们建议进行DPD表型分析以确定安全的起始剂量。
