2020年，欧洲药品管理局建议在使用氟嘧啶类药物进行全身治疗之前对患者进行二氢嘧啶脱氢酶（DPD）缺陷测试。DPD活性测试可识别患者存在严重氟嘧啶类药物毒性（FP-TOX）的高风险。DPD测试的两种最常用方法是DPYD基因型和DPD表型（血浆尿嘧啶浓度）检测。本研究的主要目的是比较在DPYD基因型实施前后，整体≥3级FP-TOX的发生频率。230名丹麦肠道癌患者在首次使用FP前接受了DPYD基因型测试，并抽取了血样，以事后评估P-尿嘧啶。变异基因携带者的初始剂量降低。 FP的前3个治疗周期后记录了≥3级FP-TOX的频率，并将其与生物库中事后确定DPYD基因型的492名患者的历史队列进行比较。 DPYD基因型引导组中整体≥3级FP-TOX的频率为27％，历史队列中为24％。在DPYD变异基因携带者中，DPYD基因型检测将FP相关住院率从19％降至0％。 在对照组中，DPYD变异基因携带者死于FP-TOX的比例为4.8％，而在接受DPYD基因型引导的FP剂量组中为0％。 在干预组中，血浆尿嘧啶值≥16 ng / ml的野生型患者FP-TOX的发生率高于血浆尿嘧啶值<16 ng / ml的野生型患者（55％与28％）。我们发现，在比较临床实施前后≥3级FP-TOX风险时，DPYD基因型检测没有人群水平的益处。 在DPYD基因型变异携带者的FP治疗指导下，我们观察到没有死亡或FP相关住院的情况。DPD表型检测在DPYD野生型患者中可能会提供有价值的信息。版权所有©2023年作者。由Elsevier Ltd.发表。保留所有权利。

In 2020, the European Medicines Agency recommended testing patients for dihydropyrimidine dehydrogenase (DPD) deficiency before systemic treatment with fluoropyrimidines (FP). DPD activity testing identifies patients at elevated risk of severe FP-related toxicity (FP-TOX). The two most used methods for DPD testing are DPYD genotyping and DPD phenotyping (plasma uracil concentration). The primary objective of this study was to compare the overall frequency of overall grade ≥3 FP-TOX before and after the implementation of DPYD genotyping.Two hundred thirty Danish, primarily gastrointestinal cancer patients, were DPYD-genotyped before their first dose of FP, and blood was sampled for post hoc assessment of P-uracil. The initial dose was reduced for variant carriers. Grade ≥3 FP-TOX was registered after the first three treatment cycles of FP. The frequency of toxicity was compared to a historical cohort of 492 patients with post hoc determined DPYD genotype from a biobank.The frequency of overall grade ≥3 FP-TOX was 27% in the DPYD genotype-guided group compared to 24% in the historical cohort. In DPYD variant carriers, DPYD genotyping reduced the frequency of FP-related hospitalization from 19% to 0%. In the control group, 4.8% of DPYD variant carriers died due to FP-TOX compared to 0% in the group receiving DPYD genotype-guided dosing of FP. In the intervention group, wild-type patients with uracil ≥16 ng/ml had a higher frequency of FP-TOX than wild-type patients with uracil <16 ng/ml (55% versus 28%).We found no population-level benefit of DPYD genotyping when comparing the risk of grade ≥3 FP-TOX before and after clinical implementation. We observed no deaths or FP-related hospitalizations in patients whose FP treatment was guided by a variant DPYD genotype. The use of DPD phenotyping may add valuable information in DPYD wild-type patients.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.