Otero-Torres Sara, Rodríguez-Mauriz Rosa, Fort-Casamartina Eduard, Clopés-Estela Ana, Soler-Rotllant Francesc, Fontanals-Martínez Sandra, Montero-Pérez Olalla
Pharmacy Department, Catalan Institute of Oncology (ICO), Hospital Duran I Reynals, 08098 L'Hospitalet de Llobregat, Spain.
Medicines Department, Catalan Health Service (Catsalut), 08007 Barcelona, Spain.
Pharmaceuticals (Basel). 2025 May 15;18(5):727. doi: 10.3390/ph18050727.
: Fluoropyrimidines are widely used chemotherapeutic agents in various solid tumors. Germline variants in the DPYD gene, which encodes the enzyme dihydropyrimidine dehydrogenase (DPD), are known to impair drug metabolism and increase the risk of severe toxicity. This umbrella review aims to synthesize the current evidence from systematic reviews on the association between DPYD variants and fluoropyrimidine-induced toxicity. A comprehensive search was conducted in PubMed, Web of Science, Scopus, and the Cochrane Library from inception to 2023, including gray literature. Systematic reviews assessing fluoropyrimidine toxicity in oncologic patients with DPYD variants were included. Study quality was assessed using the AMSTAR-2 tool. Registration number in PROSPERO: CRD42023401226. : Two independent investigators performed the study selection, quality assessment, and data collection. Eight systematic reviews met the inclusion criteria. Methodological confidence was rated as critically low in six, low in one, and medium in another one. The reviews included 125 primary studies, most of them focused on four key variants (DPYD2A, DPYD13, c.2846A>T, and HapB3), all of which showed consistent associations with an increased risk of severe toxicity. Rare variants such as DPYD*4, *5, and *6 were also examined, though evidence remains limited. Pharmacogenetics-guided dosing of fluoropyrimidines significantly reduced toxicity rates in several studies. The integration of DPYD genotyping with phenotyping approaches faces limitations; these tests should complement rather than replace genotyping information. : This umbrella review confirms the clinical relevance of DPYD genotyping to predict and mitigate fluoropyrimidine toxicity. Incorporating genotyping into clinical practice, potentially alongside phenotyping and therapeutic drug monitoring, may enhance patient safety and treatment efficacy.
氟嘧啶是广泛用于治疗各种实体瘤的化疗药物。已知编码二氢嘧啶脱氢酶（DPD）的DPYD基因中的种系变异会损害药物代谢并增加严重毒性的风险。本系统评价旨在综合当前关于DPYD变异与氟嘧啶诱导毒性之间关联的系统评价证据。从创刊至2023年在PubMed、科学网、Scopus和Cochrane图书馆进行了全面检索，包括灰色文献。纳入评估携带DPYD变异的肿瘤患者中氟嘧啶毒性的系统评价。使用AMSTAR-2工具评估研究质量。PROSPERO注册号：CRD42023401226。
两名独立研究人员进行了研究选择、质量评估和数据收集。八项系统评价符合纳入标准。六项的方法学可信度被评为极低，一项为低，另一项为中等。这些评价纳入了125项原始研究，其中大多数集中于四个关键变异（DPYD2A、DPYD13、c.2846A>T和HapB3），所有这些变异均显示与严重毒性风险增加存在一致关联。虽然证据仍然有限，但也对DPYD*4、5和6等罕见变异进行了研究。在多项研究中，氟嘧啶的药物遗传学指导给药显著降低了毒性发生率。DPYD基因分型与表型分析方法的整合存在局限性；这些检测应补充而非取代基因分型信息。
本系统评价证实了DPYD基因分型在预测和减轻氟嘧啶毒性方面的临床相关性。将基因分型纳入临床实践，可能与表型分析和治疗药物监测一起，可提高患者安全性和治疗效果。
