Elevated Risk of Fluoropyrimidine-Associated Toxicity in European Patients with DPYD Genetic Polymorphism: A Systematic Review and Meta-Analysis

Abstract

Background: Fluoropyrimidine is widely used owing to its clinical efficacy, however, patients with dihydropyrimidine dehydrogenase (DPD) deficiency can experience fluoropyrimidine-associated toxicity. The dihydropyrimidine dehydrogenase (DPYD) gene encodes DPD, and studies suggest that DPYD polymorphisms can result in DPD deficiency. Since there is not a complete consistency of how much the risk of complication is elevated, we aimed to conduct a systematic literature review and a meta-analysis to provide the risk of fluoropyrimidine-associated toxicity in patients with DPYD rs1801160 polymorphism. Methods: We searched for qualifying studies published before October 2021 from PubMed, Web of Science, and EMBASE based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between rs1801160 polymorphism and toxicities. A sensitivity analysis using the leave-one-out method was performed on the overall toxicity. Results: The pooled OR for overall toxicity in the patients with A allele was elevated 1.73 times higher than those with the GG genotype (95% CI 1.44-2.07). Sensitivity analysis yielded similar results, showing the robustness of the result. Subjects with variants showed a 2.37-fold increased hematological toxicity (95% CI 1.48-3.81); especially a 1.87-fold increased neutropenia compared to patients with wildtype (95% CI 1.49-2.34). Patients with A allele revealed 1.22 times higher gastrointestinal toxicity compared to those with GG genotype (95% CI 0.93-1.61), and among gastrointestinal toxicity, the risk of diarrhea was elevated 1.43 times higher in those with variants than patients with wildtype (95% CI 1.12-1.83). Conclusions: rs1801160 polymorphism is associated with elevated fluoropyrimidine-associated toxicity. Therefore, rs1801160 can be a potential candidate for DPD deficiency screening prior to fluoropyrimidine-based regimen.