Importance of and Strategies for Implementing DPYD Testing to Prevent Severe Fluoropyrimidine Chemotherapy Toxicity...

Recent regulatory and guideline changes have established pretreatment DPYD genotyping as a critical strategy to prevent severe fluoropyrimidine toxicity. Following earlier European leadership by the European Medicines Agency, the US Food and Drug Administration added boxed warnings to capecitabine and 5-fluorouracil labels recommending genetic testing before therapy. Concurrent updates from the National Comprehensive Cancer Network and ASCO align US with European practice supporting universal testing. Fluoropyrimidines remain foundational treatments across multiple cancers but can cause life-threatening toxicity in patients with dihydropyrimidine dehydrogenase (DPD) deficiency, most commonly because of inherited DPYD variants. DPYD variant carriers receiving standard doses experience markedly increased risk of severe toxicity and treatment-related mortality, emphasizing the clinical importance of DPYD testing and genotype-guided dosing. Evidence demonstrates that dose individualization based on guidance from the Clinical Pharmacogenetics Implementation Consortium reduces toxicity risk while maintaining treatment effectiveness and potentially reducing overall costs. Patient advocacy, particularly efforts led by Advocates for Universal DPD/DPYD Testing, has accelerated policy change, increased clinician awareness, and highlighted ethical implications of preventable harm. Despite growing adoption, implementation challenges persist, including workflow integration, clinician education, and equitable access. Integrated health systems such as the Veterans Health Administration demonstrate how centralized infrastructure and clinical decision support can facilitate uptake. Barriers are more pronounced in resource-constrained settings, where limited infrastructure, reimbursement uncertainty, and insufficient pharmacogenomic education hinder implementation. Regional initiatives illustrate education-focused, context-adapted strategies to expand testing and address population-specific variant knowledge gaps. Collectively, emerging evidence, regulatory alignment, and advocacy efforts position DPYD genotyping as a patient-safety imperative necessary to achieve safer, more equitable fluoropyrimidine therapy worldwide.