DPYD (Dihydropyrimidine Dehydrogenase)

P2, N=33, Not yet recruiting, Jennifer Dorth

We report a 36-year-old male with metastatic rectal adenocarcinoma and complete DPD deficiency who received ultra-low-dose capecitabine in combination with oxaliplatin and cetuximab...Pharmacokinetic analyses revealed markedly prolonged 5-fluorouracil exposure with undetectable fluoro-β-alanine (FBAL), consistent with complete DPD deficiency...This case illustrates that carefully individualized ultra-low-dose capecitabine, guided by pharmacokinetics and toxicity monitoring, can provide meaningful clinical benefit in patients with complete DPD deficiency. These findings highlight the therapeutic potential of a precision dosing approach in this rare but clinically challenging setting.

Background: The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), an enzyme essential for metabolising chemotherapeutic agents such as capecitabine, 5-fluorouracil (5-FU), and tegafur. No significant differences in DPYD testing rates were observed across socioeconomic groups or between ethnic backgrounds within our cohort. DPYD variants were prevalent in 7% of the cohort, and testing access was not influenced by socioeconomic status.

Fluoropyrimidine anticancer agents, exemplified by 5-fluorouracil (5-FU), induce severe adverse effects-such as myelosuppression, emesis, diarrhea, and hand-foot syndrome-in approximately 10-30% of patients...To address this gap, we conducted a comprehensive in vitro functional analysis of DPD and DHPase activity of DPYD and DPYS variants identified through large-scale whole-genome sequencing databases. This review summarizes our findings and elucidates the underlying mechanisms affecting the function of 5-FU-metabolizing enzymes, as revealed by our prior research.

DPYD sequencing identified additional relevant variants and improved the sensitivity of DPYD testing. An online calculator (https://fluoropyrimidine-toxicity-predictor.gustaveroussy.fr/) is provided to estimate the individual probability of developing life-threatening toxicity, based on clinical covariates and extended DPYD genotype.

DPYD rs4294451 T-allele count and male sex were significantly associated with reduced 5-FU drug exposure. DPYD rs4294451 and male sex merit further evaluation as candidate biomarkers to inform initial dosing of infusional 5-FU.

The discovery of rare DPYD variants followed by functional characterization may aid in further optimization of fluoropyrimidine dosing.

Several clinically relevant variants were identified: DPYD rs2297595 occurred more frequently than in European cohorts, and UGT1A1 rs8175347 was observed at a higher prevalence, underscoring the potential risk of irinotecan-related neutropenia and diarrhea... This study provides the first comprehensive description of pharmacogenetic polymorphisms in a Russian cohort of patients with gastrointestinal cancers. Our findings confirm the clinical importance of DPYD and UGT1A1 testing and highlight additional variants of potential interest.

This case report supports the clinical utility of pre-emptive DPYD genotyping to guide initial 5-FU dosing in intermediate metabolizers, and it suggests that all patients still require close monitoring and some (particularly carriers of c.2846 A > T) may require an initial dose reduction greater than the recommended 50% to prevent severe toxicity.

Individuals with DPYD mutations experience increased toxicity and dose adjustments; however, treatment efficacy was not affected. This indicates that a coordinated effort that incorporates routine DPYD testing can mitigate treatment toxicities and individualized fluoropyrimidine dosing for patients with GI and HPB cancers.

Current recommendations from clinical guidelines and scientific literature in populations of African origin, including Dominican, have been reviewed. Based on the high reported frequency, the inclusion of the c.557A>G variant (which leads to a decrease in DPD enzyme activity) in populations of Afro-Latin American ancestry is proposed.