Retrospective analysis: Does 5-FU dose adjustment per DPYD mutation status affect toxicity?

Abstract

11172 Background: 5-Fluorouracil (5-FU) forms a cornerstone in neoadjuvant chemotherapy (NACT) regimens for solid tumors including head and neck cancers. The DPYD gene encodes for enzyme dihydropyrimidine dehydrogenase (DPD) which catalyses an essential, rate-limiting step in the metabolism of 5-FU. Heterozygous genomic alteration of DPYD (30-35% of population) result in reduced potency of DPD enzyme, while homozygous DPYD alteration (0.1-0.2% of population) results in no functional DPD. Reduced functioning of DPD leads to slower metabolism of 5-FU causing toxicity such as bone marrow suppression, cytopenias etc. The Clinical Pharmacogenetics Implementation Consortium (CPIC) have released guidelines recommending reducing the dose of 5-FU in patients with these genomic alterations of DPYD from 25% to avoiding its use based on a calculated activity score (DPYD-AS). Methods: A phase III randomized study compared a DC vs DCF regimen as NACT in technically unresectable oral cancer was published in March 2024. We utilised data from the ‘DCF’ arm of this study. Patients underwent DPYD testing and we stratified these patients based on DPYD status. In the study, patients underwent the appropriate dose reductions per the CPIC guidelines based on DPYD-AS scores. We evaluate the frequency and degree of adverse events in these groups to determine whether this dose reduction effectively reduces toxicity from 5-FU in these patients. Adverse events were graded per CTCAE. Analysis by Fishers exact test. Results: 247 patients in the DCF arm were included. 85 (34.4%) did not undergo DPYD testing. 118 (47.8%) did not have any DPYD mutation, 44 (17.8%) had heterozygous mutation while 0 had homozygous mutation. The adverse events by DPYD genotypic subgroup are shown in the table. Conclusions: There was no statistically significant difference in adverse events between the group with no DPYD mutation who received the full dose of 5-FU and the heterozygous DPYD mutation group receiving a lower 5-FU dose based on DPYD-AS score. Thus, the dose reduction as set out by the CPIC appears to appropriate. [Table: see text]