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Abstract 3135: Comparative analysis of phenotypic markers of DPD activity as biomarkers of 5-FU toxicity
Abstract   Peer reviewed

Abstract 3135: Comparative analysis of phenotypic markers of DPD activity as biomarkers of 5-FU toxicity

Brianna Bembenek, Kelly Bouchonville, Carlo Largiadèr and Steven M. Offer
Cancer research (Chicago, Ill.), Vol.86(7_Supplement), pp.3135-3135
04/03/2026
DOI: 10.1158/1538-7445.AM2026-3135

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Abstract

Nearly 300,000 cancer patients are treated with fluoropyrimidine chemotherapy in the U.S. annually. Approximately one-third of patients experience severe and life-threatening toxicities, which can result in death. Deleterious genetic variants in DPYD, which encodes the rate-limiting enzyme of fluoropyrimidine catabolism (dihydropyrimidine dehydrogenase, DPD), have been correlated with severe toxicity in clinical studies. However, these variants explain only 10-30% of toxicity cases. Phenotypic measures of DPD function are attractive biomarkers of fluoropyrimidine toxicity risk with the potential to identify unknown causes of DPD deficiency. In this study, we compared two measures of DPD enzyme activity, blood plasma dihydrouracil to uracil ratio (UH2:U) and direct measurement of DPD activity in peripheral blood mononuclear cells (PBMCs) using 204 subjects with comprehensive DPYD genotype data. DPD PBMC measurements showed higher overall inter-individual variation compared to UH2:U ratios. Low correlation between UH2:U and PBMC measurements were noted for matched samples taken from the same subject. As expected, DPD metabolites (U and UH2) correlated with UH2:U ratio; however, no correlation was noted between U or UH2 levels and the PBMC DPD activity. Furthermore, when data were analyzed by genotype, no correlations were noted between UH2:U and PBMC DPD activity. We observed the expected decrease in UH2:U ratio for carriers of the four clinically tested DPYD variants and identified two novel variants associated with a significantly decreased UH2:U ratio. To further investigate the impact of rare genotypes and previously identified DPYD haplotypes on the UH2:U ratio, additional cohorts of 1994 and 500 subjects, enriched for specific genotypes, were utilized. Our results suggest that phenotyping may have limited validity as a single test when predicting DPD deficiency at an individual level and call into question the often-reported belief that PBMC DPD activity represents the "gold standard" for identifying DPD deficiency. Additional studies are needed to investigate correlations between phenotypic measures and 5-FU toxicity in patients, potentially as secondary biomarkers in conjunction with genetic tests.

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