DPYD Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach.

Priscila Villalvazo,Belén Marzal-Alfaro,Sara Salvador-Martín,Miguel Martín,Aitana Calvo,Luis Andrés López-Fernández,Malika Yakoubi,María Sanjurjo-Sáez,Flora López-López,José Luis Revuelta-Herrero,Sara López-Tarruella,Fabienne Thomas,Xandra García-González,Iker Aguilar,Pilar García-Alfonso

doi:10.3390/jpm11080792

Abstract

Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD.

Highlights

Severe adverse reactions to fluoropyrimidines are some of the main problems related to chemotherapy treatment in solid cancers [1]
This was a retrospective, observational, longitudinal case–control study. It included patients aged ≥ 18 years, diagnosed with a solid tumor and newly treated with a chemotherapy regime based on fluoropyrimidines
After review of 464 clinical records, 41 patients met the inclusion criteria. They were separated into two groups: 14 patients were included in the control group and 28 patients in the toxicity group

Summary

Introduction

Severe adverse reactions to fluoropyrimidines are some of the main problems related to chemotherapy treatment in solid cancers [1]. These reactions occur in about one in five patients [2]. The relationship between DPD deficiency and the increase in fluoropyrimidine-induced toxicity in patients who take 5-fluorouracil or its prodrug capecitabine is well established [5]. These undesirable adverse reactions may compromise treatment outcomes, due to delays in administration, dose reductions and even necessary withdrawals of the drug

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