Undetected toxicity risk in pharmacogenetic testing for dihydropyrimidine dehydrogenase.

Felicia Falvella,Emilio Clementi,Rosa Berenato,Elisa Sottotetti,Filippo Pietrantonio,Antonia Martinetti,Monica Niger,Maria Bartolomeo,Marta Caporale,Claudia Maggi,Stefania Cheli,Filippo De Braud,Ilaria Bossi,Francesca Ricchini,Francesca Bernardi

doi:10.3390/ijms16048884

Abstract

Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.

Highlights

Fluoropyrimidines and Their MetabolismFluoropyrimidine-based therapy is used extensively in oncology for the treatment of many tumour types including gastrointestinal, breast and the aerodigestive tract cancers. 5-fluorouracil (5-FU)and its oral pre-prodrug capecitabine are the most commonly used chemotherapeutic agents either in monotherapy or in combination regimens [1]
Once the initial fluoropyrimidine dose administration has been reduced according to DPYD genotypes, the dosing needs to be further titrated based on tolerance or toxicity
Based on the issue of DPYD undetected heritability, additional variants have been evaluated for Dihydropyrimidine dehydrogenase (DPD) activity and associated fluoropyrimidine toxicity

Summary

Introduction

Fluoropyrimidine-based therapy is used extensively in oncology for the treatment of many tumour types including gastrointestinal, breast and the aerodigestive tract cancers. 5-fluorouracil (5-FU). Its oral pre-prodrug capecitabine are the most commonly used chemotherapeutic agents either in monotherapy or in combination regimens [1] As it occurs with other cancer therapeutics, fluoropyrimidines have a narrow therapeutic range, with the ratio of the effective to toxic dose being small [2]. In colorectal cancer (CRC), fluoropyrimidines are often given as part of a regimen that includes other cytotoxic drugs such as oxaliplatin and irinotecan—with or without monoclonal antibodies. This approach while improving the overall therapeutic efficacy is often accompanied by additional toxic effects. Results from different studies are often contradictory and the correlation between DPYD polymorphisms and 5-FU toxicity is not yet clearly defined

Non-Functional DPYD Variants

DPYD Undetected toxicity

Common DPYD Polymorphisms

Epigenetic Regulation of DPD Expression

Findings

Conclusions