A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature.

Valeria Conti,Bruno Charlier,Amelia Filippelli,Valentina Manzo,Berenice Stefanelli,Francesco Iannello,Francesco Sabbatino,Albino Coglianese,Martina Torsiello,Fabrizio Dal Piaz,Stefano Pepe,Teresa Iannaccone,Emanuela De Bellis,Viviana Izzo,Francesca Colucci

doi:10.3390/jpm10030113

Abstract

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.

Highlights

Fluoropyrimidines (FP), including 5-fluorouracil (5-FU) and its oral prodrug capecitabine, are cytotoxic antineoplastic agents belonging to the class of antimetabolites
In the case of a partial dihydropyrimidine dehydrogenase (DPD) deficit, a reduced starting dose of FP should be considered [42].The Pharmacovigilance Risk Assessment Committee (PRAC) recommendation was transferred to the Committee for Medicinal Products for Human Use (CHMP), and, on 7 July 2020, the European Medicines Agency (EMA) Commission raised a final decision that the DPYD-PGx should be performed in naïve oncological patients prior to starting a treatment with FP [43]
The pretherapeutic DPYD-PGx represents an essential approach to personalise FP-based chemotherapy, minimising the risk of severe and life-threatening toxicity

Summary

Introduction

Fluoropyrimidines (FP), including 5-fluorouracil (5-FU) and its oral prodrug capecitabine, are cytotoxic antineoplastic agents belonging to the class of antimetabolites. They are commonly used to treat solid cancer types such as gastrointestinal, head-neck and breast cancers associated or not to other chemotherapeutics and both cytotoxic and biologic drugs [1,2]. The rate-limiting step of FP catabolism is the conversion of fluorouracil to dihydrofluorouracil, which is catalysed by an enzyme called dihydropyrimidine dehydrogenase (DPD), encoded by a highly polymorphic gene (i.e., DPYD). Several single-nucleotide polymorphisms (SNPs) have been associated to an alteration of the DPYD sequence, and some of them may determine a partial or complete DPD deficiency, leading to FP severe toxicity [1]

Methods

Results

Discussion

Conclusion