Oncovigilanza e counseling farmacogenetico: strumenti per migliorare l'appropriatezza prescrittiva e la compliance dei pazienti oncologici in trattamento con fluoropirimidine in regione Campania

Abstract

Introduction: Fluoropyridines (FP) are used in the treatment of solid tumors and are frequently associated with severe Adverse Drug Reactions (ADR). It is recommended to analyse four Single Nucleotide Polymorphisms (SNPs) of the DPYD gene (DPYD*2A, DPYD*13, DPYD c.2846A>T and c.1129-5923C> G) which are associated to the development of life-threatening FP-toxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) Guidelines advise to reduce FP starting doses in heterozygotes by 50% and administer alternative drugs in homozygotes. Two SNPs of the MTHFR gene (-C677T and -A1298C) and another one in the enhancer region of the Thymidylate Synthetase gene (TYM-TSER) have been proposed as predictive factors of FP-toxicity. The UH2/U plasma ratio and the 5FU Therapeutic Drug Monitoring (TDM) can be complementary tests to the genotyping. Objectives: The primary endpoint is the Oncovigilance action of FP-toxicity, and the analysis of the predictive toxicity value related to four DPYD, two MTHFR and another one TSER SNPs. The secondary endpoint is the evaluation of the predictive toxicity value of the UH2/U ratio and the TDM. Materials and methods: The subjects treated with FP were recruited (June 2017-January 2020) at the Oncology Unit of San Giovanni di Dio and Ruggi d'Aragona Hospital in Salerno. ADRs have been classified according to the Common Terminology Criteria for Adverse Events, CTC-AE version 5.0. DPYD variants were analysed by Real-time PCR with allelic discrimination, MTHFR-C677T and - A1298C by pyrosequencing and TYMS-TSER by PCR and agarose gel electrophoresis at the Pharmacogenetics Laboratory of the Clinical Pharmacology Unit. The UH2/U plasma ratio was evaluated by high performance liquid chromatography (HPLC) and the 5FU-TDM by high performance liquid chromatography combined with mass-tandem spectrometry (UHPLC-MS/MS) at the Pharmacokinetics Laboratory of the Clinical Pharmacology Unit. Results: 150 patients treated with FP were enrolled (59% men, 41% women, average age 64 years). Colon cancer was the most frequent disease (52,78%), followed by gastric and rectal cancer. The most common grade 3 and 4 ADR was neutropenia (13%) and diarrhea (7%). Pre-treatment genotyping DPYD heterozygous patients, after the reduction of 50% 5FU starting dose, had no serious ADRs. Regarding to MTHFR 1298, heterozygous and homozygous patients registered more severe gastrointestinal ADR compared to wild-type (CI at 95% [-0,96; -0,13] p=0,0102). Furthermore, MTHFR 677 wild-type and homo patients showed higher toxicity degree than heterozygous ones (CI at 95%: [-2,29; -0,75] p= 0,0001 haematological ADR), (CI at 95%: [-1,53; -0,76] p= 0,0000 gastrointestinal ADR) and (CI at 95%: [-1,58; -0,93] p= 0,0000 dermatological ADR). Finally, about TSER, 2R3R patients had on average more serious neurological ADR (CI at 95%: [0,05; 0,44] p= 0,0139) compared to 2R2R and 3R3R patients which affected by gastrointestinal and dermatological more debilitating ADR (CI at 95%: [-1,58; -0,85] p= 0,0000) and (CI at 95%: [-1,28; -0,58] p= 0,0000). There was an evidence of an inverse relationship among UH2/U levels and severity degree of ADR regarding to six toxicities (neutropenia, leukopenia, vomiting, paraesthesia, dysgeusia and mucositis). Conclusions: This study emphasizes the importance of the DPYD pharmacogenetic analysis in patients naïve. The MTHFR and TYM-TSER SNPs should be considered as potential toxicity predictors. A combined genotyping/phenotyping approach could be a valuable tool to personalize the FP therapy. [edited by Author]