| dc.description.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] | it_IT |
