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posted on 2018-04-13, 04:11 authored by Elena De Mattia, Erika Cecchin, Marcella Montico, Adrien Labriet, Chantal Guillemette, Eva Dreussi, Rossana Roncato, Alessia Bignucolo, Angela Buonadonna, Mario D’Andrea, Luigi Coppola, Sara Lonardi, Eric Lévesque, Derek Jonker, Félix Couture, Giuseppe Toffoli

Pharmacogenomics has largely been applied to the personalization of irinotecan-based treatment, focusing mainly on the study of genetic variants in adsorption, distribution, metabolism, and excretion (ADME) genes. The transcriptional control of ADME gene expression is mediated by a set of nuclear factors responding to cancer-related inflammation, which could have pharmacological implications. The aim of the present study was to uncover novel genetic predictors of neutropenia and gastrointestinal toxicity risk among 246 haplotype-tagging polymorphisms in 22 genes encoding inflammation-related cytokines and transcriptional regulators of ADME genes. The study comprised overall more than 400 metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI, grouped in a discovery and a replication cohorts. A concordant protective effect of STAT-3 rs1053004 polymorphism against the risk of grade 3–4 gastrointestinal toxicity was observed in both the cohorts of patients (OR = 0.51, p = 0.045, q = 0.521 and OR = 0.39, p = 0.043, respectively). VDR rs11574077 polymorphism was demonstrated to affect both irinotecan biliary index (BI) and glucuronidation ratio (GR) by a pharmacokinetic analysis. This effect was consistent with an increased risk of grade 3–4 gastrointestinal toxicity in the discovery cohort (OR = 4.46, p = 0.010, q = 0.305). The association was not significant in the replication cohort (OR = 1.44, p = 0.601). These findings suggest an effect of STAT-3 and VDR polymorphisms on FOLFIRI-related gastrointestinal toxicity. If prospectively validated as predictive markers, they could be used to improve the clinical management of mCRC.