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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.

Association of STAT-3 rs1053004 and VDR rs11574077 With FOLFIRI-Related Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients