Abstract
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.
Highlights
Irinotecan in association with FOLFIRI regimen represents the standard of care for first-line treatment of metastatic colorectal cancer (mCRC) (Fujita et al, 2015)
The present study addressed the effect of polymorphisms in genes encoding transcriptional regulators and pro-inflammatory cytokines impacting irinotecan-related ADME genes on the risk of toxicity
Neutropenia and GI toxicity are typically associated with irinotecan-containing regimens, such as FOLFIRI (Gupta et al, 1994, 1997)
Summary
Irinotecan in association with FOLFIRI regimen represents the standard of care for first-line treatment of mCRC (Fujita et al, 2015). Despite the established antineoplastic effectiveness of the FOLFIRI regimen, the sporadic occurrence of severe and occasionally life-threatening complications often causes a failure of the chemotherapy, negatively impacting patient care (Rothenberg et al, 2001). In the last few years, pharmacogenomics has largely been applied to the personalization of CRC treatment, focusing on the genetic variability in ADME genes (De Mattia et al, 2015) demonstrating the role of genetic markers in UGT1A and ABC, and SLC transporters, in combination with clinico-demographic features, in predicting FOLFIRI toxicity (Toffoli et al, 2006; Cecchin et al, 2009; Toffoli et al, 2010; De Mattia et al, 2013a; Levesque et al, 2013; Chen et al, 2015a,b). The optimization of irinotecan-based therapy remains sub-optimal and under-explored targets may significantly contribute to determining the likelihood of severe complications after chemotherapy
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