Details

Autor(en) / Beteiligte

• De Mattia, Elena
• Cecchin, Erika
• Montico, Marcella
• Labriet, Adrien
• Guillemette, Chantal
• Dreussi, Eva
• Roncato, Rossana
• Bignucolo, Alessia
• Buonadonna, Angela
• D'Andrea, Mario
• Coppola, Luigi
• Lonardi, Sara
• Lévesque, Eric
• Jonker, Derek
• Couture, Félix
• Toffoli, Giuseppe

Titel

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

Ist Teil von

• Frontiers in pharmacology, 2018-04, Vol.9, p.367-367

Ort / Verlag

Switzerland: Frontiers Research Foundation

Erscheinungsjahr

2018

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• 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 rs1053004 polymorphism against the risk of grade 3-4 gastrointestinal toxicity was observed in both the cohorts of patients (OR = 0.51, = 0.045, = 0.521 and OR = 0.39, = 0.043, respectively). 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, = 0.010, = 0.305). The association was not significant in the replication cohort (OR = 1.44, = 0.601). These findings suggest an effect of and polymorphisms on FOLFIRI-related gastrointestinal toxicity. If prospectively validated as predictive markers, they could be used to improve the clinical management of mCRC.