IL-8 and eNOS polymorphisms predict bevacizumab-based first line treatment outcomes in RAS mutant metastatic colorectal cancer patients

// Mariantonietta Di Salvatore 1 , Filippo Pietrantonio 2 , Armando Orlandi 1 , Marzia Del Re 3 , Rosa Berenato 2 , Ernesto Rossi 1 , Marta Caporale 2 , Donatella Guarino 4 , Antonia Martinetti 2 , Michele Basso 1 , Roberta Mennitto 2 , Concetta Santonocito 4 , Alessia Mennitto 2 , Giovanni Schinzari 1 , Ilaria Bossi 2 , Ettore Capoluongo 4 , Romano Danesi 3 , Filippo de Braud 2 , Carlo Barone 1 1 Unit of Clinical Oncology, Universita Cattolica del Sacro Cuore, 00168 Rome, Italy 2 Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy 3 Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy 4 Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Universita Cattolica del Sacro Cuore, 00168 Rome, Italy Correspondence to: Mariantonietta Di Salvatore, email: mariantonietta.disalvatore@gmail.com Keywords: single nucleotid polymorphisms, bevacizumab, IL-8, eNOS, colorectal cancer Received: May 23, 2016      Accepted: November 02, 2016      Published: January 25, 2017 ABSTRACT Background : Predictive biomarkers of efficacy and toxicity of bevacizumab have not yet been validated. This study assessed the influence of IL-8, eNOS and VEGF-A polymorphisms in RAS mutated metastatic colorectal cancer patients receiving bevacizumab-based chemotherapy. Methods: 120 patients treated with first-line combination FOLFOX6 plus bevacizumab were included. A historical cohort of 112 RAS mutated colorectal cancer patients treated with FOLFOX6 alone served as control group. The following SNPs were analyzed: IL-8 c.-251T>A; eNOS c.-786T>C and c.-894G>T; VEGF-A c.936C>T, c.958T>C, c.1154A>G and c.2578C>A. Correlation of SNPs, baseline IL-8 serum levels and bevacizumab-efficacy was done. Results : In the bevacizumab group, carriers of the IL-8 alleles c.-251TA+AA showed a shorter PFS (P=0.002) and OS (P=0.03) compared to TT alleles. Patients with pre-treatment IL-8 18,25 pg/ml). IL-8 c.-251TA+AA carriers had significantly higher IL-8 levels (P T was found associated with higher severe toxicity (P=0.0002) in patients carrying the c.-894TT genotype. Conclusions : Although our data need prospective validation, IL-8 and eNOS SNPs may be have a role as predictive biomarkers for bevacizumab efficacy and toxicity.