Research Papers:

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

Mariantonietta Di Salvatore _, Filippo Pietrantonio, Armando Orlandi, Marzia Del Re, Rosa Berenato, Ernesto Rossi, Marta Caporale, Donatella Guarino, Antonia Martinetti, Michele Basso, Roberta Mennitto, Concetta Santonocito, Alessia Mennitto, Giovanni Schinzari, Ilaria Bossi, Ettore Capoluongo, Romano Danesi, Filippo de Braud and Carlo Barone

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Oncotarget. 2017; 8:16887-16898. https://doi.org/10.18632/oncotarget.14810

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Mariantonietta Di Salvatore1, Filippo Pietrantonio2, Armando Orlandi1, Marzia Del Re3, Rosa Berenato2, Ernesto Rossi1, Marta Caporale2, Donatella Guarino4, Antonia Martinetti2, Michele Basso1, Roberta Mennitto2, Concetta Santonocito4, Alessia Mennitto2, Giovanni Schinzari1, Ilaria Bossi2, Ettore Capoluongo4, Romano Danesi3, Filippo de Braud2, Carlo Barone1

1Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy

2Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy

3Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy

4Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, 00168 Rome, Italy

Correspondence to:

Mariantonietta Di Salvatore, email: [email protected]

Keywords: single nucleotid polymorphisms, bevacizumab, IL-8, eNOS, colorectal cancer

Received: May 23, 2016     Accepted: November 02, 2016     Published: January 25, 2017


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 showed significantly longer median PFS and OS (PFS: 10.9 vs 7.6 months, P=0.005; OS: 30.7 vs 18.2 months, P<0.001) compared to patients with IL-8 higher levels (>18,25 pg/ml). IL-8 c.-251TA+AA carriers had significantly higher IL-8 levels (P<0.0001). Multivariate analysis confirmed association of IL-8 polymorphism with PFS, and of IL-8 baseline levels with both PFS and OS. IL-8 SNP did not affect the outcome in the control group. The eNOS polymorphism c.-894G>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.

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