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, Carlo Barone

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)16887-16898
Number of pages12
JournalOncotarget
Volume8
Issue number10
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • Bevacizumab
  • Colorectal cancer
  • ENOS
  • IL-8
  • Single nucleotid polymorphisms

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Di Salvatore, M., Pietrantonio, F., Orlandi, A., Del Re, M., Berenato, R., Rossi, E., Caporale, M., Guarino, D., Martinetti, A., Basso, M., Mennitto, R., Santonocito, C., Mennitto, A., Schinzari, G., Bossi, I., Capoluongo, E., Danesi, R., de Braud, F., & Barone, C. (2017). IL-8 and eNOS polymorphisms predict bevacizumab-based first line treatment outcomes in RAS mutant metastatic colorectal cancer patients. Oncotarget, 8(10), 16887-16898. https://doi.org/10.18632/oncotarget.14810