title: IL-8 and eNOS polymorphisms predict bevacizumab-based first line treatment outcomes in RAS mutant metastatic colorectal cancer patients.
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.
authors.affiliation: Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Mariantonietta
authors.initials: M
authors.lastname: Di Salvatore
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Pietrantonio
authors.affiliation: Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Orlandi
authors.affiliation: Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Del Re
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Berenato
authors.affiliation: Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Rossi
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Caporale
authors.affiliation: Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Guarino
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Martinetti
authors.affiliation: Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Basso
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Mennitto
authors.affiliation: Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Santonocito
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Mennitto
authors.affiliation: Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Schinzari
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bossi
authors.affiliation: Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Capoluongo
authors.affiliation: Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.affiliation: Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Barone
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D016209:Interleukin-8; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil
keywords: IL-8; bevacizumab; colorectal cancer; eNOS; single nucleotid polymorphisms