title: eNOS polymorphisms as predictors of efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer: data from a randomized clinical trial.
abstract: BACKGROUND
  Bevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of bevacizumab efficacy have not yet been identified. We analyzed vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) polymorphisms in relation to response to bevacizumab.
  
  
  METHODS
  Two hundred and thirty-seven patients with mCRC enrolled onto the phase III prospective multicentre randomized "Italian Trial in Advanced Colorectal Cancer (ITACa)" trial were evaluated. One hundred fourteen patients received chemotherapy plus bevacizumab (CT + B) and 123 received chemotherapy (CT) alone. Five single nucleotide polymorphisms (SNPs) (-2578, -1498, -1154, -634 and +936) for VEGF and 2 SNPs (-786, +894) and one variable number tandem repeat in intron 4 for eNOS were analyzed for each patient. The polymorphisms were assessed in relation to progression-free survival (PFS), objective response rate (ORR) and overall survival (OS).
  
  
  RESULTS
  VEGF 936C/T, eNOS +894 G/T and VNTR were significantly correlated with outcome in CT + B patients, but not in CT-only patients. In particular, patients with a specific haplotype combination of the 2 eNOS polymorphisms (defined eNOS Haplo1/Haplo1 and eNOS Haplo 2/Haplo2) showed significantly longer PFS (15.0 vs 9.1 months, P = 0.001) and OS (34.5 vs 20.5 months P = 0.002), and a higher ORR (71 vs 45.9%, P = 0.013) than those with the other genotypes, respectively.
  
  
  CONCLUSIONS
  Specific eNOS polymorphisms may be capable of identifying a subset of mCRC patients who are more responsive to bevacizumab-based chemotherapy. If confirmed, these results would permit individually tailored treatment with bevacizumab.
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014, Meldola, Italy. paola.ulivi@irst.emr.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Ulivi
authors.affiliation: Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola, Italy. emanuela.scarpi@irst.emr.it.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.affiliation: Department of Medical Oncology, IRST IRCCS, Meldola, Italy. alessandro.passardi@irst.emr.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Passardi
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014, Meldola, Italy. giorgia.marisi@irst.emr.it.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Marisi
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014, Meldola, Italy. daniele.calistri@irst.emr.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Calistri
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014, Meldola, Italy. wainer.zoli@irst.emr.it.
authors.forename: Wainer
authors.initials: W
authors.lastname: Zoli
authors.affiliation: Department of Clinical and Experimental Medicine, Pisa University Hospital, Pisa, Italy. marzia.delre@gmail.com.
authors.forename: Marzia
authors.initials: M
authors.lastname: Del Re
authors.affiliation: Department of Medical Oncology, IRST IRCCS, Meldola, Italy. luca.frassineti@irst.emr.it.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Frassineti
authors.affiliation: Department of Oncology, Per gli Infermi Hospital, Rimini, Italy. dtassinari@rimini.com.
authors.forename: Davide
authors.initials: D
authors.lastname: Tassinari
authors.affiliation: Oncology Unit, Degli Infermi Hospital, Faenza, Italy. s.tamberi@ausl.ra.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tamberi
authors.affiliation: Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola, Italy. bernadette.vertogen@irst.emr.it.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Vertogen
authors.affiliation: Department of Medical Oncology, IRST IRCCS, Meldola, Italy. direzione.scientifica@irst.emr.it.
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000068258:Bevacizumab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III