title: VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials.
abstract: BACKGROUND
  No biomarkers that could guide patient selection for treatment with the anti-VEGF monoclonal antibody bevacizumab have been identified. We assessed whether genetic variants in the VEGF pathway could act as biomarkers for bevacizumab treatment outcome.
  
  
  METHODS
  We investigated DNA from white patients from two phase 3 randomised studies. In AViTA, patients with metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine and erlotinib plus either bevacizumab or placebo. In AVOREN, patients with metastatic renal-cell carcinoma were randomly assigned to receive interferon alfa-2a plus either bevacizumab or placebo. We assessed the correlation of 138 SNPs in the VEGF pathway with progression-free survival and overall survival in a subpopulation of patients from AViTA. Significant findings were confirmed in a subpopulation of patients from AVOREN and functionally studied at the molecular level.
  
  
  RESULTS
  We investigated DNA of 154 patients from AViTA, of whom 77 received bevacizumab, and 110 patients from AVOREN, of whom 59 received bevacizumab. Only rs9582036, a SNP in VEGF receptor 1 (VEGFR1 or FLT1), was significantly associated with overall survival in the bevacizumab group of AViTA after correction for multiplicity (per-allele hazard ratio [HR] 2·1, 95% CI 1·45-3·06, p=0·00014). This SNP was also associated with progression-free survival (per-allele HR 1·89, 1·31-2·71, p=0·00081) in bevacizumab-treated patients from AViTA. AC and CC carriers of this SNP exhibited HRs for overall survival of 2·0 (1·19-3·36; p=0·0091) and 4·72 (2·08-10·68; p=0·0002) relative to AA carriers. No effects were seen in placebo-treated patients and a significant genotype by treatment interaction (p=0·041) was recorded, indicating that the VEGFR1 locus containing this SNP serves as a predictive marker for bevacizumab treatment outcome in AViTA. Fine-mapping experiments of this locus identified rs7993418, a synonymous SNP affecting tyrosine 1213 in the VEGFR1 tyrosine-kinase domain, as the functional variant underlying the association. This SNP causes a shift in codon usage, leading to increased VEGFR1 expression and downstream VEGFR1 signalling. This VEGFR1 locus correlated significantly with progression-free survival (HR 1·81, 1·08-3·05; p=0·033) but not overall survival (HR 0·91, 0·45-1·82, p=0·78) in the bevacizumab group in AVOREN.
  
  
  CONCLUSIONS
  A locus in VEGFR1 correlates with increased VEGFR1 expression and poor outcome of bevacizumab treatment. Prospective assessment is underway to validate the predictive value of this novel biomarker.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: Laboratory of Translational Genetics, Vesalius Research Center, VIB and KULeuven, Leuven, Belgium. diether.lambrechts@vibkuleuven.be
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Bart
authors.initials: B
authors.lastname: Claes
authors.forename: Paul
authors.initials: P
authors.lastname: Delmar
authors.forename: Joke
authors.initials: J
authors.lastname: Reumers
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Betül T
authors.initials: BT
authors.lastname: Yesilyurt
authors.forename: Roland
authors.initials: R
authors.lastname: Devlieger
authors.forename: Chris
authors.initials: C
authors.lastname: Verslype
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.forename: Hans
authors.initials: H
authors.lastname: Wildiers
authors.forename: Sanne
authors.initials: S
authors.lastname: de Haas
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001483:Base Sequence; D000068258:Bevacizumab; D015415:Biomarkers; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040281:Vascular Endothelial Growth Factor Receptor-1