title: Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy.
abstract: BACKGROUND
  Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified.
  
  
  METHODS
  We performed a meta-analysis of individual patient data from six randomized phase III trials in colorectal, pancreatic, lung, renal, breast, and gastric cancer to explore the potential relationships between 195 common genetic variants in the vascular endothelial growth factor (VEGF) pathway and bevacizumab treatment outcome.
  
  
  RESULTS
  The analysis included 1,402 patients (716 bevacizumab-treated and 686 placebo-treated). Twenty variants were associated (P < 0.05) with progression-free survival (PFS) in bevacizumab-treated patients. Of these, 4 variants in EPAS1 survived correction for multiple testing (q < 0.05). Genotype-by-treatment interaction tests revealed that, across these 20 variants, 3 variants in VEGF-C (rs12510099), EPAS1 (rs4953344), and IL8RA (rs2234671) were potentially predictive (P < 0.05), but not resistant to multiple testing (q > 0.05). A weak genotype-by-treatment interaction effect was also observed for rs699946 in VEGF-A, whereas Bayesian genewise analysis revealed that genetic variability in VHL was associated with PFS in the bevacizumab arm (q < 0.05). Variants in VEGF-A, EPAS1, and VHL were located in expression quantitative loci derived from lymphoblastoid cell lines, indicating that they affect the expression levels of their respective gene.
  
  
  CONCLUSIONS
  This large genetic analysis suggests that variants in VEGF-A, EPAS1, IL8RA, VHL, and VEGF-C have potential value in predicting bevacizumab treatment outcome across tumor types. Although these associations did not survive correction for multiple testing in a genotype-by-interaction analysis, they are among the strongest predictive effects reported to date for genetic variants and bevacizumab efficacy.
authors.affiliation: F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Sanne
authors.initials: S
authors.lastname: de Haas
authors.forename: Paul
authors.initials: P
authors.lastname: Delmar
authors.forename: Aruna T
authors.initials: AT
authors.lastname: Bansal
authors.forename: Matthieu
authors.initials: M
authors.lastname: Moisse
authors.forename: David W
authors.initials: DW
authors.lastname: Miles
authors.forename: Natasha
authors.initials: N
authors.lastname: Leighl
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.forename: Celine
authors.initials: C
authors.lastname: Pallaud
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001499:Bayes Theorem; D000068258:Bevacizumab; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D009369:Neoplasms / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D051792:Basic Helix-Loop-Helix Proteins; D000068258:Bevacizumab; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C467484:VEGFA protein, human; C467486:VEGFC protein, human; C497446:VHL protein, human