title: Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab.
abstract: OBJECTIVE
  We evaluated the prognostic and predictive use of circulating VEGF-A levels in phase III trials of bevacizumab in colorectal cancer, lung cancer, and renal cell carcinoma.
  
  
  METHODS
  Baseline plasma samples from 1,816 patients were analyzed for VEGF-A using an ELISA, which recognizes the major isoforms with equivalent sensitivity. HR and 95% confidence intervals (CI) for study end points were estimated using Cox regression analysis. A subset of matched archival tumor samples was analyzed for VEGF-A expression using in situ hybridization.
  
  
  RESULTS
  Higher VEGF-A levels showed trends toward adverse prognostic significance in the control arms of multiple trials, reaching statistical significance for overall survival (OS) in AVF2107 (highest vs. lowest 50%: HR = 1.76; 95% CI, 1.28-2.41), AVAiL (HR = 1.52; 95% CI, 1.16-2.00), and AVOREN (HR = 1.67; 95% CI, 1.18-2.36). In predictive analyses, the HRs for progression-free survival were similar across low and high VEGF-A subgroups and favored bevacizumab-containing treatment. In the low VEGF-A subgroups, HRs (95% CIs) were 0.61 (0.43-0.87) in AVF2107, 0.71 (0.43-1.16) in E4599, 0.74 (0.59-0.94) in AVAiL (low-dose), 0.89 (0.70-1.13) in AVAiL (high-dose), and 0.56 (0.40-0.78) in AVOREN. Analyses of OS data have shown similar results. No correlation between primary tumor VEGF-A expression and plasma VEGF-A levels was observed.
  
  
  CONCLUSIONS
  In this comprehensive evaluation, pretreatment total circulating VEGF-A was prognostic for outcome in metastatic colorectal, lung, and renal cell cancers, but it was not predictive for bevacizumab-based treatment benefit.
authors.affiliation: Department of Oncology Biomarkers, Genentech, Inc., South San Francisco, CA 94080, USA. hegde.priti@gene.com
authors.forename: Priti S
authors.initials: PS
authors.lastname: Hegde
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Dafeng
authors.initials: D
authors.lastname: Chen
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Li
authors.forename: Y Gloria
authors.initials: YG
authors.lastname: Meng
authors.forename: Coen
authors.initials: C
authors.lastname: Bernaards
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elliott
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000097:blood*; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy*; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab