title: Association between VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with bevacizumab.
abstract: OBJECTIVE
  Bevacizumab improves survival for patients with metastatic colorectal cancer with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF(165)b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF(165)b levels treated with bevacizumab.
  
  
  METHODS
  Blinded tumor samples from the phase III trial of FOLFOX4 ± bevacizumab were assessed for VEGF(165)b and VEGF(total) by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF(165)b:VEGF(total) for 44 samples from patients treated with FOLFOX + bevacizumab (arm A) and 53 samples from patients treated with FOLFOX4 (arm B), and PFS, and overall survival (OS) analyzed on the basis of PI relative to median ratio.
  
  
  RESULTS
  Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF(165)b:VEGF(total) ratio scores below median treated with FOLFOX4 + bevacizumab compared with FOLFOX4 alone (median, 8.0 vs. 5.2 months; P < 0.02), but no effect of bevacizumab on PFS in patients with VEGF(165)b:VEGF(total) ratio >median (5.9 vs. 6.3 months). These findings held after adjustment for other clinical and demographic features. OS was increased in arm A (median, 13.6 months) compared with arm B (10.6 months) in the low VEGF(165)b group, but this did not reach statistical significance. There was no difference in the high VEGF(165)b:VEGF(total) group between FOLFOX + bevacizumab (10.8 months) and FOLFOX alone (11.3 months).
  
  
  CONCLUSIONS
  Low VEGF(165)b:VEGF(total) ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit.
authors.affiliation: Microvascular Research Laboratories, Department of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom. Dave.Bates@bristol.ac.uk
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Catalano
authors.forename: Kirsty E
authors.initials: KE
authors.lastname: Symonds
authors.forename: Alex H R
authors.initials: AH
authors.lastname: Varey
authors.forename: Pramila
authors.initials: P
authors.lastname: Ramani
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Giantonio
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Meropol
authors.forename: Al Bowen
authors.initials: AB
authors.lastname: Benson
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Harper
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000627:therapeutic use; D015337:Multicenter Studies as Topic; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D020033:Protein Isoforms / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil