title: Vascular endothelial growth factor D  expression is a potential biomarker of  bevacizumab benefit in colorectal cancer.
abstract: BACKGROUND
  Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects.
  
  
  METHODS
  We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population.
  
  
  RESULTS
  Patients with low expression of VEGF-D (0, 1þ) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CBþCBM), 0.21; 95% CI, 0.08–0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13–0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2þ PFS HR, 0.67; 95% CI, 0.45–1.00; OS HR, 0.82; 95% CI, 0.52–1.30; VEGF-D 3þ PFS HR, 0.77; 95% CI, 0.50–1.17; OS HR, 1.28; 95% CI, 0.79–2.09) (P interaction o0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression.
  
  
  CONCLUSIONS
  The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.
authors.forename: A J
authors.initials: AJ
authors.lastname: Weickhardt
authors.forename: D S
authors.initials: DS
authors.lastname: Williams
authors.forename: C K
authors.initials: CK
authors.lastname: Lee
authors.forename: F
authors.initials: F
authors.lastname: Chionh
authors.forename: J
authors.initials: J
authors.lastname: Simes
authors.forename: C
authors.initials: C
authors.lastname: Murone
authors.forename: K
authors.initials: K
authors.lastname: Wilson
authors.forename: M M
authors.initials: MM
authors.lastname: Parry
authors.forename: K
authors.initials: K
authors.lastname: Asadi
authors.forename: A M
authors.initials: AM
authors.lastname: Scott
authors.forename: C J A
authors.initials: CJ
authors.lastname: Punt
authors.forename: I D
authors.initials: ID
authors.lastname: Nagtegaal
authors.forename: T J
authors.initials: TJ
authors.lastname: Price
authors.forename: J M
authors.initials: JM
authors.lastname: Mariadason
authors.forename: N C
authors.initials: NC
authors.lastname: Tebbutt
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D016685:Mitomycin / Q000008:administration & dosage; D009362:Neoplasm Metastasis; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D042643:Vascular Endothelial Growth Factor D; D003841:Deoxycytidine; D000068258:Bevacizumab; D016685:Mitomycin; D000069287:Capecitabine; D005472:Fluorouracil