title: Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer.
abstract: OBJECTIVE
  The addition of bevacizumab to cytotoxic chemotherapy has demonstrated a progression-free survival (PFS) benefit in the first-line and second-line treatment of advanced or metastatic breast cancer (MBC). However, the addition of bevacizumab to capecitabine in heavily pretreated MBC patients did not show a PFS benefit (AVF2119g phase III trial). The aim of this study was to evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in retrospective subset analyses of the AVF2119g trial.
  
  
  METHODS
  In the AVF2119g trial, 462 patients with MBC were randomly assigned to receive capecitabine or capecitabine plus bevacizumab. Primary tumor tissue and outcome data were available for 223 patients. Biomarker expression was assessed by in situ hybridization (VEGF-A, VEGF-B, thrombospondin-2 and Flt4) or immunohistochemistry (VEGF-C, PDGF-C, neuropilin-1, delta-like ligand (Dll) 4, Bv8, p53 and thymidine phosphorylase) on formalin-fixed, paraffin-embedded tissue. PFS was associated with these variables in retrospective subset analyses.
  
  
  RESULTS
  Patients with low scores for Dll4, VEGF-C, and neuropilin-1 showed trends toward improvement in PFS associated with the addition of bevacizumab to capecitabine (P values = 0.01, 0.05, and 0.07, respectively). These observations were not statistically significant following correction for multiple hypothesis testing.
  
  
  CONCLUSIONS
  These retrospective subset analyses suggest that expression of Dll4, VEGF-C, and neuropilin-1 may predict benefit from bevacizumab. Such observations are not conclusive but warrant additional testing.
authors.affiliation: Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom. adrian.jubb@ndcls.ox.ac.uk
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Dafeng
authors.initials: D
authors.lastname: Chen
authors.forename: James D
authors.initials: JD
authors.lastname: Reimann
authors.forename: Melody A
authors.initials: MA
authors.lastname: Cobleigh
authors.forename: Maike
authors.initials: M
authors.lastname: Schmidt
authors.forename: Virginia K
authors.initials: VK
authors.lastname: Langmuir
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Hillan
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Chen
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000069287:Capecitabine; D017326:Clinical Trials, Phase III as Topic; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D039942:Neuropilin-1; D042582:Vascular Endothelial Growth Factor C
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D042582:Vascular Endothelial Growth Factor C; D003841:Deoxycytidine; D039942:Neuropilin-1; D000068258:Bevacizumab; D000069287:Capecitabine; D005472:Fluorouracil