title: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial.
abstract: OBJECTIVE
  The AVAGAST study showed that adding bevacizumab to chemotherapy in patients with advanced gastric cancer improves progression-free survival and tumor response rate but not overall survival. To examine the hypothesis that angiogenic markers may have predictive value for bevacizumab efficacy in gastric cancer, AVAGAST included a prospective, mandatory biomarker program.
  
  
  METHODS
  Patients with previously untreated, locally advanced or metastatic gastric cancer were randomly assigned to bevacizumab (n = 387) or placebo (n = 387) in combination with chemotherapy. Blood and tumor tissue samples were collected at baseline. Prespecified biomarkers included plasma vascular endothelial growth factor-A (VEGF-A), protein expression of neuropilin-1, and VEGF receptors-1 and -2 (VEGFR-1 and VEGFR-2). Correlations between biomarkers and clinical outcomes were assessed by using a Cox proportional hazards model.
  
  
  RESULTS
  Plasma was available from 712 patients (92%), and tumor samples were available from 727 patients (94%). Baseline plasma VEGF-A levels and tumor neuropilin-1 expression were identified as potential predictors of bevacizumab efficacy. Patients with high baseline plasma VEGF-A levels showed a trend toward improved overall survival (hazard ratio [HR], 0.72; 95% CI, 0.57 to 0.93) versus patients with low VEGF-A levels (HR, 1.01; 95% CI, 0.77 to 1.31; interaction P = .07). Patients with low baseline expression of neuropilin-1 also showed a trend toward improved overall survival (HR, 0.75; 95% CI, 0.59 to 0.97) versus patients with high neuropilin-1 expression (HR, 1.07; 95% CI, 0.81 to 1.40; interaction P = .06). For both biomarkers, subgroup analyses demonstrated significance only in patients from non-Asian regions.
  
  
  CONCLUSIONS
  Plasma VEGF-A and tumor neuropilin-1 are strong biomarker candidates for predicting clinical outcome in patients with advanced gastric cancer treated with bevacizumab.
authors.affiliation: University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Sanne
authors.initials: S
authors.lastname: de Haas
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
authors.forename: Jian
authors.initials: J
authors.lastname: Ming Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Peng Yong
authors.forename: Bernd
authors.initials: B
authors.lastname: Langer
authors.forename: Paul
authors.initials: P
authors.lastname: Delmar
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018572:Disease-Free Survival; D006801:Humans; D009362:Neoplasm Metastasis; D039942:Neuropilin-1 / Q000096:biosynthesis; D010919:Placebos; D016016:Proportional Hazards Models; D011446:Prospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D010919:Placebos; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D000068258:Bevacizumab; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2