title: Association of matrix metalloproteinase 2 plasma level with response and survival in patients treated with bevacizumab for recurrent high-grade glioma.
abstract: BACKGROUND
  A predictive marker of bevacizumab activity is an unmet medical need. We evaluated the predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent high-grade glioma treated with bevacizumab.
  
  
  METHODS
  Analyzed in plasma were a set of 11 prebiomakers of interest (vascular endothelial growth factor receptor [VEGF]; VEGF receptor 2; basic fibroblast growth factor; stromal cell derived factor 1; placenta growth factor; urokinase-type plasminogen activator; plasminogen activator inhibitor 1; matrix metalloproteinases 2, 7, and 9; and adrenomedulline), using ELISA, at baseline and 2 weeks after bevacizumab initiation in a prospective cohort of 26 patients (Cohort 1). Correlations were validated in a separate retrospective cohort (Cohort 2; n = 50) and tested in cohort patients treated with cytotoxic agents without bevacizumab (Cohort 3; n = 34). Dosages were correlated to objective response, progression-free survival (PFS), and overall survival (OS).
  
  
  RESULTS
  In Cohort 1, high MMP2 baseline level was associated with a probability of objective response of 83.3% versus 15.4% for low MMP2 level (P = .001). In multivariate analysis, baseline level of MMP2 correlated with PFS (hazard ratio, 3.92; 95% confidence interval [CI]:1.46-10.52; P = .007) and OS (hazard ratio, 4.62; 95% CI: 1.58-13.53; P = .005), as decrease of VEGF (P = .038 for PFS and P = .013 for OS) and MMP9 (P = .016 for PFS and P = .025 for OS). In Cohort 2, MMP2, but not MMP9, confirmed its predictive significance. In Cohort 3, no association was found between MMP2, MMP9, and outcome.
  
  
  CONCLUSIONS
  In patients with recurrent high-grade glioma treated with bevacizumab, but not with cytotoxic agent, high MMP2 plasma levels are associated with prolonged tumor control and survival. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role reassessed.
authors: Aix-Marseille Université, INSERM CRO2, Marseille, France (E.T., F.B., D.F.-B., L.O., O.C.); Assistance Publique-Hôpitaux de Marseille (AP-HM), CHU Timone, Service de Neuro-Oncologie, Marseille, France (E.T., M.B., M.M., C.B.); Aix-Marseille Université, Public Health Research Unit-EA3279 AP-HM, Marseille, France (A.L.); Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Avicenne, Service de Neurologie, Bobigny, France (A.C.); Université Paris Descartes, Laboratoire de Recherches Biochirurgicales, Hôpital Européen Georges Pompidou, Paris, France (A.C.); INSERM U 975, CNRS UMR 7225, Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moëlle Épinière UMR-S975, Paris, France (M.S.); AP-HP, Service Neurologie 2, Groupe Hospitalier Pitié-Salpêtrière, Paris, France (M.S.); AP-HM, CHU Timone, Service de Neurochirurgie, Marseille, France (P.M.); AP-HM, CHU Timone, Service d'Anatomopathologie, Marseille, France (D.F.-B.); CHU Nord, Laboratoire de Transfert, Marseille (L.O.).
authors: Emeline
authors: E
authors: Tabouret
authors: Françoise
authors: F
authors: Boudouresque
authors: Maryline
authors: M
authors: Barrie
authors: Mona
authors: M
authors: Matta
authors: Celine
authors: C
authors: Boucard
authors: Anderson
authors: A
authors: Loundou
authors: Antoine
authors: A
authors: Carpentier
authors: Marc
authors: M
authors: Sanson
authors: Philippe
authors: P
authors: Metellus
authors: Dominique
authors: D
authors: Figarella-Branger
authors: L'houcine
authors: L
authors: Ouafik
authors: Olivier
authors: O
authors: Chinot
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000068258:Bevacizumab; D015415:Biomarkers; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality*; D005260:Female; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy* / Q000401:mortality*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D000068258:Bevacizumab; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: bevacizumab; high grade glioma; matrix metalloproteinase 2; matrix metalloproteinase 9; predictive factor