title: High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis.
abstract: OBJECTIVE
  c-Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); there is no consensus regarding the immunostaining scoring method for this marker. We aimed to assess the prognostic value of c-Met overexpression in resected PDAC, and to elaborate a robust and reproducible scoring method for c-Met immunostaining in this setting.
  
  
  RESULTS
  c-Met immunostaining was graded according to the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c-Met: ≥ 20% of tumour cells with strong membranous staining), in stage I-II PDAC. A computer-assisted classification method (Aperio software) was developed. Clinicopathological parameters were correlated with disease-free survival (DFS) and overall survival(OS). One hundred and forty-nine patients were analysed retrospectively in a two-step process. Thirty-seven samples (whole slides) were analysed as a pre-run test. Reproducibility values were optimal with the simplified score (kappa = 0.773); high c-Met expression (7/37) was associated with shorter DFS [hazard ratio (HR) 3.456, P = 0.0036] and OS (HR 4.257, P = 0.0004). c-Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable with a specific computer-assisted algorithm. In the whole cohort (n = 131), patients with c-Met(high) tumours (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR 2.165, P = 0.0005) and OS (18.2 versus 35.0 months, HR 1.832, P = 0.0098) in univariate and multivariate analysis.
  
  
  CONCLUSIONS
  Simplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival.
authors: INSERM UMR1149.|Department of Digestive Oncology, Beaujon University Hospital, Clichy, France.|Paris 7 Denis Diderot University, Paris, France.
authors: Cindy
authors: C
authors: Neuzillet
authors: INSERM UMR1149.|Paris 7 Denis Diderot University, Paris, France.|Department of Pathology, Bichat-Beaujon University Hospital, Paris-Clichy, France.
authors: Anne
authors: A
authors: Couvelard
authors: Department of Translational Research, AAREC Filia Research, Boulogne-Billancourt, France.
authors: Annemilaï
authors: A
authors: Tijeras-Raballand
authors: INSERM UMR1149.
authors: Louis
authors: L
authors: de Mestier
authors: Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors: Armand
authors: A
authors: de Gramont
authors: INSERM UMR1149.|Paris 7 Denis Diderot University, Paris, France.|Department of Pathology, Bichat-Beaujon University Hospital, Paris-Clichy, France.
authors: Pierre
authors: P
authors: Bédossa
authors: INSERM UMR1149.|Paris 7 Denis Diderot University, Paris, France.|Department of Pathology, Bichat-Beaujon University Hospital, Paris-Clichy, France.
authors: Valérie
authors: V
authors: Paradis
authors: Paris 7 Denis Diderot University, Paris, France.|Department of Biliary and Pancreatic Surgery, Beaujon University Hospital, Clichy, France.
authors: Alain
authors: A
authors: Sauvanet
authors: Department of Gastroenterology, Pitié-Salpêtrière University Hospital, Paris, France.
authors: Jean-Baptiste
authors: JB
authors: Bachet
authors: INSERM UMR1149.|Paris 7 Denis Diderot University, Paris, France.|Department of Gastroenterology and Pancreatology, Beaujon University Hospital, Clichy, France.
authors: Philippe
authors: P
authors: Ruszniewski
authors: Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors: Eric
authors: E
authors: Raymond
authors: INSERM UMR1149.|Department of Digestive Oncology, Beaujon University Hospital, Clichy, France.|Paris 7 Denis Diderot University, Paris, France.
authors: Pascal
authors: P
authors: Hammel
authors: INSERM UMR1149.|Paris 7 Denis Diderot University, Paris, France.|Department of Pathology, Bichat-Beaujon University Hospital, Paris-Clichy, France.
authors: Jérôme
authors: J
authors: Cros
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D021441:Carcinoma, Pancreatic Ductal / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D016016:Proportional Hazards Models; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis*; D015203:Reproducibility of Results; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D019859:Proto-Oncogene Proteins c-met
keywords: biomarker; immunochemistry; invasion; pancreatic cancer; survival