title: Expression of pERK and VEGFR-2 in advanced hepatocellular carcinoma and resistance to sorafenib treatment.
abstract: OBJECTIVE
  The study aimed to evaluate the tissue expression of molecules involved in intracellular signalling pathways as predictors of response to sorafenib in advanced hepatocellular carcinoma (HCC).
  
  
  METHODS
  We considered 77 patients enrolled into three prospective trials of sorafenib treatment for whom pretreatment tumour tissue was available. The tissue expression of β-catenin, glutamine synthetase (GS), phosphorylated extracellular signal regulated kinase (pERK), phosphorylated v-akt murine thymoma viral oncogene homolog (pAKT) and vascular endothelial growth factor receptor-2 (VEGFR-2) was analysed by immunostaining. Stains were scored semiquantitatively and compared with a reference group of 56 untreated HCCs.
  
  
  RESULTS
  Overall, the expression of antigens was comparable between treated and untreated patients. Shorter progression-free survival (PFS) and overall survival (OS) were associated with increased pERK staining (≥ 2+ scores) (PFS: 75th percentile 4.4 vs 8.4 months; P = 0.01; OS: 75th percentile 7.0 vs 15.0 months; P = 0.005) and VEGFR-2 staining (≥ 2+ scores) (PFS: 75th percentile 3.8 vs 7.0 months; P = 0.039; OS: 75th percentile 6.3 vs 15.0 months; P = 0.004). At multivariate analysis, both pERK and VEGFR-2 staining maintained an independent effect on OS (HR 2.09; 95% CI, 1.13-3.86, P = 0.019 and HR 2.28; 95% CI, 1.13-4.61, P = 0.021 respectively). No effect was observed for the other tested biomarkers.
  
  
  CONCLUSIONS
  Elevated tissue expression of pERK and VEGFR-2 was predictive of poor outcome in advanced HCC treated with sorafenib.
authors.affiliation: Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
authors.forename: Francesca V
authors.initials: FV
authors.lastname: Negri
authors.affiliation: Department of Pathology, IRCCS-Fondazione Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dal Bello
authors.affiliation: Medical Oncology Unit, IRCCS-Fondazione Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.affiliation: Department of Pathology, University Hospital of Parma, Parma, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Campanini
authors.affiliation: VI Internal Medicine, IRCCS-Fondazione Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Clinical Epidemiology and Biometric Unit, IRCCS-Fondazione Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Tinelli
authors.affiliation: Medical Oncology Unit, Istituto di Cura Città di Pavia, Pavia, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Poggi
authors.affiliation: Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Missale
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliera ASMN, IRCCS, Reggio Emilia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fanello
authors.affiliation: Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Salvagni
authors.affiliation: Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
authors.affiliation: Department of Pathology, University Hospital of Parma, Parma, Italy.|Centre for Molecular and Translational Oncology (COMT), University of Parma, Parma, Italy.
authors.forename: Silini Enrico
authors.initials: SE
authors.lastname: Maria
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D000077157:Sorafenib; D016019:Survival Analysis; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase
keywords: VEGFR-2 expression; hepatocellular carcinoma; pERK expression; sorafenib