title: Molecular determinants of outcome in sorafenib-treated patients with hepatocellular carcinoma.
abstract: OBJECTIVE
  Preclinical studies show that sorafenib, a multitarget kinase inhibitor, displays anti-proliferative, anti-angiogenic, and pro-apoptotic properties in hepatocellular carcinoma (HCC). However, the determinants of sorafenib sensitivity in vivo remain largely unknown.
  
  
  METHODS
  We assessed the expression of Mcl-1, activated/phosphorylated extracellular signal-regulated kinase (pERK) 1/2, and activated/phosphorylated AKT (pAKT) in pretreatment tumor specimens from 44 patients with advanced HCC who received sorafenib. Furthermore, we assessed MYC and MET gene copy numbers (GCN) by fluorescence in situ hybridization.
  
  
  RESULTS
  Poorer overall survival (OS) times were correlated with pERK expression [hazard ratio (HR) 1.013; 95 % CI 1.003-1.035] and Mcl-1 expression (HR 1.016; 95 % CI 1.002-1.030) in pretreatment tumor samples. Expression levels of pERK and Mcl-1, however, were not correlated with time to tumor progression (TTP). Increased pERK expression was positively associated with higher Cancer of Liver Italian Program scores (P = 0.012) and was prognostic in patients with scores 2-6 but not in those with scores 0-1. pERK expression was significantly less frequent in specimens sourced from previous surgical procedures compared to biopsy samples (9.6 vs. 92.3 %, respectively; P < 0.0001). Analysis of pAKT expression, MET and MYC GCN, did not indicate any prognostic nor predictive values for these biomarkers in terms of survival.
  
  
  CONCLUSIONS
  Expression levels of Mcl-1 and pERK are associated with reduced OS in HCC patients treated with sorafenib and might be useful markers for risk stratification. However, in contrast to previous findings, pERK expression levels, as well as other biomarkers tested, did not affect TTP.
authors.affiliation: Department of Oncology-Hematology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Mi, Italy. nic_personeni@hotmail.com
authors.forename: Nicola
authors.initials: N
authors.lastname: Personeni
authors.forename: Lorenza
authors.initials: L
authors.lastname: Rimassa
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pressiani
authors.forename: Annarita
authors.initials: A
authors.lastname: Destro
authors.forename: Claudia
authors.initials: C
authors.lastname: Ligorio
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Tronconi
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozzarelli
authors.forename: Carlo
authors.initials: C
authors.lastname: Carnaghi
authors.forename: Luca
authors.initials: L
authors.lastname: Di Tommaso
authors.forename: Laura
authors.initials: L
authors.lastname: Giordano
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D018572:Disease-Free Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D016259:Genes, myc; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D012189:Retrospective Studies; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D009536:Niacinamide; D000077157:Sorafenib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases