title: Integrative biomarker analyses indicate etiological variations in hepatocellular carcinoma.
abstract: The purpose of this study was to determine whether biomarkers from baseline plasma and archival tissue specimens collected from patients enrolled in the EVOLVE-1 trial - a randomized phase 3 study of everolimus in hepatocellular carcinoma (HCC) - were associated with prognosis, etiology or ethnicity.
  
  
  
  Circulating plasma levels of bFGF, PLGF, VEGF, VEGF-D, c-Kit, collagen IV, sVEGFR1 and VEGFR2 were measured by ELISA (N=503). Protein levels of IGF-1R, c-Met, mTOR, Tsc2 were assayed by immunohistochemistry (N=125). Genomic DNA sequencing was conducted on a panel of 287 cancer-related genes (N=69).
  
  
  
  Patients with baseline plasma concentrations of VEGF or sVEGFR1 above the cohort median had significantly shorter overall survival. These plasma biomarkers retained prognostic significance in a multivariate Cox regression model with geographic region, macroscopic vascular invasion and alpha fetoprotein AFP levels. Membranous c-Met protein levels were significantly lower for Asian patients, as well as for hepatitis B viral etiology. The prevalence of genetic changes were similar to previous reports, along with a trend towards higher PTEN and TSC2 mutations among Asians.
  
  
  
  The angiogenesis biomarkers VEGF and sVEGFR1 were independent prognostic predictors of survival in patients with advanced HCC. Potential differences in c-Met and mTOR pathway activation between Asian and non-Asian patients should be considered in future clinical trials.
  
  
  
  Our study demonstrates that circulating angiogenesis biomarkers can predict the survival outcome in patients with advanced hepatocellular carcinoma independent of the clinical variables. There is etiology and ethnicity variation in molecular pathway activation in hepatocellular carcinoma, which should be considered for future clinical trial design of targeted therapy.
  
  
  
  NCT01035229.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. Electronic address: azhu@partners.org.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanai
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Voi
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital, Koahsiung, Taiwan.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, G Rummo Hospital, Benevento, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Daniele
authors.affiliation: Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.affiliation: Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: Derek Y
authors.initials: DY
authors.lastname: Chiang
mesh_terms: D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular; D006801:Humans; D008113:Liver Neoplasms; D019859:Proto-Oncogene Proteins c-met; D042643:Vascular Endothelial Growth Factor D
chemical_list: D014408:Biomarkers, Tumor; D042643:Vascular Endothelial Growth Factor D; D019859:Proto-Oncogene Proteins c-met
keywords: Everolimus; Next-generation sequencing; PI-3 kinase pathway; Tsc2; c-Met; mTOR