title: COX-2 expression in hepatocellular carcinoma is an initiation event; while EGF receptor expression with downstream pathway activation is a prognostic predictor of survival.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and is a leading cause of cancer mortality with over 90% of HCC patients succumbing to the disease. Current systemic therapies have had no measurable impact on survival in this disease; however there are small subsets of patients who benefit from systemic therapy who have been difficult to identify. Improvements in patient stratification and the development of biological therapies have resulted from the elucidation of the molecular mechanisms integral to tumor development and progression. Recent studies have found that COX-2 and EGFR are frequently inappropriately expressed in HCC compared to normal liver expression; however the presence of surface receptors does not always mean that the downstream pathway is active. In this study, we investigate the incidence and impact of activated EGFR downstream messengers phosphorylated akt (pakt) and/or phosphorylated MAPK (pMAPK) on survival in patients with HCC.
  
  
  METHODS
  Thirty consecutive HCC patients treated at a single institution were retrospectively reviewed. Patient data including age, sex, Child's score, histological type, grade, stage, and survival were analyzed. Immunohistochemical staining was performed on formalin fixed, paraffin embedded tissues using monoclonal antibodies to COX-2, EGF receptor, pMAPK, and pakt. Histoscores were determined for each marker and evaluated for impact in survival, stage, and tumor grade.
  
  
  RESULTS
  The median age was 67 years (39-83) and 67% of patients were male. Median survival was 9.8 months (1-47 months) for the whole group. COX-2 and EGFR expression was present in 90 and 67% of the tumors, respectively. Expression of activated downstream EGFR messengers was present in 53% of tumors (pMAPK 41%, pakt 31%). Median survival was significantly better in patients with downstream messenger expression, 24.4 months, compared to no expression, 4.7 months (P = 0.03). These groups were matched in age, stage, and Child's score.
  
  
  CONCLUSIONS
  COX-2 and EGFR expression are commonly seen in HCC. Activated downstream EGFR expression is also common in HCC and is a predictor of improved survival. There may be a therapeutic role for EGFR tyrosine kinase inhibitors in this subset of patients and further investigation is warranted.
authors.affiliation: Department of Surgery, Roswell Park Cancer Institute, State University of New York at Buffalo, Elm & Carlton Streets, Buffalo, NY, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Foster
authors.forename: Jennifer
authors.initials: J
authors.lastname: Black
authors.forename: Charles
authors.initials: C
authors.lastname: LeVea
authors.forename: Thaer
authors.initials: T
authors.lastname: Khoury
authors.forename: Boris
authors.initials: B
authors.lastname: Kuvshinoff
authors.forename: Miland
authors.initials: M
authors.lastname: Javle
authors.forename: John F
authors.initials: JF
authors.lastname: Gibbs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases