EGFR Related Signaling Pathway Has Prognostic Significance in Cholangiocarcinoma

Abstract

Purpose: Overexpression of signaling proteins including EGFR, Akt, MAPK and COX-2 was reported in cholangiocarcinoma cell lines. However, clinical prognostic value of these markers is unknown. No prior study correlated the expression of these signaling proteins with clinical outcome. Further, co-expression of these proteins is undefined. Co-expression may reflect cross-talk between signaling pathways. In this clinicopathologic study, we report the overexpression and co-expression of EGFR and related signaling proteins in cholangiocarcinoma describe their relationship to clinical outcome. Methods: Twenty-four consecutive cases of cholangiocarcinoma treated from 1996 – 2002 at Roswell Park Cancer Institute were included. Immunohistochemical staining of paraffin-embedded tissue sections was performed using antibodies against Akt, p-Akt, MAPK, p-MAPK, COX-2, EGFR and p-EGFR. Two pathologists (JG, TK) independently scored the protein expression and there was full concordance. Clinical data were obtained in accordance with IRB approved protocol. Results: COX-2, Akt, and p- MAPK were commonly expressed in biliary cancers (91%, 88% and 74% of malignant cells respectively). EGFR (50%) and p- EGFR overexpression (13%) was also detected. There was a significant association between EGFR and p EGFR (p = 0.027) as well as Akt and p-Akt (p = 0.017) expression in tumor tissue. A noteworthy association was shown between MAPK (ERK) and p-Akt (p = 0.054). Multivariate analysis using the Cox-proportional hazard model identified use of combined modality therapy [Hazard ratio (HR) = 0.185, p = 0.0008] and p-AKT [HR = 0.238, p = 0.0373] as the best predictors of overall prognosis. Conclusions: Activation of EGFR signaling pathway is commonly seen in cholangiocarcinoma. Expression of p-Akt and use of combined modality therapy may predict favorable prognosis.