Amplification and overexpression of c‐erbB‐2, epidermal growth factor receptor, and c‐met in biliary tract cancers

Abstract

Carcinomas of the biliary tract have a poor prognosis. It is important to understand the molecular genetic characteristics of these tumours in order to employ newer effective treatments and to improve patient prognosis. There is increasing evidence that overexpression of tyrosine kinase growth factor receptors such as ErbB-2, epidermal growth factor receptor (EGFR), and Met may play important roles in the development of biliary tract carcinomas. The aim of this study was to assess the potential for novel chemotherapies targeting these receptors. Overexpression of the tyrosine kinase receptor proteins was examined by immunohistochemistry in 221 biliary tract carcinomas, of which 28 were from the intrahepatic bile duct, 78 from the extrahepatic bile duct, 89 from the gall bladder, and 26 from the ampulla of Vater. Positively stained tumours were further examined for gene amplification by fluorescence in situ hybridization. Overexpression of ErbB-2 was found in 15.7%, 11.5%, and 5.1% of carcinomas of the gall bladder, ampulla of Vater, and extrahepatic bile duct, respectively, and gene amplification was present in 79% of these. Overexpression of EGFR was found in 8.1% of tumours with no predominant location and was also associated with gene amplification with high frequency (77%). Met overexpression, most frequent in intrahepatic bile duct carcinomas (21.4%), was not associated with gene amplification. It is proposed that the new adjuvant chemotherapies could be directed to carcinomas of the biliary tract in which ErbB-2 and EGFR are overexpressed.

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

“…We explored any potential explanation for this survival advantage in IHC patients despite similar PFS. In this subgroup, the median number of cycles was 6 (range, [3][4][5][6][7][8][9][10][11][12] in the P-GEMOX group and 11 (range, 2-12) in the GEMOX group, with more patients in the standard arm completing the preplanned 12-cycle treatment (10 patients in the GEMOX group vs 6 patients in the P-GEMOX group). Moreover, we could not demonstrate any significant difference in the causes of the end of treatment, occurrence of adverse events, second-line treatments, or surgery between the arms (data not shown).…”

“…EGFR is often overexpressed in this disease, and in some cases, activating mutations have been detected. 6,7 Initial phase 2 studies using anti-EGFRtargeted agents have shown promising results 8 and have paved the way to randomized trials.…”

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

“…c-Met activation and elevation of c-met mRNA and protein expression have been shown in mouse chemically induced cholangiocarcinoma, different cholangiocarcinoma cell lines, and human cholangiocarcinoma patients. c-Met overexpression is more prominent in induced cholangiocarcinoma in rats and human cholangiocarcinoma cell lines as compared to normal and hyperplastic intrahepatic biliary epithelium [3,5,126,[129][130][131] . The presence of HGF-c-Met-STAT3 positive autocrine/paracrine loop in cholangiocarcinoma may confer increased survival, growth, and invasiveness during cholangiocarcinoma progression.…”

“…Overexpression of both ErbB1 (EGFR) and ErbB2 may serve as a base for enhancement of EGF signaling in cholangiocarcinoma. Altered ERbB2 expression occurs early in cholangiocarcinogenesis and may play an important role in its progression [129,130,139,143,144] .…”

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

“…Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) have emerged as potential therapeutic targets in cholangiocarcinoma. Several studies have shown overexpression of EGFR, amplification and mutation of EGFR genes (Gwak et al, 2005;Nakazawa et al, 2005;Leone et al, 2006), and overexpression of VEGF protein (Tang et al, 2006) in cholangiocarcinoma. A phase II study of erlotinib, an EGFR kinase inhibitor, for advanced cholangiocarcinoma suggests the clinical benefit for EGFR inhibition in patients with cholangiocarcinoma (Philip et al, 2006).…”