Somatic Mutations of Epidermal Growth Factor Receptor in Bile Duct and Gallbladder Carcinoma

Abstract

Objective: Conventional therapies are still unsuccessful in patients with carcinoma arising from the biliary tract. Somatic mutations of the epidermal growth factor receptor (EGFR) gene and the activation of its downstream pathways predict the sensitivity to small-molecule inhibitors in non^small cell lung carcinoma. Therefore, we analyzed EGFR mutations and related pathways in gallbladder and bile duct carcinomas to consider the possible application of these alternative therapeutic strategies. Experimental Design: Forty paraffin-embedded samples, including intrahepatic or extrahepatic cholangiocarcinoma and gallbladder carcinoma, were studied after tumor cell isolation by laser microdissection and sequencing of EGFR tyrosine kinase domain (exons 18-21). Activation of EGFR pathway was studied by evaluating phosphorylation of mitogen-activated protein kinase and Akt. Results: None of the 40 specimens had mutations in exon 18; one had one missense point mutation in exon19, two in exon 20, and three in exon 21. In addition, 36 of 40 specimens had the same silent mutation at codon 787 in exon 20, which was also found in peripheral blood cells from healthy donors. Tumor samples harboring EGFR mutation had phosphorylation of one or both downstream transducers analyzed. Conclusions: This is the first evidence of somatic mutations of the EGFR gene in bile duct carcinoma. Our findings suggest that a subgroup of patients with cholangiocarcinoma or gallbladder carcinoma exhibits somatic mutations of EGFR in the tyrosine kinase domain that can elicit cell signals sustaining survival and proliferation. These tumors might be further evaluated for their susceptibility to small-molecule inhibitor treatment.

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

“…Of the cell lines without KRAS mutation, TKKK, which has EGFR amplification, was most sensitive to vandetanib. The incidence of EGFR mutations in cholangiocarcinoma is reported as 13.6 -15.0% (Gwak et al, 2005;Leone et al, 2006). However, we did not detect mutation in the kinase domain of the EGFR gene in the cell lines used in this study.…”

“…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).…”

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.…”

Significance of epithelial growth factor in the epithelial–mesenchymal transition of human gallbladder cancer cells

“…(7) Amplification and point mutations of the EGFR gene have been reported to be 1% and 15 -26.5%, respectively, in GBC. (8)(9)(10) The HGF receptor c-Met is involved in the early carcinogenesis of BTC. (11) c-Met is expressed in 74% of invasive GBC and is associated with invasive depth.…”