EGFR, K-RAS, PI3KCA, and BRAF Mutations of Intrahepatic Cholangiocarcinoma in Taiwan---Rational Research before Application of Cetuximab

Intrahepatic cholangiocarcinoma (ICC) is a fatal malignant neoplasms and constitutes about 5% of primary liver cancers. Taiwan is an endemic area of ICC. Surgical resection offers the only chance of long-term cure. Unfortunately, the resection rates are generally low because of early intrahepatic and distant metastasis, nodal involvement, and vascular compromise. Several therapeutic strategies, including chemotherapy, radiation therapy, transplant and photodynamic therapy have not shown significant survival benefit. Pooled results of predominately phase II trials and international consensus highlighted that gemcitabine with or without platinum compounds is currently the most acceptable chemotherapy for advanced biliary tract cancer, nevertheless with a disappointing response rate around 20%.Thus, a novel therapeutic strategy is urgently needed. Recently, EGFR monoclonal antibody (e.g. cetuximab) is emerging to treat various solid cancers such as head-and neck cancer, colorectal cancer and non-small cell lung cancer. It is therefore desirable to test the efficacy of cetuximab, either as monotherapy or combined with other cytotoxic agent, employed to treat advanced or metastatic ICC. Nevertheless, the following issues should be clarified, which are considered important to be implicated to the potential drug response and drug resistance. A) Over expression of EGFR protein and/or EGFR gene amplification B) Mutational status of EGFR (exon 18, 19, 20, 21) C) Mutational status of PI3KCA (exon 9, 20) D) Mutational status of KRAS (exon 2, 3) E) Mutational status of BRAF(exon 15) The aims of this two-year proposal are therefore as follows: 1) To elucidate the above issues (A to E) using our archive tissue of ICC (n=120). 2) To design a preclinical study using cholangiocarcinoma (k-ras mutation and wild-type, respectively) xenograft models, which are treated with cetuximab±chemotherapy and evaluated the tumor response and relevant molecular mechanism.

Project ID:PC10009-0097
External Project ID:NSC100-2314-B182-057