The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets


The anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials.

Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor, Kirsten rat sarcoma viral oncogene homolog, v-raf murine sarcoma viral oncogene homolog and tumor protein p53, novel mutations in isocitrate dehydrogenase, BRCA1-Associated Protein 1 and AT-rich interactive domain-containing protein 1A, and novel fusions such as fibroblast growth factor receptor 2 and ROS proto-oncogene 1.

In this review, the authors will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions and somatic mutations, which are promising actionable molecular targets.

Dr. Andrew X. Zhu from the Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA said, "Cholangiocarcinoma (CCA) comprises of malignancy arising from the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) is the second most common primary hepatic malignancy, after hepatocellular carcinoma, and accounts for 10-20% of primary liver cancers."

Figure 1: Key signaling pathways in the pathogenesis of cholangiocarcinoma and established targeted agents.

Figure 1: Key signaling pathways in the pathogenesis of cholangiocarcinoma and established targeted agents.

Chronic inflammation from liver fluke infestation, hepatitis B and C infections, primary sclerosing cholangitis and inflammatory bowel disease are the main risk factors of CCA.

However, the available evidence remains conflicting as randomized adjuvant trials are still ongoing.

A meta-analysis of 6,712 biliary tract cancer patients who received varying forms of adjuvant therapy demonstrated no clear survival benefit with adjuvant treatment 0.74, 95% Confidence interval 0.55-1.01; P = 0.06.

Liver transplantation, though not considered as standard therapy for CCA, has also been explored in selected patients with early stage perihilar CCA, where complete resection is impossible due to vascular or biliary invasion.

A meta-analysis of 605 CCA patients who underwent liver transplantation demonstrated a 5-year OS of 39%, with superior outcomes in those who underwent perioperative chemoradiotherapy.

Majority of the patients present at an advanced stage, with limited treatment options which include locoregional or systemic therapy.

The Zhu Research Team concluded that the results of EGFR inhibitors have been disappointing. As the majority of the trials are performed in unselected population, it will be informative to conduct trials in patients enriched for the presence of molecular signatures implicated in predicting EGFR sensitivity to determine its efficacy.

Furthermore, the identification of oncogenic addiction loops, or novel combination strategy that targets critical molecular pathways simultaneously will be paramount to improve the clinical outcome in CCA.

Full text - https://doi.org/10.18632/oncotarget.8775

Correspondence to - Andrew X. Zhu - [email protected]

Keywords - cholangiocarcinoma, genetics, IDH, FGFR2

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