Researchers have found that intrahepatic cholangiocarcinomas (ICCs) are really 2 different groups of tumors, based on molecular and genetic analyses, reported in the April issue of Gastroenterology. These findings identify class-specific mechanisms of oncogenesis that could lead to new treatment approaches for this common liver cancer.
Cholangiocarcinoma is the second most common type of liver cancer (after hepatocellular carcinoma), accounting for 10%–15% of all primary liver malignancies. Cholangiocarcinoma is clinically classified as intrahepatic cholangiocarcinoma (ICC), which arises from the small bile ducts within the liver, or extrahepatic cholangiocarcinoma (ECC), which arises from the ductal epithelium of the extrahepatic bile duct. These tumors have distinct genetic and histologic features, risk factors, and outcomes. However, the incidence of ICC has increased significantly in recent years, whereas the incidence of ECC has remained stable or even decreased.
Unlike many other solid tumors, no molecular targeted agents have been approved for the treatment of ICCs. There have been few phase III trials to test specific targeted therapies or even chemotherapy regimens in patients with this specific form of liver cancer.
To learn more about the molecular and genetic features of ICCs, Daniela Sia et al. performed gene expression, copy number, and mutational analyses of tumor samples collected from 149 patients.
They identified 2 distinct classes of ICC, based on gene expression patterns and genomic features. The group they call the ‘inflammation class’ (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. Then, the group they call the ‘proliferation class’ (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes of patients with HCC.
The identification of these 2 classes has raised questions about whether all patients with ICC should receive the same treatment. Sia et al. propose conducting preclinical studies to test different therapeutic agents in models of these ICC classes. For example, multi-kinase inhibitors with a broad spectrum of action could be effective against all ICCs or just a specific subclass (see below figure).
Sorafenib, a small-molecule inhibitor of several tyrosine kinases, is currently used to treat patients with advanced HCC, but has shown marginal activity in patients with cholangiocarcinoma, compared with systemic chemotherapy. However, Siu et al. propose that based on the molecular similarities between the proliferation class of ICCs and the HCC signatures of poor prognosis, along with activation of KRAS, multi-kinase inhibitors such as regorafenib, sorafenib, or sunitinib might be most effective for patients with the proliferation class of ICC. Alternatively, JAK–STAT inhibitors might be more effective for patients with inflammation class of ICC.
Siu et al. remind us that concerns about the liver toxicity of certain drugs in patients with cirrhosis (such as sunitinib for patients with HCC) are less relevant to patients with ICC. ICCs often develop in patients without cirrhosis, and without clear etiologic risk factors or any form of liver disease. In this study, only 17% of patients had cirrhosis.
In an editorial that accompanies the article, Jesper Andersen and Snorri Thorgeirsson agree that the increasing incidence and poor outcomes of patients with ICC, along with the lack of molecular targeted therapies for this neoplasm are major scientific challenges. They state that continued integrative research strategies, to collect multiple layers of data from carefully selected patient cohorts along with comprehensive clinical and pathology information, are needed to advance our understanding of the molecular pathogenesis of ICC and improve design of future trials.
More Information on Cholangiocarcinoma:
Read the article online.
Sia D, Hoshida Y, Villaneuva A, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 2013;144:829–840.
Read the accompanying editorial.
Andersen JB, Thorgeirsson SS. Genomic decoding of intrahepatic cholangiocarcinoma reveals therapeutic opportunities.Gastroenterology 2013;144:687–690.