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Review Highlights Potential Targets for Precision Medicine in Cholangiocarcinoma


The prognosis for cholangiocarcinoma remains poor despite advances in targeted therapy, but several targets hold promise for improving treatment strategies and patient outcomes.

Cholangiocarcinoma (CCA), a highly aggressive subtype of biliary tract cancer, has several treatment options yet carries a poor prognosis. Targeted therapies have changed the way cancer in general is treated in recent years, and a recent review published in Life (Basel) summarized the potential for precision medicine in patients with CCA.

Despite advances in treatment, patients with CCA have a median survival time of less than 2 years from diagnosis, and the 5-year survival rate is 10% globally. CCA is often caught in later stages, but even early CCA removed by surgical resection typically recurs within 2 years. A chemotherapy regimen of gemcitabine plus cisplatin has long been the standard of care for unresectable advanced CCA despite low efficacy.But in recent years, targeted therapy options have emerged, and next-generation sequencing has identified several genetic alterations in CCA. 

Various subtypes of CCA have been identified, with 4 main groups, or clusters, based on clinical features and genetic alterations. CCA can be either intrahepatic or extrahepatic, each of which is typically associated with distinct mutations. A variety of potential targeted agents are being tested in preclinical studies and in human clinical trials, but only 5 agents are currently approved for CCA with certain mutations.

For CCA patients with fibroblast growth factor receptor 2 (FGFR2) gene fusions, the FGFR inhibitors pemigatinib andinfigratinib are approved and other agents are under investigation; ivosidenib is approved for patients with isocitrate dehydrogenase gene (IDH1) mutations; and larotrectinib and entrectinib are approved for patients with neurotrophin receptor tyrosine kinase gene (NRTK) fusions. Even with these advances, overall response generally remains low in most CCA patients, including those with FGFR2 fusions, IDH1 mutations, or NRTK mutations.

Epidermal growth factor receptor (EGFR) is rare, and targeting EGFR has not yet produced consistently positive results in CCA. Human epidermal growth factor receptor 2 (HER2) overexpression is common in CCA, and ongoing trials are exploring agents such as trastuzumab to target HER2 in combination with chemotherapy. A pan-HER inhibitor, neratinib, is also under investigation in HER2-mutant solid tumors.

Additional therapies targeting VEGFR, KRAS, BRAF, and the PI3K/AKT/mTOR signaling pathway may also hold potential in certain patients with CCA. In particular, dabrafenib plus trametinib has shown promise in CCA with BRAF mutations but is not yet approved. Mutations of TP53 may also be a future target in addition to tumor microenvironment factors such as cancer-associated fibroblasts, endothelial cells, and the extracellular matrix. Pembrolizumab, which is used in patients with high tumor mutational burdens (TMBs), couldhold potential as a treatment for CCA patients with high TMB but requires further studies in CCA specifically.

Although potential targets have been identified, the approved treatments are only used in later-line settings, while chemotherapy is still the go-to option for most cases.

“The efficacy of first-line targeted therapy compared to that of standard chemotherapy is unknown,” the authors wrote.“Before successful clinical studies are carried out, we do not suggest frontline targeted therapy in clinical settings unless the patient is unfit for chemotherapy.” They note that chemotherapy is only recommended in patients with good performance status, but targeted therapy and immunotherapy do not require good performance status.

Overall, the authors conclude that more progress in disease understanding and more CCA-specific trials are needed to identify effective treatments and improve patient outcomes.

“Precision medicine for CCA can be enhanced by a better understanding of the genetic expression of CCA, developing innovative targeted therapies, and conducting personalized clinical trials on different CCA genotypes,” they wrote. "There is further need for improvement in precision medicine therapies in the treatment of CCA.”



Cheng CY, Chen CP, Wu CE. Precision medicine in cholangiocarcinoma: Past, present, and future. Life (Basel). Published online June 2, 2022. doi:10.3390/life12060829

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