Cholangiocarcinoma (CCA) is a group of cancers classified according to their location along the biliary tree. Most patients are only diagnosed at later stages of the disease when clinical symptoms are more apparent. Currently, the first-line therapy for these patients is chemotherapy using cisplatin and gemcitabine. 

Over the years, researchers have delved deeper into the carcinogenesis of CCA than ever before. Our understanding of the molecular mechanisms behind CCA means that we now know enough to implement “precision oncology,” defined by Schwartzberg et al as the “molecular profiling of tumors to identify targetable alterations.” 

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Scientists have discovered a whole host of molecular alterations in intrahepatic CCA, extrahepatic CCA, and other bile duct cancers. A team of researchers presented a series of druggable molecular alterations in bile duct cancers and published their study in Expert Opinion on Investigational Drugs. We will discuss some of their findings in this article. 

In this study, the authors referenced the work of Jusakul et al, who used resected CCA to identify 4 distinct molecular subtypes of CCA: 

  • Clusters 1 and 2 were found to be enriched with TP53 mutations and erythroblastic oncogene B 2 (ERBB2, otherwise known as HER2) amplification. 
  • Cluster 3 demonstrated programmed cell death protein 1 (PD-1) and PD-1 – ligand 2 (PDL2) expression. 
  • Cluster 4 demonstrated isocitrate dehydrogenase 1/2 (IDH1/2) mutations and fibroblast growth factor receptor (FGFR) alterations.

This classification presents an opportunity for better therapeutics to be developed to target the various molecular alterations of CCA, some of which we will explore in this article. 

Common Mutations 

We will now briefly mention some of the more common molecular mutations in CCA and the drugs that are under investigation to inhibit them. 

IDH1 mutations have been shown to occur in 10% to 20% of CCA cases. Ivosidenib, an oral IDH1-inhibitor, has been considered to be an excellent therapeutic candidate. Studies have found that it prolonged progression-free survival for 2.7 months (compared to 1.4 months in the placebo group) and carried a relatively low hazard ratio of 0.37. 

FGFR2 fusions occur in about 10% to 15% of CCA cases. Pemigatinib is a selective oral inhibitor of FGFR 1 to 3, with studies showing 35% of patients receiving the drug obtaining an objective response compared to controls. Infigratinib, an oral pan-FGFR inhibitor, achieved an overall response rate of 23.1% in a clinical trial. 

A BRAF V600E mutation can be found in around 5% of CCA cases. Studies have shown that the combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) produced a 51% overall response rate. 

HER2 amplifications have been exhibited in 1% to 16% of patients with CCA. A study that treated 14 patients with HER2-directed therapy (trastuzumab-lapatinib or trastuzumab-pertuzumab) had the following results: 4 had a partial response, 1 had a mixed response, 1 had a complete response, and 3 had stable disease. 

Challenges to Overcome 

Although the potential of therapeutic molecular alterations in CCA is indeed promising, this study highlighted a few challenges to their implementation that we would be wise to recognize. 

The first is the need to provide a tissue sample for the vast majority of patients. To complicate matters further, the biopsies obtained must be adequate for molecular screening to be performed; for example, liver biopsies are usually obtained through endoscopy, but samples obtained this way are often too small for molecular analysis. This means that physicians need to work together to plan the best way to obtain a biopsy of sufficient size for molecular screening. A possible antidote to this problem is the use of liquid biopsies for molecular screening, but data on this remains very limited. 

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The second challenge is the lack of studies on the subtypes of CCA. IDH1 or FGFR2 alterations represent around 10% to 20% of CCA cases. Therefore, relatively large studies looking into these alterations have taken place; for example, a study of IDH1-FGFR2 inhibitors managed to recruit more than 100 patients. However, researchers might struggle to gain the sponsorship to study less frequent alterations. It is worth remembering that CCA itself is a rare disease, and rare alterations of a rare disease mean that there is less incentive to investigate them thoroughly. 

The third challenge is patient access to drugs due to a lack of regulatory approval. Conducting clinical trials on a drug is one matter; receiving regulatory approval for its mass consumption is quite another. One such example is the drug ivosidenib, for which phase III trials have been completed. However, it has yet to be approved by any regulatory agency. What could be the reason for this? A possible explanation is that the clinical trials did not show statistically positive overall survival in the intention-to-treat analysis. For other drugs, the relative rarity of some of the molecular alterations in CCA poses a challenge for researchers to conduct phase III trials in a timely manner. 

Future Directions

Druggable molecular alterations in CCA may represent an innovative path forward in the development of new therapies to treat CCA. At present, most of the drugs inhibiting molecular alterations are still under investigation, and even after they have been proven to be safe and effective, they still face challenges in gaining regulatory approval. However, as the authors of the study concluded, “The current increasing interest in patients with these relatively rare tumors by both industry and academics might facilitate implementation of precision oncology in the treatment pathway for these poor prognosis patients.”


Bourien H, Lamarca A, McNamara MG, Hubner RA, Valle JW, Edeline J. Druggable molecular alterations in bile duct cancer: potential and current therapeutic applications in clinical trials. Expert Opin Investig Drugs. 2021;30(9):975-983. doi:10.1080/13543784.2021.1964470

Schwartzberg L, Kim ES, Liu D, Schrag D. Precision oncology: who, how, what, when, and when not? Am Soc Clin Oncol Educ Book. 2017;37:160-169. doi:10.1200/EDBK_174176