Abstract
Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients.
Highlights
Biliary tract cancer (BTC) represents the second-most common primary liver malignancy, with an estimated incidence rate of 6/100,000
BTC can be classified by anatomic localization into intrahepatic cholangiocarcinoma, perihilar and distal or extrahepatic cholangiocarcinoma, and gallbladder carcinoma (GBCA) (Figure 1)
The tumor mutational burden (TMB) did not correlate with the progression-free survival (PFS) or OS. Based on these promising results, combinations of IT with chemotherapy are further being investigated within the phase III TOPAZ-1 (NCT03875235) and KEYNOTE-966 (NCT04003636) trials, in which patients are randomized to gemcitabine and cisplatin alone or in combination with durvalumab or pembrolizumab, respectively
Summary
Biliary tract cancer (BTC) represents the second-most common primary liver malignancy, with an estimated incidence rate of 6/100,000. The phase III BILCAP trial pursued an adjuvant approach with the oral fluoropyrimidine (FU) capecitabine in patients with BTC, following resection [7]. Gemcitabine-based adjuvant therapies standard in the first-line treatment for unselected patients with recurrence after resection have been tested vs observation, the former standard of care, within the phase III BCAT or with primarily advanced-stage disease since. The mOS was improved from 8.1 to 11.7 months with studies failed to meet their primary endpoint, implying that gemcitabine should not be gemcitabine and cisplatin compared to gemcitabine alone Despite positive results of both phase III ABC-02 and ABC-06 trials for unselected patients with BTC, the survival benefits of chemotherapy remain modest and highlight the necessity of improving systemic treatments. The current review will, outline recent advances in molecular characterization and subgrouping of iCCA, with a focus on translational and novel therapeutic approaches that explore the sizeable number of oncogenic alterations in this deadly disease
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