Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma

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.

Keywords: FGFR; IDH1; cholangiocarcinoma; immunotherapy; targeted therapy.

Figure 1

Molecular alterations of cholangiocarcinoma (CCA) subtypes. AT-Rich Interaction Domain 1A (AIRD1A); BRCA1 Associated Protein 1 (BAP-1); proto-oncogene B-Raf (BRAF); Ductus hepaticus communis (DHC); human epidermal growth factor receptor 2 (Her2); E74 Like ETS Transcription Factor 3 (ELF3); Ephrin type-A receptor 2 (EPHA2); Erb-B2 Receptor Tyrosine Kinase 3 (ERBB3); Fibroblast Growth Factor Receptor gene 2 (FGFR 2), Isocitrate dehydrogenase 1 and 2 (IDH1/2); Kirsten rat sarcoma (KRAS); Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA); Protein Kinase CAMP-Activated Catalytic Subunit Alpha/-Beta (PRKACA/-B); SMAD family member 4 (SMAD4); Tumor Protein P53 (TP53).

Figure 2

Conventional and precision oncological treatment approaches in advanced intrahepatic cholangiocarcinomas (iCCAs). proto-oncogene B-Raf (BRAF); human epidermal growth factor receptor 2 (Her2); Fibroblast Growth Factor Receptor gene 2 (FGFR 2), Isocitrate dehydrogenase 1 and 2 (IDH1/2); Neurotrophic tyrosine receptor kinase (NTRK); microsatellite instability (MSI).