Intrahepatic cholangiocarcinoma: Insights on molecular testing, targeted therapies, and future directions from a multidisciplinary panel

Abstract

Biliary tract cancers (BTCs) are a histologically and molecularly diverse group of malignancies arising from the gallbladder and the ductal epithelium of the biliary tree. Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver malignancy in the United States. Surgical resection with negative margins is the only recognized curative treatment option for iCCA; however, most patients will present with advanced or unresectable disease. The clinical presentation is largely non-specific, with the characteristic symptoms of biliary malignancies being less frequent than extrahepatic cholangiocarcinoma. Clinical management in iCCA is heavily influenced by the molecular profile of individual tumors. Hence, pathologists must exercise caution to prevent tissue exhaustion during the diagnostic workup of iCCA and ensure the availability of tissue samples for molecular testing. Establishing standardized procedures for obtaining adequate tissue and using molecular testing is vital. Circulating tumor DNA (ctDNA) offers a potential alternative to tissue-based analysis, especially in cases with insufficient tissue samples. Drugs targeting alterations in NTRK, IDH1, BRAF, FGFR2, and HER2 are commonly utilized. Targeting the MDM2-p53 pathway represents an avenue for future investigations in advanced BTCs. Liver transplantation and locoregional therapies are treatment modalities that may represent curative intent treatments for patients with unresectable disease, and larger explorations are warranted. Akin to HCC, a multidisciplinary team-based approach is essential for patients with BTCs. Through this narrative review of literature, we provide an overview of the current management of iCCA with perspectives regarding future directions in the clinical management of iCCA. We also present patient perspectives regarding the importance of patient advocacy and access to advances in clinical research for patients with BTCs.

Keywords: biliary tract cancers; cholangiocarcinoma; liver transplantation; molecular testing; targeted therapies.

FIGURE 1

Anatomic classification of cholangiocarcinoma and common target genes altered in cholangiocarcinoma subtypes. Abbreviations: CCA, cholangiocarcinoma; eCCA, extrahepatic cholangiocarcinoma; iCCA, intrahepatic cholangiocarcinoma. Reprinted from Gopal et al with permission from Archives of Pathology & Laboratory Medicine. Copyright 2024. College of American Pathologists.

FIGURE 2

A comprehensive approach to systemic therapies in intrahepatic cholangiocarcinoma. Abbreviations: dMMR, mismatch repair deficiency; FOLFOX, leucovorin/fluorouracil/oxaliplatin; GemCis, gemcitabine/cisplatin; MSI-H, microsatellite instability—high; Nal-IRI/FU/LV, liposomal irinotecan/fluorouracil/leucovorin; NGS, next-generation sequencing; PS, performance status.