Modern therapeutic approaches in cholangiocarcinoma: A narrative review of key biomarkers and clinical trials

Cholangiocarcinoma (CCA), the second most common hepatic malignancy after hepatocellular carcinoma, presents a significant clinical challenge. This epithelial cell malignancy occurs in various anatomical subtypes, including intrahepatic, perihilar, and distal, each associated with unique genetic aberrations, clinical presentations, and treatment options. Early diagnosis is challenging, leading to poor survival rates, especially in advanced cases. Precision medicine offers hope for improved management of CCA by tailoring treatments based on molecular profiling. In recent years, the investigation of eight specific molecular aberrations has emerged as a promising avenue for targeted therapy in CCA. These include six oncogenic gene alterations (HER2 overexpression, IDH1 mutations, FGFR2 fusions, BRAF mutations, NTRK fusions, and RET fusions) as well as two immunotherapy-predictive biomarkers (TMB-H [tumor mutational burden-high] and MSI-H/dMMR [microsatellite instability-high/mismatch repair deficiency]). Studies have revealed distinct therapeutic approaches for each aberration, such as HER2-targeted therapies, IDH1 inhibitors, selective FGFR inhibitors, immune checkpoint inhibitors for TMB-H and MSI-H/dMMR cases, and RET kinase inhibitors. Notably, some of these treatments have received FDA approval, providing new hope for patients with these specific molecular profiles. The era of precision medicine shows promise in revolutionizing the diagnosis and treatment of CCA, improving patient outcomes and prognosis. The aim of this review is to summarize recent advances in precision medicine for cholangiocarcinoma (CCA), focusing on the identification of specific molecular aberrations and their corresponding targeted therapeutic interventions.