[Cholangiocarcinoma as a model disease: new pathways in personalized medicine]

Biliary tract cancer comprises a biologically heterogeneous group of malignant tumors, including intrahepatic, perihilar and distal cholangiocarcinoma, as well as gallbladder cancer. In cases of advanced disease, systemic treatment has changed significantly in just a few years. Immunochemotherapy with gemcitabine/cisplatin plus durvalumab or pembrolizumab has become the standard first-line treatment, while the choice of second-line therapy increasingly depends on molecular results. Clinically relevant alterations include FGFR2 fusions or rearrangements, IDH1 mutations, HER2 amplification or overexpression, MSI-high or mismatch repair deficiency, NTRK, RET and NRG1 fusions and, in selected situations, BRAF-V600E, KRAS-G12C or DNA repair alterations such as germline BRCA1/2 or PALB2 variants. Biliary tract cancer is therefore a clinically useful model for precision oncology: anatomical and histological subtyping, the collection of high-quality tissue, early comprehensive molecular testing, and interdisciplinary evaluation via a molecular tumor board have a direct impact on treatment options and patient outcome. Molecular profiling should be performed early and not only after first-line treatment failure. A combination of DNA- and RNA-based next-generation sequencing, supplemented by immunohistochemistry and in situ hybridization, is required to detect both point mutations and complex fusion events. This article summarizes recent developments with direct relevance for clinical practice.