Precision Oncology in Cholangiocarcinoma: Current Standards and Future Directions

The therapeutic landscape of cholangiocarcinoma (CCA) has undergone a paradigm shift towards precision oncology following recognition of its molecularly heterogenous landscape and rapid development of novel targeted therapeutics. Although outcomes remain poor, particularly in locally advanced or metastatic disease, comprehensive genomic profiling has identified multiple clinically actionable genomic alterations, leading to the successful implementation of biomarker-directed therapies. Targeted therapies are being rapidly developed; both to exploit additional molecular alterations that are not currently targeted in CCA and to overcome mechanisms of acquired treatment resistance. This review covers the current standard-of-care systemic treatments for localised, locally advanced and metastatic CCA with a particular emphasis on molecularly targeted therapies and immunotherapy. We discuss established precision oncology strategies targeting FGFR2 fusions and rearrangements, IDH1 mutations, ERBB2 amplification / HER2 overexpression and BRAFV600E mutations, together with the current evidence supporting immune checkpoint inhibition. Emerging therapeutic targets with the potential to further expand precision oncology in CCA are also reviewed, including homologous recombination deficiency (BRCA1/2 and PALB2), MDM2 amplification, NTRK fusions and MTAP loss. Finally, we discuss the current challenges to implementing precision oncology in CCA, including limitations in tumour tissue acquisition for comprehensive genomic profiling and difficulties performing adequately powered molecularly stratified clinical trials in this rare malignancy. We highlight how advances in molecular diagnostics, next-generation targeted therapies and innovative basket and umbrella trial designs are expected to further expand precision oncology strategies with the aim of further improving clinical outcomes for patients with CCA.