Gustave Roussy, Université Paris-Saclay, Département de Médecine Oncologique, Unité d’oncologie digestive, 114 rue Edouard Vaillant, 94800 Villejuif
Cholangiocarcinomas (CC) are infrequent tumors subdivided into intrahepatic (ICC) and extrahepatic CC, which are further subdivided into perihilar or distal CC, depending on their location on the biliary epithelium. Surgery remains the only curative-intent treatment, but the diagnosis is often made too late for it to be considered. In cases of locally advanced (unresectable), metastatic or recurrent CC after surgery, palliative chemotherapy combining cisplatin and gemcitabine is the standard of care. However, its benefit is limited, with median overall survival remaining less than one year. There is therefore an urgent need for new and more effective treatment options. The anatomical and therefore clinical heterogeneity of CC is coupled with molecular heterogeneity. The deciphering of this heterogeneity by high-throughput genomic sequencing has revealed the richness of CC, particularly ICC, in ‘actionable’ molecular targets. In particular, two molecular targets are observed with a respective frequency reaching or exceeding 10% to 20% of CC cases (and even more if we consider only ICC, among which these alterations are almost exclusively observed): fusions and rearrangements of the FGFR2 gene and mutations of the IDH1 gene. In addition to these two flagship alterations, there is a growing list of rarer ‘actionable’ molecular alterations, such as HER2 gene mutations and amplifications, BRAF mutations and NTRK gene fusions and rearrangements. Thus, it is now possible to envisage a strategy of early systematic molecular profiling of CC. It will then be possible to refer patients with CC resistant to conventional chemotherapy (perhaps at the time of initial diagnosis or even in the adjuvant setting) to therapeutic trials evaluating therapies targeting these alterations and, once European approval and reimbursement in France have been obtained (which is not yet the case for any of them), to consider molecular precision medicine for CC.