Towards greater clarity in the treatment of cholangiocarcinoma

Biliary tract carcinomas represent a heterogeneous group of tumours, both at an anatomical and molecular level.1 For metastatic biliary tract carcinomas, treatment mainly relies on chemotherapy, which has shown modest but significant results in terms of overall survival.2,3 However, although EGFR inhibitors and antiangiogenics failed to show any benefit in addition to chemotherapy (versus chemotherapy alone) in advanced biliary tract carcinomas,4,5 genome-wide analyses identified several actionable alterations (eg, IDH1/2, FGFR2, BRAF, HER2, MSI, NTRK) providing novel targets for drug therapies.6,7 Among them, the genes isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) produce key metabolic enzymes that prevent cell oxidative damage by catalysing the conversion of isocitrate to α-ketoglutarate. Gain-of-function IDH1/2 mutations result in a neomorphic ability to produce the oncometabolite 2-hydroxyglutarate from α-ketoglutarate.8 The rate of IDH mutations in biliary tract carcinomas ranges from 10 to 20%, the most common mutation in IDH1 occurring mostly in intrahepatic cholangiocarcinomas.8 Several IDH inhibitors are under investigation in solid tumours, such as the IDH1 inhibitor ivosidenib and the IDH2 inhibitor enasidenib, which have been approved by the US Food and Drug Administration for patients with IDH-mutant relapsed or refractory acute myeloid leukaemia. [...]the study by Abou-Alfa and colleagues reinforces the need for genetic testing for all patients with biliary tract carcinoma, especially intrahepatic cholangiocarcinoma, to identify candidates for personalised treatment.