Targeting extracellular and juxtamembrane FGFR2 mutations in chemotherapy-refractory cholangiocarcinoma.

3. September 2021

Bitzer M1 2 3 4, Spahn S5, Babaei S5, Horger M6, Singer S7, Schulze-Osthoff K8 9 10, Missios P5, Gatidis S6, Nann D7, Mattern S7, Scheble V5, Nikolaou K6, Armeanu-Ebinger S11, Schulze M12, Schroeder C11, Biskup S12, Beha J13, Claassen M5, Ruhm K13, Poso A8 9 14, Malek NP5 13 8 9


Intrahepatic cholangiocarcinoma (iCCA) has emerged as a promising candidate for precision medicine, especially in the case of activating FGFR2 gene fusions. In addition to fusions, a considerable fraction of iCCA patients reveals FGFR2 mutations, which might lead to uncontrolled activation of the FGFR2 pathway but are mostly of unknown functional significance. A current challenge for molecular tumor boards (MTB) is to predict the functional consequences of such FGFR2 alterations to guide potential treatment decisions. We report two iCCA patients with extracellular and juxtamembrane FGFR2 mutations. After in silico investigation of the alterations and identification of activated FGFR2 downstream targets in tumor specimens by immunohistochemistry and transcriptome analysis, the MTB recommended treatment with an FGFR-inhibiting tyrosine kinase inhibitor. Both patients developed a rapidly detectable and prolonged partial response to treatment. These two cases suggest an approach to characterize further detected FGFR2 mutations in iCCA to enable patients´ selection for a successful application of the FGFR -inhibiting drugs.