Fig. 2: Juxtamembrane FGFR2 in-frame deletion and mutation of Patient Case 2, downstream FGFR2 activation, and clinical course during treatment with lenvatinib.

a Amino acid change in the juxtamembrane part of FGFR2 caused by the c.1107_1113delinsCTGC; p.370_371delinsCys (ENST00000358487) alteration of Case 2. Upper part: normal FGFR2 protein sequence, lower part: altered sequence. b Immunohistochemistry of FGFR2 downstream targets in tumor biopsy of Case 2 prior to the treatment with lenvatinib. Scale bar 100 µm, magnification x200, objective x20. c Transcriptome analysis with expression levels of selected tyrosine kinases. Expression levels of the tyrosine kinases FGFR1-4, FLT1, FLT4, KDR, KIT, PDGFRA, PDGFRB, and RET from the transcriptome data of Case 2 (red) and of 29 cholangiocarcinoma patients from the TCGA database (blue). Samples with FGFR2 fusion genes from the TCGA cohort are shown as a triangle. The table shows the log2-fold change of the patient´s expression level in comparison to the TCGA cohort. d Before treatment with lenvatinib, a local relapse of the tumor at the edge of the liver resection area is seen dorsally to a known post-surgical biloma with a partial enhancement of the mass in a CT scan. The lesion showed a late arterial enhancement phase by a predominantly heterogeneous tumor attenuation (baseline, upper row). An additional ¹⁸F-FDG-PET examination was performed with a highly positive PET signal (lower row). After 7 weeks of treatment with lenvatinib the mass decreased, while the contrast medium enhancement (upper row) and the FDG uptake (lower row) totally disappeared. Note, a second mass next to the local relapse showed identical behavior. After 6 months of treatment, the two tumor areas coalesced, whereas they stayed unchanged in terms of water-equivalent attenuation (lack of solid, enhancing tumor parts) and loss of FDG-uptake. The last scan after more than 10 months showed an ongoing response to treatment.