Molecular Characterisation and Therapeutic Implications of FGFR2 Fusions in Tissue and Circulating Tumor DNA from Patients with Intrahepatic Cholangiocarcinoma: A Review

Abstract

FGFR2 fusion is the one alteration in intrahepatic cholangiocarcinoma that reliably changes what a patient is offered. Finding it is harder than the literature implies, because the fusion partner varies from case to case and most assays are built around partners they already know. Objectives: To review the published evidence on FGFR2 fusions in intrahepatic cholangiocarcinoma: how often they occur, how reliably the available assays detect them in tissue and in plasma, what response and survival have been reported with FGFR inhibition, and how acquired resistance emerges and is detected. Material and Methods: Narrative review of discovery studies, diagnostic accuracy and proficiency studies, prospective trials and correlative sequencing analyses indexed in PubMed and the major oncology and pathology journals. Studies were eligible if they reported the prevalence or architecture of FGFR2 fusions, the performance of a detection assay in tissue or plasma, outcomes with FGFR-directed therapy, or mechanisms of acquired resistance.
No new patient data were generated; every frequency, accuracy estimate and survival figure quoted is one published by the original investigators. Results: FGFR2 fusions occur in roughly 10 to 15 per cent of intrahepatic cholangiocarcinomas. In a series of 226 cases assayed three ways, detection rates were 10.2 per cent by break-apart FISH, 9.7 per cent by RNA-based sequencing and 7.1 per cent by DNA-based sequencing, and only 57.7 per cent of the cases called positive by any method were positive by all three. Against RNA sequencing as reference, FISH showed 95.2 per cent sensitivity and DNA sequencing 71.4 per cent. Plasma performs worse still with standard panels: among patients with a tissue-confirmed fusion, cell-free DNA recovered the fusion in 18 per cent overall, 58 per cent where the partner was BICC1 and 2 per cent where it was not. A custom panel tiling the FGFR2 intron recovered fusions in 88.9 per cent. Objective response with FGFR inhibition ranged from 23.1 per cent with infigratinib to 46.5 per cent with lirafugratinib, and median overall survival reached 17.5 months with pemigatinib and 21.7 months with futibatinib. Conclusion: The limiting factor in this disease is assay design rather than biology. A negative FGFR2 result carries a materially different weight depending on which test produced it, and a negative plasma result from a standard panel is close to uninformative. Plasma earns its place in serial
monitoring, where it detects the polyclonal resistance mutations that tissue rebiopsy cannot practically capture. Abbreviations: iCCA – Intrahepatic Cholangiocarcinoma, CCA – Cholangiocarcinoma, FGFR – Fibroblast Growth Factor Receptor, FGFRi – FGFR
Inhibitor, NGS – Next-Generation Sequencing, FISH – Fluorescence In Situ Hybridisation, IHC – Immunohistochemistry, cfDNA – Cell-Free DNA, ctDNA – Circulating Tumour DNA, FFPE – Formalin-Fixed Paraffin-Embedded, ORR – Objective Response Rate, DCR – Disease Control Rate, PFS – Progression-Free Survival, OS – Overall Survival, VAF – Variant Allele Frequency.