FGFR2 fusion testing

Molecular profiling for the treatment of cholangiocarcinoma (CCA)

Genomic alterations such as chromosomal translocations and fusions contribute to malignant transformation.¹

Genomic studies reveal that ~50% of patients with CCA have actionable alterations, including fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements.²

FGFR2 fusions/rearrangements are strong oncogenic drivers and are the most common FGFR alteration, occurring almost exclusively in 10–16% of intrahepatic cholangiocarcinoma (iCCA) cases.^1,3-6

FGFR2 fusions are detectable early in disease progression and are key drivers of tumour growth.^7,8
Molecular profiling is necessary to identify FGFR2 fusions and rearrangements.^1,7,8

Methodologies to determine FGFR alterations

Genomic alterations with potential therapeutic implication are frequently found in patients with CCA,² supporting the rationale for molecular profiling at diagnosis. A variety of molecular profiling methods are now available, with next-generation sequencing (NGS) and fluorescence in situ hybridisation (FISH) among the most common assays.^2,9,10

NGS allows the opportunity to analyse a tissue sample for multiple alterations at the same time. Although the specimen size for NGS is initially larger and the turnaround time can be longer than for other methodologies, its more extensive coverage of genes of interest can be an advantage.^11-13

FISH was originally designed to identify one specific, predetermined alteration at a time. Although multigene FISH assays can detect multiple prespecified genetic alterations, NGS may provide additional, non-prespecified information not possible to detect through FISH.^9,10

FGFR2 fusions have a wide range of fusion partners.² Therefore, to identify patients with FGFR2 fusions, it is important to select a validated assay that:

Can detect FGFR2 fusions (which are distinct from FGFR2 point mutations).^1,14,15
Can detect all FGFR2 fusions, including those with known or unknown fusion partners
(ie, FGFR2 fusion-partner agnostic).^1,14,15

The European Society for Medical Oncology (ESMO) recommends parallel sequencing of several genes using focused NGS over single gene testing in patients with advanced disease.¹⁶

References:

Jain A, et al. Cholangiocarcinoma with FGFR genetic aberrations: A unique clinical phenotype. JCO Precis Oncol. 2018;2:1⁠–⁠12.
Lowery MA, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: Potential targets for intervention. Clin Cancer Res. 2018;24:4154⁠–⁠61.
Graham RP, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol. 2014;45:1630⁠–⁠8.
PEMAZYRE^® (pemigatinib). Swiss Professional Information, November 2022; https://www.swissmedicinfo.ch/ (accessed 16 December 2022).
Farshidfar F, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017;18:2780⁠–⁠94.
Ross JS, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist. 2014;19:235–42.
Arai Y, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.Hepatology. 2014;59:1427–34.
Borad MJ, et al. Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma. Curr Opin Gastroenterol. 2015;31:264–8.
Dudley JC, et al. Next-generation sequencing and fluorescence in situ hybridization have comparable performance characteristics in the analysis of pancreaticobiliary brushings for malignancy. J Mol Diagn. 2016;18:124–30.
Hu L, et al. Fluorescence in situ hybridization (FISH): An increasingly demanded tool for biomarker research and personalized medicine. Biomark Res. 2014;2:3.
Cree IA, et al. Guidance for laboratories performing molecular pathology for cancer patients. J Clin Pathol. 2014;67:923–31.
Damodaran S, et al. Clinical tumor sequencing: Opportunities and challenges for precision cancer medicine. Am Soc Clin Oncol Educ Book. 2015;e175–82.
Su D, et al. High performance of targeted next generation sequencing on variance detection in clinical tumor specimens in comparison with current conventional methods. J Exp Clin Cancer Res. 2017;36:121.
Silverman IM, et al. Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib. Cancer Discov. 2021;11:326–39.
Barr FG. Fusion genes in solid tumors: The possibilities and the pitfalls. Expert Rev Mol Diagn. 2016;16:921–3.
Vogel A, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022; doi: https://doi.org/10.1016/j.annonc.2022.10.506.

All references are available upon request.

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