FGFR2 fusion testing

Diamonds Diamonds

Molecular profiling for the treatment of cholangiocarcinoma (CCA)

Targeted medicine

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

Microscope

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 an 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 routine use of multigene NGS to detect level 1 actionable alterations (IDH1 mutations, FGFR2 fusions, NTRK fusions and MSI-H) in advanced CCA.16

An illustration of the liver
References:
  1. Jain A, Borad MJ, Kelley RK, Wang Y, Abdel-Wahab R, Meric-Bernstam F, et al. Cholangiocarcinoma with FGFR genetic aberrations: a unique clinical phenotype. JCO Precis Oncol. 2018; 2:1–12.
  2. Lowery MA, Ptashkin R, Jordan E, Berger MF, Zehir A, Capanu M, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res. 2018 Sep 1; 24(17):4154–61.
  3. Graham RP, Barr Fritcher EG, Pestova E, Schulz J, Sitailo LA, Vasmatzis G, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol. 2014 Aug; 45(8):1630–8.
  4. PEMAZYRE® (pemigatinib). Summary of product characteristics: Section 5.1. February 2022.
  5. Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017 Mar 14; 18(11):2780–94.
  6. Ross JS, Wang K, Gay L, Al-Rohil R, Rand JV, Jones DM, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist. 2014 Mar; 19(3):235–42.
  7. Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, Ojima H, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014 Apr; 59(4):1427–34.
  8. Borad MJ, Gores GJ, Roberts LR. Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma. Curr Opin Gastroenterol. 2015 May; 31(3):264‑8.
  9. Dudley JC, Zheng Z, McDonald T, Le LP, Dias-Santagata D, Borger D, Batten J, 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 Jan; 18(1):124–30.
  10. Hu L, Ru K, Zhang L, Huang Y, Zhu X, Liu H, et al. Fluorescence in situ hybridization (FISH): an increasingly demanded tool for biomarker research and personalized medicine. Biomark Res. 2014 Feb 5; 2(1):3.
  11. Cree IA, Deans Z, Ligtenberg MJ, Normanno N, Edsjö A, Rouleau E, et al. Guidance for laboratories performing molecular pathology for cancer patients. J Clin Pathol. 2014 Nov; 67(11):923–31.
  12. Damodaran S, Berger MF, Roychowdhury S. Clinical tumor sequencing: opportunities and challenges for precision cancer medicine. Am Soc Clin Oncol Educ Book. 2015; e175–82.
  13. Su D, Zhang D, Chen K, Lu J, Wu J, Cao X, 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 Sep 7; 36(1):121.
  14. Silverman IM, Hollebecque A, Friboulet L, Owens S, Newton RC, Zhen H, et al. Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib. Cancer Discov. 2021 Feb; 11(2):326–39.
  15. Barr FG. Fusion genes in solid tumors: the possibilities and the pitfalls. Expert Rev Mol Diagn. 2016 Sep; 16(9):921–3.
  16. Mosele F, Remon J, Mateo J, Westphalen CB, Barlesi F, Lolkema MP, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2020 Nov; 31(11):1491–505.

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