FGFR2-IIIb Expression by Immunohistochemistry Has High Specificity in Cholangiocarcinoma with FGFR2 Genomic Alterations.
Cholangiocarcinoma
FGFR2 protein
Genomics
Immunohistochemistry
Journal
Digestive diseases and sciences
ISSN: 1573-2568
Titre abrégé: Dig Dis Sci
Pays: United States
ID NLM: 7902782
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
06
09
2021
accepted:
21
10
2021
pubmed:
14
11
2021
medline:
20
7
2022
entrez:
13
11
2021
Statut:
ppublish
Résumé
FGFR2 genomic alterations are observed in 10-20% of cholangiocarcinoma (CCA). Although FGFR2 fusions are an important actionable target, FGFR2 protein expression has not been thoroughly characterized. To evaluate FGFR2 protein expression in cholangiocarcinoma harboring FGFR2 genomic alterations. FGFR2 protein expression was evaluated in 99 CCA cases with two different antibodies. FGFR2 genomic alterations were confirmed via next-generating sequencing (NGS) or FISH. Primary objective was to determine the specificity and sensitivity of FGFR2 immunohistochemistry staining for detecting FGFR2 genomic alterations. Secondary objectives included overall FGFR2 immunohistochemistry staining in CCA patients, and evaluation of whether FGFR2 expression correlates with clinical outcomes including overall survival (OS), progression-free survival (PFS), and time-to-tumor recurrence (TTR). Immunohistochemistry staining with two antibodies against FGFR2, FPR2-D, and clone 98706 showed high accuracy (78.7% and 91.9%) and specificity (82.9% and 97.7%), and moderate sensitivity (53.9% and 57.1%), respectively, when compared with the standard methods for detecting FGFR2 genomic alterations. In a median follow-up of 72 months, there were no statistically significant differences in OS, PFS, and TTR, for patients with positive or negative FGFR2 staining. FGFR2 protein expression by immunohistochemistry has high specificity and therefore could be used to imply the presence of FGFR2 genomic alterations in the context of a positive test. In the case of a negative test, NGS or FISH would be necessary to ascertain cases with FGFR2 genomic alterations.
Sections du résumé
BACKGROUND
FGFR2 genomic alterations are observed in 10-20% of cholangiocarcinoma (CCA). Although FGFR2 fusions are an important actionable target, FGFR2 protein expression has not been thoroughly characterized.
AIMS
To evaluate FGFR2 protein expression in cholangiocarcinoma harboring FGFR2 genomic alterations.
METHODS
FGFR2 protein expression was evaluated in 99 CCA cases with two different antibodies. FGFR2 genomic alterations were confirmed via next-generating sequencing (NGS) or FISH. Primary objective was to determine the specificity and sensitivity of FGFR2 immunohistochemistry staining for detecting FGFR2 genomic alterations. Secondary objectives included overall FGFR2 immunohistochemistry staining in CCA patients, and evaluation of whether FGFR2 expression correlates with clinical outcomes including overall survival (OS), progression-free survival (PFS), and time-to-tumor recurrence (TTR).
RESULTS
Immunohistochemistry staining with two antibodies against FGFR2, FPR2-D, and clone 98706 showed high accuracy (78.7% and 91.9%) and specificity (82.9% and 97.7%), and moderate sensitivity (53.9% and 57.1%), respectively, when compared with the standard methods for detecting FGFR2 genomic alterations. In a median follow-up of 72 months, there were no statistically significant differences in OS, PFS, and TTR, for patients with positive or negative FGFR2 staining.
CONCLUSION
FGFR2 protein expression by immunohistochemistry has high specificity and therefore could be used to imply the presence of FGFR2 genomic alterations in the context of a positive test. In the case of a negative test, NGS or FISH would be necessary to ascertain cases with FGFR2 genomic alterations.
Identifiants
pubmed: 34773565
doi: 10.1007/s10620-021-07303-9
pii: 10.1007/s10620-021-07303-9
doi:
Substances chimiques
FGFR2 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3797-3805Subventions
Organisme : NCI NIH HHS
ID : DP2 CA195764
Pays : United States
Organisme : NCI NIH HHS
ID : K12 CA090628
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA210964
Pays : United States
Organisme : NCI NIH HHS
ID : K01 CA234324
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Ross JS, Wang K, Javle MM et al. Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and frequency of clinically relevant genomic alterations. J Clin Oncol 2015;33:40009. https://doi.org/10.1200/jco.2015.33.15_suppl.4009 .
doi: 10.1200/jco.2015.33.15_suppl.4009
Goyal L, Govindan A, Sheth RA et al. Prognosis and clinicopathologic features of patients with advanced stage isocitrate dehydrogenase (IDH) mutant and IDH wild-type intrahepatic cholangiocarcinoma. Oncologist 2015;20:1019–1027.
doi: 10.1634/theoncologist.2015-0210
Farshidfar F, Zheng S, Gingras MC et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep 2017;19:2878–2880.
doi: 10.1016/j.celrep.2017.06.008
Graham RP, Barr Fritcher EG, Pestova E et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Human pathology 2014;45:1630–1638.
doi: 10.1016/j.humpath.2014.03.014
Arai Y, Totoki Y, Hosoda F et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 2014;59:1427–1434.
doi: 10.1002/hep.26890
Javle M, Lowery M, Shroff RT et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol 2018;36:276–282.
doi: 10.1200/JCO.2017.75.5009
Lipika G, Hendrik-Tobias A, Ben T et al. Early clinical efficacy of TAS-120, a covalently bound FGFR inhibitor, in patients with cholangiocarcinoma. Ann Oncol 2017;28:ii145.
Papadopoulos KP, El-Rayes BF, Tolcher AW et al. A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours. Br J Cancer 2017;117:1592–1599.
doi: 10.1038/bjc.2017.330
Abou-Alfa GK, Sahai V, Hollebecque A et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol 2020;21:671–684.
doi: 10.1016/S1470-2045(20)30109-1
Wu YM, Su F, Kalyana-Sundaram S et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 2013;3:636–647.
doi: 10.1158/2159-8290.CD-13-0050
Xie D, Ren Z, Fan J, Gao Q. Genetic profiling of intrahepatic cholangiocarcinoma and its clinical implication in targeted therapy. Am J Cancer Res 2016;6:577–586.
pubmed: 27152236
pmcid: 4851838
Bogenberger J, DeLeon T, Arora M, Ahn D, Borad M. Emerging role of precision medicine in biliary tract cancers. NPJ Prec Oncol 2018;2:1–9.
doi: 10.1038/s41698-017-0044-8
Krook MA, Bonneville R, Chen H et al. Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy. Mol Case Studies 2019;5:a004002.
doi: 10.1101/mcs.a004002
Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 2005;16:139–149.
doi: 10.1016/j.cytogfr.2005.01.001
Borad MJ, Champion MD, Egan JB et al. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet 2014;10:e1004135.
doi: 10.1371/journal.pgen.1004135
Choi CH, Chung J, Kim J, Kim B, Hewitt SM. Expression of fibroblast growth factor receptor family members is associated with prognosis in early stage cervical cancer patients. J transl med 2016;14:124. https://doi.org/10.1186/s12967-016-0874-0 .
doi: 10.1186/s12967-016-0874-0
pubmed: 27154171
pmcid: 4859953
Ohashi R, Matsuda Y, Ishiwaka T, Naito Z. Downregulation of fibroblast growth factor receptor 2 and its isoforms correlates with a high proliferation rate and poor prognosis in high-grade glioma. Oncol Rep 2014;32:1163–1169.
doi: 10.3892/or.2014.3283
Li CF, He HL, Wang JY et al. Fibroblast growth factor receptor 2 overexpression is predictive of poor prognosis in rectal cancer patients receiving neoadjuvant chemoradiotherapy. J Clin Pathol 2014;67:1056–1061.
doi: 10.1136/jclinpath-2014-202551
Ahn S, Lee J, Hong M et al. FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival. Mod Pathol 2016;29:1095.
doi: 10.1038/modpathol.2016.96
Bekaii-Saab TS, Valle J, Borad MJ et al. Trial design for a phase 3 study evaluating pemigatinib (INCB054828) versus gemcitabine plus cisplatin chemotherapy in first-line treatment of patients with cholangiocarcinoma with FGFR2 rearrangement. J Clin Oncol. 2019. https://doi.org/10.1200/JCO.2019.37.4_suppl.TPS462 .
doi: 10.1200/JCO.2019.37.4_suppl.TPS462
pubmed: 30856044
Abou-Alfa GK, Borbath I, Clarke SJ et al. Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase III study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: The PROOF trial. Ann Oncol 2019;30:v319–v320.
doi: 10.1093/annonc/mdz247.158
Hechtman JF, Benayed R, Hyman DM et al. Pan-Trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol 2017;41:1547–1551.
doi: 10.1097/PAS.0000000000000911
Uruga H, Mino-Kenudson M. ALK (D5F3) CDx: an immunohistochemistry assay to identify ALK-positive NSCLC patients.". Pharmgenomics Pers Med 2018;11:147–155. https://doi.org/10.2147/PGPM.S156672 .
doi: 10.2147/PGPM.S156672
pubmed: 30271189
pmcid: 6147206
Solomon JP, Linkov I, Rosado A et al. NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol 2020;33:38–46.
doi: 10.1038/s41379-019-0324-7
Pu XH, Ye Q, Yang J et al. Low-level clonal FGFR2 amplification defines a unique molecular subtype of intrahepatic cholangiocarcinoma in a Chinese population. Hum pathol 2018;76:100–109.
doi: 10.1016/j.humpath.2017.12.028