Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape.
Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA).
FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Most common FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations.
Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.
ESMO open. 2022 Nov 30 [Epub ahead of print]
K Murugesan, A Necchi, T C Burn, O Gjoerup, R Greenstein, M Krook, J A López, M Montesion, H Nimeiri, A R Parikh, S Roychowdhury, S Schwemmers, I M Silverman, A Vogel
Cancer Genomics Research, Foundation Medicine, Inc., Cambridge, USA., Genitourinary Medical Oncology, Vita-Salute San Raffaele University, Milan; Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy., Translational and Data Sciences, Incyte Corporation, Wilmington., Scientific and Medical Publications, Foundation Medicine, Inc., Cambridge, USA., Research Scientist, Ohio State University, Columbus, USA., Integrated Healthcare Solutions, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Global Clinical Development Lead Oncology, Foundation Medicine, Inc., Cambridge, USA., Oncology (Medical/Hematology), Jefferson Health, Philadelphia, USA., Medical Oncology, Ohio State University, Columbus, USA., Integrated HealthCare Solutions PDMA (Oncology), F. Hoffmann-La Roche Ltd, Basel, Switzerland., Clinical Bioinformatics, Incyte Corporation, Wilmington., Clinic for Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: .