Abstract 100P
Background
Selective tyrosine kinase inhibitors targeting FGFR1–4 genomic alterations (GAs) are in development or have been granted FDA-accelerated approval for FGFR-altered cancers (i.e. advanced iCCA and BC). Understanding FGFR inhibitor resistance mechanisms is increasingly relevant; the genomic co-mutational landscape influencing inhibitor response should be studied comprehensively.
Methods
iCCA, BC and glioma solid tissue samples underwent hybrid capture-based comprehensive genomic profiling (CGP; Foundation Medicine, Inc., Cambridge, MA, USA) to assess all classes of GAs. Tumour mutational burden (TMB; non-driver somatic mutations per megabase) was determined on up to 1.1 megabases of sequenced DNA and microsatellite instability (MSI) on up to 114 loci.
Results
Most common FGFR GAs for iCCA, BC and glioma were FGFR2 rearrangements (REs; 9.3%; n = 618/6,641), FGFR3 short variants (SVs; 13.6%; 1,051/7,739) and FGFR1 SVs (2.1%; 239/11,550), respectively. FGFR2 RE-mutant (mt) iCCAs were significantly less likely to be TMB-high (0.5% vs 4.0%; P=1.3x10-7) and MSI-high (0.3% vs 1.4%; P=0.03) vs wildtype (wt). FGFR3 SV-mt BC was significantly less likely to be TMB-high (24.7% vs 34.9%; P=3.5x10-11) and more likely to be MSI-high (1.6% vs 0.7%; P=0.004) vs wt. Across the cohort (Table), TP53 and EGFR were significantly depleted in FGFR-mt tumours vs wt. In iCCA and BC, ERBB2 and KRAS were depleted, whilst BAP1 was enriched. For iCCA and glioma, IDH1 and TERT were depleted; in glioma, ATRX and H3-3A were both enriched. CDKN2A/B, TERT and STAG2 had contrasting trends between BC and glioma. Table: 100P
| % | iCCA (n = 6,641) | BC (n = 7,739) | Glioma (n = 11,550) | ||||||
| FGFR2 RE | FGFR3 SV | FGFR1 SV | |||||||
| Mt | Wt | P | Mt | Wt | P | Mt | Wt | P | |
| ATRX | 0.5 | 0.6 | 1 | 1 | 1 | 1 | 25.1 | 15.3 | 9.1x10-5 |
| BAP1 | 31.1 | 11.9 | 2.7x10-32 | 4.2 | 2.1 | 0.0002 | 0 | 0.2 | 1 |
| CDKN2A/B | 29.8 | 30.8 | 0.6 | 63.8 | 32.7 | 9.0x10-81 | 20.1 | 45.9 | 1.6x10-16 |
| EGFR | 0.8 | 2.3 | 0.01 | 0.8 | 4.8 | 2.3x10-12 | 1.7 | 28.5 | 1.7x10-28 |
| ERBB2 | 0 | 5.6 | 3.7x10-15 | 6.8 | 17.5 | 1.1x10-21 | 0.4 | 0.2 | 0.38 |
| H3-3A | 0 | 0.1 | 1 | 0.4 | 0.3 | 0.56 | 26.8 | 3.1 | 6.4x10-39 |
| IDH1 | 1.1 | 15.8 | 1.4x10-33 | 0.1 | 0.3 | 0.51 | 4.2 | 21.4 | 1.2x10-13 |
| KRAS | 1.3 | 22 | 1.2x10-50 | 1.4 | 6.8 | 6.2x10-15 | 2.9 | 2.1 | 0.36 |
| NF1 | 0.6 | 2.9 | 0.0002 | 2.1 | 3 | 0.11 | 26.8 | 15.3 | 7.6x10-6 |
| STAG2 | 0.3 | 0.3 | 1 | 20.7 | 5.8 | 5.5x10-49 | 0.4 | 2.6 | 0.035 |
| TERT | 2.3 | 6.6 | 2.7x10-6 | 81.6 | 70.3 | 5.2x10-15 | 12.1 | 58.6 | 1.3x10-49 |
| TP53 | 10.8 | 35.8 | 3.2x10-42 | 29.5 | 66.6 | 3.9x10-114 | 13 | 39.6 | 3.3x10-19 |
Conclusions
Appropriate combination therapy may differ between FGFR-altered tumours. CGP can inform molecular-based patient stratification for future clinical trials, next-generation FGFR inhibitor development and combination therapy for FGFR-altered tumours. Prof. Necchi and Dr Murugesan are co-first authors.
Clinical trial identification
Editorial acknowledgement
Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
A. Necchi: Financial Interests, Personal, Member, Steering Committee member: Astellas, AstraZeneca, Bayer, Clovis Oncology, F. Hoffmann-La Roche Ltd., Janssen, Merck; Non-Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Gilead Sciences, Inc., Ipsen, Merck; Non-Financial Interests, Personal, Leadership Role: Global Society of Rare Genitourinary Tumors (GSRGT); Non-Financial Interests, Personal, Principal Investigator, Coordinating Principal Investigator: Incyte; Non-Financial Interests, Personal, Principal Investigator, Local Principal Investigator: Pfizer; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd. K. Murugesan: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Full or part-time Employment: Foundation Medicine, Inc. T. Burn: Financial Interests, Personal, Full or part-time Employment, Previous employment: Incyte Corporation; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland. F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: Incyte Corporation, Tyra Biosciences; Financial Interests, Personal, Full or part-time Employment: Tyra Biosciences. O. Gjoerup: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Full or part-time Employment: Foundation Medicine, Inc. R. Greenstein: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Full or part-time Employment: Foundation Medicine, Inc. J.A. López: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd. M. Montesion: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Full or part-time Employment: Foundation Medicine, Inc. H. Nimeiri: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Full or part-time Employment: Foundation Medicine, Inc. A.R. Parikh: Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal and Institutional, Advisory Role, Consultancy services: Foundation Medicine, Inc. S. Roychowdhury: Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Funding, Advisory Board: AbbVie, Bayer, Merck; Financial Interests, Personal, Funding, Honoraria: IDT DNA Technologies; Financial Interests, Personal and Institutional, Funding, Advisory Board, Research Grant: Incyte, QED Therapeutics. S. Schwemmers: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd. I.M. Silverman: Financial Interests, Personal, Full or part-time Employment, Previous employment: Incyte Corporation; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd. A. Vogel: Financial Interests, Personal, Advisory Board, Speaker, consultancy and advisory role: AstraZeneca, Bayer, BMS, BTG, Daiichi Sankyo, Eisai, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., GSK, Imaging Equipment Ltd (AAA), Incyte, Ipsen, Merck, MSD, Pierre Fabre, Sanofi, Servier, Sirtex, Terumo; Non-Financial Interests, Personal, Funding, Research support for third-party writing assistance for this abstract, furnished by Stephen Salem, BSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland: F. Hoffmann-La Roche Ltd.