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Molecular Diagnostics

Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer: a real world experience

A Correction to this article was published on 11 March 2022

Abstract

Background

FGFR3-altered urothelial cancer (UC) correlates with a non-T cell-inflamed phenotype and has therefore been postulated to be less responsive to immune checkpoint blockade (ICB). Preclinical work suggests FGFR3 signalling may suppress pathways such as interferon signalling that alter immune microenvironment composition. However, correlative studies examining clinical trials have been conflicting as to whether FGFR altered tumours have equivalent response and survival to ICB in patients with metastatic UC. These findings have yet to be validated in real world data, therefore we evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance.

Methods

103 patients with metastatic UC treated with ICB at a single academic medical center from 2014 to 2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing, were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3-alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients.

Results

Our findings from this dataset confirm that FGFR3-altered (n = 17) and wild type (n = 86) bladder cancers are equally responsive to ICB (12 vs 19%, p = 0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumours have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response.

Conclusions

Our work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumours have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response.

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Fig. 1: FGFR3-altered patients treated with ICB have similar clinical benefit.
Fig. 2: FGFR3-altered tumours express higher FGFR3 and pathways associated with PPARG activation.
Fig. 3: FGFR3-altered tumours are enriched in luminal and differentiated molecular subtypes.
Fig. 4: FGFR3-altered tumours have differential stromal and immunosuppression residuals.

Data availability

DNA sequencing data are available upon request. RNAseq data have been deposited to Gene Expression Omnibus under accession ID GSE176307.

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Acknowledgements

We acknowledge the members of the Kim Lab for useful discussions, the UNC translational pathology laboratory (TPL) and the UNC Translational Genomics Facility (TGL) for their technical assistance.

Funding

This work was supported by the University Cancer Research Fund (UCRF) and NCI grant R01-CA241810 [WYK], a research collaboration agreement between Janssen Research & Development, LLC and GeneCentric Therapeutics, Inc. and a sponsored research agreement between GeneCentric Therapeutics, Inc and the University of North Carolina at Chapel Hill. TLR is supported by the National Cancer Institute K12 Career Development Award in Clinical Oncology (grant 5K12CA120780) and K08CA248967, as well as the Doris Duke Charitable Foundation (grant number 2015213).

Author information

Authors and Affiliations

Authors

Contributions

Tracy L Rose: Conceptualisation, methodology, validation, formal analysis, data curation, writing—original draft, writing—review and editing, visualisation, project administration. William H Weir: Formal analysis, data curation, writing—original draft, writing—review and editing, visualisation. Greg M Mayhew: Methodology, formal analysis, data curation, writing—review and editing. Yoichiro Shibata: Software, validation, formal analysis, data curation, writing—original draft. Patrick Eulitt: Data curation. Josh M Uronis: Project administration, Mi Zhou: Data curation, writing—original draft. Matthew Nielsen: Resources, writing— review and editing. Angela Smith: Writing—review and editing. Michael Woods: Writing—review and editing. Michele C Hayward: Data curation, project administration, writing—review and editing. Ashley H Salazar: Data curation. Matthew I Milowsky: Writing—review and editing. Sara E Wobker: Formal analysis, data curation. Katrina McGinty: Formal analysis, data curation. Michael V Millburn: Conceptualisation, supervision. Joel R Eisner: Writing—original draft, supervision, writing—review and editing, supervision. William Y Kim: Conceptualisation, methodology, validation, writing—original draft, writing—review and editing, supervision. Tracy L Rose was placed first in the co-first authorship spot because she conceived the project. William H. Weir was placed as second in the co-first authorship because he made substantial contributions to computational biology analysis, figure generation, and intellectual insights.

Corresponding author

Correspondence to William Y. Kim.

Ethics declarations

Ethics approval and consent to participate

This study was reviewed and approved by the Institutional Review Board at UNC with an approved IRB 18-1478. All patient data were de-identified at the time of data abstraction from the electronic medical record. The study was performed in accordance with the Declaration of Helsinki.

Consent to publish

Not applicable. No individual patient data are included in the publication.

Competing interests

This work was funded in part through a research collaboration agreement between Janssen Research & Development, LLC and GeneCentric Therapeutics, Inc. and a sponsored research agreement between GeneCentric Therapeutics, Inc and the University of North Carolina at Chapel Hill. TLR is supported by the Doris Duke Charitable Foundation (grant number 2015213) and the National Cancer Institute of the National Institutes of Health (1K08CA248967-01 Clinical Investigator Award). WYK and TLR receive research funding from GeneCentric Therapeutics and Merck. TLR receives research funding from Genentech/Hoffman-La Roche and Bristol-Myers Squibb. GMM, YS, MVM, JMU and JRE are employees of GeneCentric Therapeutics, Inc. and have stock interest in the company. GM a patent holder of the GeneCentric bladder cancer subtype classifier.

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Rose, T.L., Weir, W.H., Mayhew, G.M. et al. Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer: a real world experience. Br J Cancer 125, 1251–1260 (2021). https://doi.org/10.1038/s41416-021-01488-6

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