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Urothelial Bladder Cancer: Genomic Alterations in Fibroblast Growth Factor Receptor
Maroun Bou Zerdan1, Gennady Bratslavsky2, Joseph Jacob2
1Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, NY, USA.
Background And Objective:
Genomic alterations in fibroblast growth factor receptor (FGFR) genes have been linked to a reduced response to immune checkpoint inhibitors. Some of the immune microenvironment of urothelial bladder cancer (UBC) could be distorted because of the inhibition of interferon signaling pathways. We present a landscape of FGFR genomic alterations in distorted UBC to evaluate the immunogenomic mechanisms of resistance and response.
Methods:
There were 4035 UBCs that underwent hybrid, capture-based comprehensive genomic profiling. Tumor mutational burden was determined in up to 1.1 Mbp of sequenced DNA and microsatellite instability was determined in 114 loci. Programmed death ligand expression in tumor cells was assessed by immunohistochemistry (Dako 22C3).
Results:
The FGFR tyrosine kinases were altered in 894 (22%) UBCs. The highest frequency of alterations was in FGFR genomic alterations with FGFR3 at 17.4% followed by FGFR1 at 3.7% and FGFR2 at 1.1%. No FGFR4 genomic alterations were identified. The age and sex distribution were similar in all groups. Urothelial bladder cancers that featured FGFR3 genomic alterations were associated with lower driver genomic alterations/tumors. 14.7% of the FGFR3 genomic alterations were FGFR3 fusions. Other findings included a significantly higher frequency of ERBB2 amplification in FGFR1/2-altered UBCs compared with FGFR3-altered UBCs. Urothelial bladder cancers with FGFR3 genomic alterations also had the highest frequency of the activating mTOR pathway. FGFR3-altered UBCs also featured significantly higher frequencies of biomarkers associated with a lack of response to immune checkpoint inhibitors including a lower tumor mutational burden, lower programmed death-ligand 1 expression, and higher frequencies of genomic alterations in MDM2. Also linked to IO drug resistance, CDKN2A/B loss and MTAP loss were observed at a higher frequency in FGFR3-driven UBC.
Conclusions:
An increased frequency of genomic alterations is observed in UBC FGFR. These have been linked to immune checkpoint inhibitor resistance. Clinical trials are needed to evaluate UBC FGFR-based biomarkers prognostic of an immune checkpoint inhibitor response. Only then can we successfully incorporate novel therapeutic strategies into the evolving landscape of UBC treatment.
Insights
Fibroblast growth factor receptor (FGFR) alterations in urothelial bladder cancer (UBC) are linked to reduced immune checkpoint inhibitor response. Understanding these FGFR alterations is crucial for developing effective UBC treatments.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Genomic alterations in fibroblast growth factor receptor (FGFR) genes are associated with diminished responses to immune checkpoint inhibitors (ICIs).
- The tumor immune microenvironment in urothelial bladder cancer (UBC) can be compromised by inhibited interferon signaling pathways.
- Investigating FGFR alterations in UBC is essential for understanding resistance and response mechanisms to immunotherapy.
Purpose of the Study:
- To characterize the landscape of FGFR genomic alterations in urothelial bladder cancer (UBC).
- To evaluate the immunogenomic mechanisms underlying resistance and response to immune checkpoint inhibitors in UBC with FGFR alterations.
- To identify potential biomarkers for predicting ICI response in UBC.
Main Methods:
- Comprehensive genomic profiling was performed on 4035 UBC samples.
- Tumor mutational burden, microsatellite instability, and programmed death-ligand 1 (PD-L1) expression were assessed.
- FGFR genomic alterations were identified and correlated with other genomic features and clinical biomarkers.
Main Results:
- FGFR alterations were identified in 22% of UBCs, with FGFR3 alterations being the most frequent (17.4%).
- FGFR3-altered UBCs showed lower tumor mutational burden, reduced PD-L1 expression, and increased alterations in MDM2, CDKN2A/B, and MTAP, suggesting resistance to ICIs.
- FGFR3-altered UBCs also exhibited activating mTOR pathway and ERBB2 amplification in FGFR1/2-altered UBCs.
Conclusions:
- Genomic alterations in FGFR are prevalent in UBC and are associated with resistance to immune checkpoint inhibitors.
- Biomarkers related to FGFR alterations may predict ICI response in UBC.
- Further clinical trials are necessary to validate these biomarkers and integrate FGFR-targeted strategies into UBC treatment.
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