Urothelial Bladder Cancer: Genomic Alterations in Fibroblast Growth Factor Receptor.

Abstract

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. 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). The FGFR tyrosine kinases were altered in 894 (22%) UBCs. The highest frequency of alterations was inFGFRgenomic alterations withFGFR3at 17.4% followed byFGFR1at 3.7% andFGFR2at 1.1%. No FGFR4 genomic alterations were identified. The age and sex distribution were similar in all groups. Urothelial bladder cancers that featuredFGFR3genomic alterations were associated with lower driver genomic alterations/tumors. 14.7% of theFGFR3genomic alterations were FGFR3 fusions. Other findings included a significantly higher frequency ofERBB2amplification inFGFR1/2-altered UBCs compared withFGFR3-altered UBCs. Urothelial bladder cancers withFGFR3genomic 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 inMDM2. Also linked to IO drug resistance, CDKN2A/Bloss andMTAPloss were observed at a higher frequency in FGFR3-driven UBC. 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.