Characterization of Fibroblast Growth Factor Receptor Alterations and Activation in Patients with High-Risk Non-Muscle Invasive Bladder Cancer

Abstract Purpose: The GARNER study investigated fibroblast growth factor receptor (FGFR) alteration (ALT) frequency and the clinical outcome relationship with Bacillus Calmette-Guérin (BCG) treatment in high-risk non-muscle invasive bladder cancer (HR-NMIBC). An FGFR predictive response signature (FGFR-PRS) was discovered that identifies patients with an activated FGFR pathway who could potentially benefit from FGFR-targeted therapy beyond those who are FGFR ALT (+). Experimental Design: Pre-treatment tumor samples and clinical data were analyzed from 582 BCG-treated HR-NMIBC patients. FGFR-PRS was discovered using a separate BC dataset and applied to the GARNER and other BC cohorts. FGFR-PRS was also applied to in vitro data from UC cell lines treated with FGFR-active agents. Results: 31% of pre-treatment GARNER HR-NMIBC tumors were FGFR ALT (+) but this was not significantly associated with BCG response. For the subset of patients with paired pre- and post-BCG treatment samples, nearly one-third pre-treatment ALT (+) patients were ALT (-) post-treatment. FGFR-PRS identified patients with an activated FGFR pathway and identified approximately 2-fold additional patients compared to ALT status alone, and this increase was similar across tumor stage. A positive relationship between tumor growth inhibition and FGFR-PRS score was shown in BC in vitro models treated with FGFR-active agents. Conclusions: These data provide support for FGFR-targeted therapy use in FGFR ALT (+) HR-NMIBC and describe tumors with shared FGFR pathway-activated biology that are FGFR ALT (-) but FGFR-PRS (+). The latter suggests a broader potential patient population for FGFR-targeted therapy, which will require subsequent validation in patients treated with FGFR-targeted therapy.