Impact of FGFR3 Pathway Activation in Patients with Muscle-Invasive Bladder Cancer Treated with Neoadjuvant Chemotherapy

Background
The prognostic value of FGFR3 pathway activation in patients with muscle- invasive bladder cancer (MIBC) treated with neoadjuvant chemotherapy (NAC) has not been established. Activation of FGFR3 signaling drives a subset of urothelial bladder cancers and classically results from pathogenic gene mutations (mut) or fusions (fus). Additionally, an RNA signature (FGFR-PRS) representing activation of the FGFR3 pathway independent from pathogenic FGFR3 mut or fus has been identified (Eisner et al. Clin Can Res 2024). We previously reported that high tumor mutational burden (TMB) may be associated with improved pathological complete response (pCR) and survival in a cohort of MIBC patients treated with cisplatin-based NAC (Burgess et al. GU ASCO ‘26). In the current analysis, we assessed the impact of FGFR3 pathway activation detected by either FGFR3 gene mut/fus or FGFR-PRS (+) on clinical outcomes in the previously reported cohort.

Methods
91 patients with MIBC who received cisplatin-based NAC followed by radical cystectomy underwent genomic analysis of diagnostic transurethral resection of bladder tumor specimens with the Tempus xT platform. Sample size was prespecified by statistical design. A subset of 61 patients had sufficient RNA for FGFR-PRS analysis. Correlation of FGFR3 molecular status with TMB and clinical outcomes was performed using logistic regression, Cox proportional hazards models, and Kaplan-Meier techniques.

Results
Median follow up for the cohort was 63.6 months. pCR was achieved in 31.9%. 41.8% of patients relapsed. FGFR3 mut were found in 8 (8.8%) and included p.R248C (n = 2), p.S249C (n = 5), and p.G370C (n = 1). One (1.1%) patient had a FGFR3-TACC3 fus. In the subset with RNA analysis (n = 61), FGFR-PRS (+) was detected in 33 (54.1%), of which 28 (84.8%) were FGFR3 wild type (wt) without detected mut/fus. pCR occurred in 12.5% and 33.7% with and without FGFR3 mut [OR 0.281, p = 0.428]. pCR was similar regardless of FGFR-PRS status [OR 1.372, p = 0.602]. All tumors with FGFR3 mut/fus (n = 9) had TMB < 10 Mut/Mb. Nineteen (57.6%) tumors with FGFR-PRS (+) had TMB < 10 compared to 13 (46.4%) of FGFR-PRS (-) tumors. Six (75%) patients with FGFR3 mut [OR 3.188, p = 0.064] and 10 (30.3%) with FGFR-PRS (+) [OR 1.087, p = 0.999] relapsed. Patients with FGFR3 mut had inferior relapse-free survival (RFS) [HR 2.58, p = 0.028], but those with FGFR-PRS (+) did not [HR 1.37, p = 0.451].

Conclusions
The presence of FGFR3 mutations was associated with an inferior relapse rate and RFS in this MIBC cohort treated with cisplatin-based NAC. FGFR3 pathway activation by RNA signature (FGFR-PRS+) was not associated with inferior outcomes. Whether peri- operative FGFR3 inhibition improves prognosis in MIBC patients with FGFR3 mutations should be studied.