Characterization of FGFR Alterations and Activation in Patients with High-Risk Non-Muscle-Invasive Bladder Cancer

Area of Science:

• Oncology
• Genomics
• Urothelial Carcinomas

Background:

• High-risk non-muscle-invasive bladder cancer (HR-NMIBC) presents treatment challenges.
• Bacillus Calmette-Guérin (BCG) is a standard treatment, but response varies.
• Fibroblast Growth Factor Receptor (FGFR) pathway alterations are implicated in bladder cancer progression.

Purpose of the Study:

• To investigate the frequency of FGFR alterations (ALT) in HR-NMIBC.
• To determine the relationship between FGFR ALT and clinical outcomes with BCG treatment.
• To discover and validate an FGFR predictive response signature (FGFR-PRS) for identifying patients who may benefit from FGFR-targeted therapy.

Main Methods:

• Analysis of pretreatment tumor samples and clinical data from 582 BCG-treated HR-NMIBC patients in the GARNER study.
• Discovery of FGFR-PRS using a separate bladder cancer dataset.
• Application of FGFR-PRS to GARNER and other bladder cancer cohorts, as well as in vitro urothelial cancer cell line data treated with FGFR-active agents.

Main Results:

• FGFR ALT was present in 31% of tumors but not significantly associated with BCG response.
• FGFR-PRS identified an activated FGFR pathway in approximately twofold more patients than ALT status alone.
• In vitro models showed a positive correlation between FGFR-PRS score and tumor growth inhibition with FGFR-active agents.

Conclusions:

• FGFR ALT status alone is insufficient to predict BCG response in HR-NMIBC.
• FGFR-PRS identifies a broader patient population with FGFR pathway activation, suggesting potential benefit from FGFR-targeted therapy.
• Further validation is needed to confirm the utility of FGFR-PRS in patients receiving FGFR-targeted therapy.