Real-world urinary detection of FGFR alterations to guide FGFR inhibitor therapy in bladder cancer.

Abstract

848 Background: FGFR inhibitors have emerged as a promising therapeutic option for urothelial bladder cancer (UBC) patients harboring FGFR alterations ( FGFRalt ). While tissue-based testing is the gold standard for detecting FGFRalt , urinary tumor DNA (utDNA) analysis offers distinct advantages, including non-invasiveness and ease of sampling accessibility. Although utDNA testing has demonstrated potential in guiding clinical decision-making for FGFR inhibitor therapy, its implementation in real-world practice requires further evaluation to establish its reliability and utility. Methods: We performed longitudinal utDNA analysis on a real-world cohort of 155 UBC patients, utilizing 322 urine samples, with the well-established PredicineCARE assay, a capture-based next-generation sequencing platform. The study aimed to evaluate the utility of utDNA in patient selection, monitoring therapeutic efficacy, and detecting disease recurrence. Results: Our findings demonstrate high genomic concordance between utDNA and tissue DNA, supporting the reliability of utDNA as a diagnostic tool. Analysis of baseline urine samples from 155 patients using the PredicineCARE assay identified the five most frequently altered genes in utDNA: TP53 (56%), TERT (52%), FGFR3 (30%), PIK3CA (26%), and ARID1A (26%). These findings are consistent with mutation profiles reported in previous studies. Notably, we observed stage-specific differences in FGFRalt prevalence, with FGFR alterations detected in 51.9% of non-muscle-invasive bladder cancer (NMIBC) cases and 34.6% of muscle-invasive bladder cancer (MIBC) cases. Serial urine analyses revealed that a consistent decline in utDNA levels was associated with an objective response to treatment, while an early rise in utDNA levels predicted subsequent pathological evidence of recurrence. Conclusions: These results highlight the utility of utDNA analysis using the PredicineCARE assay in tailoring FGFR inhibitor therapy to improve patient outcomes. The use of utDNA as a biomarker has the potential to enhance precision medicine in UBC management, offering a non-invasive and accessible approach for real-world clinical practice.