Molecular markers increase precision of the European Association of Urology non-muscle invasive bladder cancer progression risk groups

Purpose: The European Association of Urology (EAU) guidelines for non-muscle invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathological parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC. Experimental Design: We prospectively included 1239 patients in follow-up for NMIBC in six European countries. Fresh frozen tumor samples were analyzed for GATA2, TBX2, TBX3 and ZIC4 methylation and FGFR3, TERT, PIK3CA and RAS mutation status. Cox-regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR=rate of progression per 100 patient-years) was calculated for subgroups. Results: In our cohort, 276 patients had a low, 273 an intermediate and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared to older studies is likely due to improved treatment in the last two decades. Overall, wild type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR 0.34, 2.53 and 2.64, respectively). The PIR for EAU high risk patients was 4.25. Based on FGFR3 mutation status and methylation of GATA2 this cohort could be reclassified into a good class (PIR=0.86, 26.2% of patients), a moderate class (PIR=4.32, 49.7%) and a poor class (PIR=7.66, 24.0%). Conclusions: We conclude that addition of selected biomarkers to the EAU risk stratification, increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression.

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