Association of non-luminal subtype with overall survival in high-risk non-muscle invasive bladder cancer patients: Biomarker results from the Bladder Cancer Prognosis Programme.

843 Background: High-risk non-muscle-invasive bladder cancer (HR-NMIBC) is associated with substantial progression and recurrence rates. Some patients with HR-NMIBC will die from their disease, and aggressive tumors could be treated earlier with radical cystectomy (RC). Previous work revealed higher rates of pathological upstaging at RC for NMIBC with a non-luminal molecular subtype. Methods: The Decipher Bladder genomic subtyping classifier (GSC; Veracyte, San Diego, CA, USA) was performed on bladder TURBT specimens from HR-NMIBC patients included in the prospectively followed Bladder Cancer Prognosis Programme (BCPP) registry (University of Birmingham, UK). GSC, a classifier originally developed for MIBC were evaluated for the primary endpoint of overall survival (OS) using Kaplan-Meier and Cox hazards analysis. Subgroup analyses included very high-risk NMIBC (VHR-NMIBC) as categorized by the 2025 Guidelines on NMIBC by the European Association of Urology (EAU). Results: A total of 259 HR-NMIBC patients were analyzed of which 67 patients (26%) were stage Ta and 192 patents were stage T1 (74%). 83 patients (32%) died. The median follow-up time for censored patients was 5.2 years (IQR 4.1-5.9 years). Molecular subtyping identified 219 luminal and 40 non-luminal tumors. Comparing luminal and non-luminal HR-NMIBC we found no significant differences for patient age and sex, whereas cT1 disease was significantly more present among non-luminal disease (p=0.007). Patients with non-luminal tumors had worse OS with 22 (55%) deaths in patients with non-luminal tumors and 61 (28%) deaths in patients with luminal tumors, corresponding to 5-year OS estimates of 44% for non-luminal and 72% for luminal HR-NMIBC. Multivariable analyses (MVA) revealed a significant association between molecular tumor subtype and OS after adjusting for baseline clinical variables (HR: 1.91 95% CI; 1.16 - 3.15, p=0.01). Application of the EAU 2025 guidelines revealed 56 patients (22%) were classified as very-high risk. Among these, non-luminal subtype at baseline was significantly associated with OS on MVA (HR 2.55 95% CI; 1.08 – 6.00, p=0.03). Conclusions: Non-luminal tumors at initial presentation harbor more aggressive disease among HR-NMIBC, reflected by worse OS on long-term follow-up as compared to luminal tumors.