# Genomic Subtypes and Computational Biomarkers in Non-Muscle-Invasive Bladder Cancer Guiding Optimal Timing of Radical Cystectomy and BCG Response Prediction

## TL;DR

This review explores how genomic and immune-based biomarkers can help decide the best treatment timing for non-muscle-invasive bladder cancer patients who do not respond to BCG therapy.

## Contribution

The paper introduces a conceptual framework integrating molecular and immune data to guide treatment decisions in BCG-unresponsive bladder cancer.

## Key findings

- Genomic and immune biomarkers like BRS1–3 and UROMOL21 improve risk stratification in NMIBC.
- Early radical cystectomy may offer better recurrence-free survival in selected BCG-failure cases.
- Tumor biology and immune context influence BCG response and treatment outcomes.

## Abstract

Non-muscle-invasive bladder cancer (NMIBC) accounts for approximately 70% of newly diagnosed bladder cancer cases but exhibits significant clinical heterogeneity in treatment response and progression risk. While intravesical bacillus Calmette–GuérinCa (BCG) therapy remains the gold standard for high-risk disease, approximately 30–50% of patients experience BCG failure, creating a critical decision point between additional bladder-sparing therapy (BST) and early radical cystectomy (RC). Recent clinical data from the CISTO study suggest that, in appropriately selected patients, RC may be associated with higher 12-month recurrence-free survival while maintaining comparable cancer-specific survival and physical functioning. In this narrative review, we synthesize contemporary evidence on NMIBC genomic and transcriptomic subtypes, immune contexture, and clinicopathologic features associated with BCG response and progression risk, with emphasis on clinically oriented classification systems such as BCG Response Subtypes (BRS1–3) and UROMOL21. We highlight how tumor-intrinsic biology (e.g., EMT-associated programs), immune phenotypes (inflamed vs. immune-cold microenvironments), and genomic alterations may help refine risk stratification beyond traditional clinicopathologic models. To facilitate clinical integration, we propose a conceptual decisional framework that combines molecular subtype assignment, immune profiling, key pathologic risk factors, and patient considerations to generate probabilistic risk tiers that support selection among early RC, BST, and clinical trial strategies. Standardized multicenter cohorts and prospective evaluation are needed to validate integrated models and define their clinical utility for the precision timing of cystectomy in BCG-unresponsive NMIBC.