December 2025

UROLOGY

KEY DRIVERS FOUND TO PREDICT NMIBC RECURRENCE AND BCG RESPONSE

High-risk non–muscle-invasive bladder cancer (NMIBC), particularly stage T1 tumors, are a major clinical challenge. Despite surgical resection and Bacillus Calmette-Guérin (BCG) immunotherapy, 30% of cases recur within two years, and 10% progress to metastasis. Global shortages of BCG emphasize the urgent need for alternative or complementary strategies. This Northwestern Medicine study published in European Urology aimed to define molecular subtypes of T1 NMIBC and develop a precise framework to predict recurrence risk and guide treatment.

Researchers analyzed 106 T1 tumors using:
  • Transcriptomic profiling and targeted genomic sequencing (194-gene panel).
  • Validation through single-cell RNA sequencing and spatial transcriptomics.
  • Unsupervised clustering of the 1,500 most variable genes to identify subtypes.
  • A machine learning model integrating genomic and transcriptomic features to predict recurrence risk.

Key findings:
  • Four molecular subtypes identified: Each with distinct genomic and microenvironment characteristics.
  • Inflamed subtype: Tumors with high immune cell infiltration, endogenous retroelement expression and commensal bacteria showed best response to BCG therapy.
  • Predictive model performance: Achieved AUC = 0.87 (95% CI: 0.72–1.0) for recurrence risk.
  • Clinical implications: Tumors with greater baseline immune activity respond better to BCG, enabling precision treatment strategies.
  • Limitations: Small sample size; requires validation in larger cohorts.

​This study introduces a molecularly driven classification system for high-risk NMIBC, offering a roadmap for personalized therapy and improved outcomes amid BCG shortages.
Joshua Meeks, MD, PhD, the Edward M. Schaeffer, MD, PhD Professor of Urology and Associate Professor of Urology at Northwestern Medicine
Sarki Abdulkadir, MD, PhD, the John T. Grayhack, MD, Professor of Urological Research and Vice Chair for Research in the Department of Urology at Northwestern Medicine

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