Molecular Subtypes and Response to BCG Treatment in Patients with NMIBC - Expert Commentary
The investigators performed transcriptomic analysis on two high-risk NMIBC patient cohorts: a discovery cohort with 132 pre-BCG tumors and 44 post-BCG tumors and a validation cohort with 151 pre-BCG tumors. Clustering the samples based on differential gene expression yielded three subtypes that are referred to as BRS1, BRS2, and BRS3. In terms of survival, patients with BRS3 tumors had the worst progression-free survival (PFS, 61%) compared to BRS2 (78%, p = 0.017) and BRS1 (83%, p = 0.003). These findings were confirmed in the validation cohort. At the molecular level, the BRS3 tumors exhibited increased activity of the epithelial-to-mesenchymal transition pathway and were enriched for mutations associated with the extracellular matrix. BRS3 tumors were also characterized by upregulation of immune-suppressive genes, including PD-1/PD-L1. In contrast, BRS1 and BRS2 tumors overexpressed the luminal marker peroxisome proliferator-activated receptor gamma (PPARG). BRS1 tumors also exhibited upregulation in cell cycle genes and processes such as autophagy and proteasome degradation, which may be linked to the subgroup’s more favorable outcome upon BCG treatment. The study further characterized immune activity in BRS3 tumors, which exhibited high immune scores and low tumor purity. There was high infiltration of B cells, tumor-associated macrophages, CD8+ T cells, and regulatory T cells. Patients with BRS3 tumors and progressive disease showed more macrophages and regulatory T cells.
Importantly, the different subtypes exhibited distinct responses to BCG treatment, with response rates of 85% for BRS1, 82% for BRS2, and 68% for BRS3 (p = 0.017). BRS3 was an independent predictor of PFS in a multivariable analysis. Integrating the BRS model with the existing European Association of Urology (EAU) risk stratification model improved patients' risk stratification. To determine whether the BRS model was valid for use with commercially approved and available techniques, researchers tested the OncoSignal PCR-based assay, which measures the activity of seven signaling pathways. The assay successfully distinguished BRS3 from BRS1/2 tumors. BRS-predicted tumors were enriched in post-BCG recurrences compared to pre-BCG tumors, with 14 of 26 BRS1/2 tumors switching to BRS3 post-BCG. Genes linked to BCG attachment and EMT genes were differentially altered in the post-BCG tumors
This important study de Jong et al. uncovered mechanisms of BCG treatment failure among a subset of NMIBC patients, who may be identified by examining tumor samples for immune suppression markers including Tregs and B cells. It is possible that the BRS3-subgroup patients may require more aggressive treatment.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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