Molecular Subtypes of T1 Bladder Cancers - Expert Commentary

Understanding the biological characteristics that determine clinical outcomes of T1 bladder cancers can guide clinicians in making optimal therapeutic decisions. A recent study published by Robertson et al. in European Urology subcategorized the T1 of nonmuscle-invasive bladder cancers (NMIBC) based on their molecular characteristics. The authors also investigated the predictive value of these subtypes on disease recurrence after treatment. The study included 73 primary tumors. Eighty-four percent of tumors had repeat transurethral resection, and all received induction and maintenance Bacillus Calmette-Guérin (BCG) (64%) if they did not recur. The authors performed RNA sequencing followed by unsupervised consensus clustering to define T1 tumor subtypes. They chose a five-cluster solution whose subtypes had distinct clinical outcomes and biological characteristics. This solution classified T1 tumors into five subtypes of T1 tumors with distinct biological features and clinical behavior, namely T1-luminal genomically unstable (T1-LumGU), T1-Inflamed (T1-Inflam), T1-True Luminal (T1-TLum), T1-Myc, and T1-Early. These subtypes were compared to outputs from other classifiers.


The majority of T1 tumors were classified as luminal papillary. The T1-TLum subtype had the highest median luminal papillary score and FGFR3 expression, no recurrence events, and the fewest copy number gains. The T1-LumGU subtype was associated with carcinoma in situ (CIS; 6/13, 46% of all CIS), had high E2F1 and EZH2 expression. The T1-Inflam subtype was characterized by infiltration with immune cells and increased expression of a set of 170 inflammation-related genes. The T1-Early subtype had five (38%) recurrences within the first six months of BCG and repressed IFN-a and IFN-g signatures. T1-Myc and T1-Early subtypes had the highest recurrence rates (14/30 within 24 months), the highest median MYC expression. These subtypes had significantly worse recurrence-free survival compared to the other three subtypes. The investigators developed a single-patient classifier to predict the molecular subtype of individual tumors.

This important study deepens our understanding of the biology of T1 nonmuscle-invasive bladder cancers. Prospective of these findings in other datasets could help guide T1 tumors' risk-stratification and guide personalized therapeutic decision-making.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

Reference:

  1. Robertson, A. Gordon, Clarice S. Groeneveld, Brian Jordan, Xiquo Lin, Kimberly A. McLaughlin, Arighno Das, Leigh Ann Fall et al. "Identification of Differential Tumor Subtypes of T1 Bladder Cancer." European urology (2020).
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