Many patients have residual disease after neoadjuvant therapy but their prognosis and need for adjuvant therapy is unclear. This study evaluates patient prognosis based on the molecular profiling of residual disease at cystectomy.
RNA-seq data from TURBT samples was available from N=84 ABACUS patients of whom N=64 had matched RC samples, including 10 patients with pathologic complete response (pCR, ypT0N0). Pre- and post-atezolizumab tumor gene expression data was classified into molecular subtypes using the consensus subtyping model as a benchmark. Unsupervised consensus clustering (CC) was performed to categorize RC samples de novo, and each cluster was characterized using gene expression signatures. Two RC cohorts (NAC, N=133 & UTSW, N=94) known to harbor a scar-like biologic cluster were used for training and testing of a single-sample transcriptomic classifier (TC) that was validated in two independent (PURE-01, N=26 & ABACUS, N=64) RC cohorts after neoadjuvant immunotherapy.
Unsupervised CC revealed four distinct post-atezolizumab clusters (scar-like, basal, luminal-stromal & luminal). The scar-like cluster was present in 25% (16/64) of the post-atezolizumab samples and expressed genes associated with wound healing/scarring. A transcriptomic classifier (TC) trained to identify a favorable scar-like transcriptomic profile in residual bladder tumors showed robust performance in two validation cohorts, indicating a patient subgroup with favorable prognosis among NAC-treated, pembrolizumab-treated and atezolizumab-treated residual bladder cancer patients.
This study contributes to the framework for defining molecular subtypes at radical cystectomy. Residual bladder cancer with a scar-like transcriptomic profile may predict favorable patient prognosis after neoadjuvant chemo- and immunotherapy.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2025 Jul 15 [Epub ahead of print]
Joep J de Jong, Moritz J Reike, Yair Lotan, Roland Seiler, Elai Davicioni, Andrea Necchi, Thomas Powles, Peter C Black, Bernadett Szabados, Ewan A Gibb
Erasmus MC, Rotterdam, Netherlands., University of British Columbia Hospital, Vancouver, Canada., University of Texas Southwestern, Dallas, Texas, United States., Spitalzentrum Centre hospitalier Biel- Bienne, Biel, Switzerland., Veracyte (United States), San Diego, California, United States., IRCCS Ospedale San Raffaele, Milan, Italy., Barts Cancer Institute, Queen Mary University of London, Royal Free NHS Trust, London, United Kingdom., University of British Columbia, Vancouver, BC, Canada., Queen Mary University of London, London, United Kingdom., University of British Columbia, Vancouver, British Columbia, Canada.