A1 Refereed original research article in a scientific journal
Non-muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Guérin
Authors: de Jong Florus C, Laajala Teemu D, Hoedemaeker Robert F, Jordan Kimberley R, van der Made Angelique CJ, Boevé Egbert R, van der Schoot Deric KE, Nieuwkamer Bart, Janssen Emiel AM, Mahmoudi Tokameh, Boormans Joost L, Theodorescu Dan, Costello James C, Zuiverloon Tahlita CM
Publisher: American Association for the Advancement of Science
Publication year: 2023
Journal: Science Translational Medicine
Journal name in source: Science translational medicine
Journal acronym: Sci Transl Med
Volume: 15
Issue: 697
ISSN: 1946-6234
eISSN: 1946-6242
DOI: https://doi.org/10.1126/scitranslmed.abn4118
Web address : https://www.science.org/doi/10.1126/scitranslmed.abn4118
The recommended treatment for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. If progression to advanced disease occurs, then patients must undergo a radical cystectomy with risks of substantial morbidity and poor clinical outcome. Identifying tumors unlikely to respond to BCG can translate into alternative treatments, such as early radical cystectomy, targeted therapies, or immunotherapies. Here, we conducted molecular profiling of 132 patients with BCG-naive HR-NMIBC and 44 patients with recurrences after BCG (34 matched), which uncovered three distinct BCG response subtypes (BRS1, 2 and BRS3). Patients with BRS3 tumors had a reduced recurrence-free and progression-free survival compared with BRS1/2. BRS3 tumors expressed high epithelial-to-mesenchymal transition and basal markers and had an immunosuppressive profile, which was confirmed with spatial proteomics. Tumors that recurred after BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive patients with HR-NMIBC, and the molecular subtypes outperformed guideline-recommended risk stratification based on clinicopathological variables. For clinical application, we confirmed that a commercially approved assay was able to predict BRS3 tumors with an area under the curve of 0.87. These BCG response subtypes will allow for improved identification of patients with HR-NMIBC at the highest risk of progression and have the potential to be used to select more appropriate treatments for patients unlikely to respond to BCG.
