Molecular pathology selected abstracts

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Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; Andrés G. Madrigal, MD, PhD, assistant professor, clinical, Ohio State University Wexner Medical Center, Columbus; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; and Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center.

Value of identifying molecular subtypes for non-muscle-invasive bladder cancer

July 2023—Non-muscle-invasive bladder cancer accounts for the majority of bladder tumors and is typically treated with transurethral resection of the bladder tumor followed by adjuvant intravesical Bacillus Calmette-Guérin instillations. However, the long-term effectiveness of Bacillus Calmette-Guérin (BCG) is limited, and patients with recurrent or progressive disease have lower survival rates. Understanding the genetic makeup of tumors and identifying molecular subtypes associated with BCG response could provide valuable insights that aid in developing personalized treatments. The authors conducted a study in which they performed whole-transcriptome sequencing of non-muscle-invasive bladder cancers (NMIBCs) from 132 patients who had never received BCG treatment and 44 patients whose cancer recurred after BCG treatment. Based on these patients’ results, the authors identified three unique molecular subtypes among the tumors—BRS1, 2, and 3. Patients with BRS3 showed increased epithelial-to-mesenchymal transition pathway activity and their tumors were enriched for mutations associated with the extracellular matrix when compared with the other two subtypes. Patients with BRS3 tumors also demonstrated a worse progression-free survival and increased activity in epithelial-mesenchymal transition (EMT) pathways. BRS1 and BRS2 tumors displayed luminal characteristics and were associated with a more favorable patient outcome after BCG treatment. The BRS3 tumor microenvironment exhibited immune-suppressive features, with higher infiltration of B cells, tumor-associated macrophages, CD8⁺ T cells, and regulatory T cells. BRS3 tumors also showed higher intratumoral vimentin protein expression, suggesting increased immune suppression and potential treatment failure. BRS3 was associated with more aggressive biology, including enrichment of EMT, complement, IL6-JAK-STAT3, and angiogenesis pathways. Matching subtypes with clinical outcomes showed that patients with BRS3 tumors had a higher risk of recurrence after BCG therapy. BRS stratification was validated in a second cohort of 151 BCG-naïve patients who had high-risk NMIBC, and the molecular subtypes outperformed guideline-recommended risk stratification based on clinicopathological characteristics. The BRS classifier improved the clinical risk stratification of high-risk NMIBC and identified patients with BRS3 tumors who were at increased risk of progression. Post-BCG tumors that recurred were enriched for BRS3, and the gene-expression signatures of these tumors provided insight into potential therapeutic targets. Notably, BRS3 tumors displayed increased expression of immune checkpoint-related genes and DDR2, suggesting the potential for combination therapy with checkpoint inhibitors or anti-DDR2 treatments. The authors concluded that BRS3 tumors are associated with an aggressive phenotype and poorer survival, while BRS1 and BRS2 tumors display more favorable characteristics. Their findings highlight the importance of molecular profiling in predicting treatment response and provide potential targets for therapeutic interventions in NMIBC.

de Jong FC, Laajala TD, Hoedemaeker RF, et al. Non-muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Guérin. Sci Transl Med. 2023;15. doi:10.1126/scitranslmed.abn4118

Correspondence: Dr. Dan Theodorescu at dan.theodorescu@cshs.org or Dr. James C. Costello at james.costello@cuanschutz.edu