Non–muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Guérin

Abstract

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.

Increased stromal densities of B cells, CD103+ cells, and CD163+ M2-like macrophages associate with poor clinical outcomes in BCG treated non-muscle invasive bladder cancer

“…Our findings demonstrate a robust association between CD79a+ B cell infiltration in both stromal and epithelial compartments, which is more pronounced in high-grade tumors from female patients who experienced early recurrence and disease progression following BCG therapy. These observations align with current literature highlighting the importance of CD79a+ B cells in driving tumor progression and fostering resistance to BCG therapy, particularly within the stromal milieu [21].…”

“…Increased expression of CD79A and CD163 genes in pre-treatment tumors is associated with shorter progression free survival following treatment with BCG We first determined the association between expression levels of CD79A and CD163 transcripts and clinical outcomes using the publicly available and recently published large independent cohort of BCG treated patients [21]. In this cohort of 283 patients, 20% of the patients were female and the entire cohort was BCG-naive high-risk NMIBC with 34% of the patients exhibiting progression after treatment with BCG.…”

“…In silico analysis of CD79A, CD103 and CD163 gene expression profiles in transcriptomic profiles of tumors from BCG naïve high-risk patients Based on our previous findings [18] on the associations between tumor infiltrating CD79a+ B cells and M2-like macrophage densities and overall poor clinical outcomes in patients with NMIBC, irrespective of the treatment type, we first evaluated the publicly available normalized bulk RNA-sequencing based tumor whole transcriptome profiles of 283 patients with NMIBC that was recently generated by Jong et al, [21]. The patients in this cohort were stratified into different quartiles according to their CD79a and CD163 gene expression levels.…”

“…The pre-treatment TIME is a major determinant of response to immunotherapy across various cancers [11,16,17]. Recent studies have established that the pre-treatment TIME plays an important role in determining BCG therapy response in patients with NMIBC [18][19][20][21]. This is especially important when considering BCG therapy, which involves a live bacterial preparation and its efficacy is dependent on multiple factors including the dose, viability of bacteria at the time of instillation, immune physiological status of the host, bacterial contact with the urothelium and uptake by cells in the bladder mucosal immune environment.…”

Use of genomic markers to improve epidemiologic and clinical research in urology

“…These efforts have provided important prognostic information compared to clinical characteristics. This approach was recently extended in a study of patients with high-risk NMI treated with Bacillus Calmette-Gu erin (BCG) to define three molecular subtypes that were predictive of BCG treatment response [51]. In MI bladder cancer, tumor profiling is also being evaluated to guide the selection of individualized neoadjuvant or adjuvant chemo-or immunotherapy [52 && ].…”