Molecular profile of bladder cancer progression to clinically aggressive subtypes.

Bladder cancer is a histologically and clinically heterogenous disease. Most bladder cancers are urothelial carcinomas, which frequently develop distinct histological subtypes. Several urothelial carcinoma histological subtypes, such as micropapillary, plasmacytoid, small-cell carcinoma and sarcomatoid, show highly aggressive behaviour and pose unique challenges in diagnosis and treatment. Comprehensive genomic characterizations of the urothelial carcinoma subtypes have revealed that they probably arise from a precursor subset of conventional urothelial carcinomas that belong to different molecular subtypes - micropapillary and plasmacytoid subtypes develop along the luminal pathway, whereas small-cell and sarcomatoid subtypes evolve along the basal pathway. The subtypes exhibit distinct genomic alterations, but in most cases their biological properties seem to be primarily determined by specific gene expression profiles, including epithelial-mesenchymal transition, urothelial-to-neural lineage plasticity, and immune infiltration with distinct upregulation of immune regulatory genes. These breakthrough studies have transformed our view of bladder cancer histological subtype biology, generated new hypotheses for therapy and chemoresistance, and facilitated the discovery of new therapeutic targets.

Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer.

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.

Correlative Analysis of ATM, RB1, ERCC2, and FANCC Mutations and Pathologic Complete Response After Neoadjuvant Chemotherapy in Patients with Muscle-invasive Bladder Cancer: Results from the SWOG S1314 Trial.

We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC). We found that a mutation in any one of these four genes predicted for pT0 at surgery (odds ratio = 5.36; 95% confidence interval [CI] 2.05, 14.02; two-sided p = 0.0006). The biomarker was better at predicting the presence of disease (negative predictive value for pT0 86%; 95% CI 73%, 94%) than the absence of disease (positive predictive value for pT0 48%; 95% CI 35%, 62%). There was no evidence of an interaction between the treatment arm (DDMVAC vs GC) and the genetic variant in terms of pT0. When combined with clinical assessment, these findings help inform patient selection for bladder preservation after cisplatin-based chemotherapy. PATIENT SUMMARY: A common standard of care for patients with muscle-invasive bladder cancer is neoadjuvant chemotherapy (NAC) followed by cystectomy to achieve cure. We previously discovered that specific DNA mutations in tumor samples collected at initial biopsy (transurethral resection of a bladder tumor) were predictive of a complete response to NAC. In other words, patients with these mutations were more likely to have a bladder found to be cancer free after surgery. In this study, we analyzed a larger set of tumor samples from a national clinical trial of chemotherapy followed by cystectomy to validate these earlier findings. We conclude that this biomarker test, when combined with careful clinical assessment, can be used to allocate patients to careful bladder surveillance instead of surgery. This hypothesis has been tested in the RETAIN trial presented previously (NCT02710734).

Neoadjuvant Cisplatin, Gemcitabine, and Docetaxel in Sarcomatoid Bladder Cancer: Clinical Activity and Whole Transcriptome Analysis.

BACKGROUND: Sarcomatoid urothelial cancer of the bladder (SBC) is a rare, but aggressive histological subtype for which novel treatments are needed. OBJECTIVE: We evaluated the clinical activity and safety of neoadjuvant cisplatin plus gemcitabine plus docetaxel (CGD) in muscle-invasive patients with SBC and assessed SBC tumor biology by whole transcriptome RNA sequencing. METHODS: A single-institution, retrospective analysis of muscle-invasive SBC patients treated with neoadjuvant CGD with molecular analysis. Patients received cisplatin 35 mg/m2 + gemcitabine 800 mg/m2 + docetaxel 35 mg/m2 intravenously on days 1 and 8 + pegfilgrastim 6 mg subcutaneously on day 9 every 3 weeks for 4 cycles followed by cystectomy. The primary endpoint was pathologic complete response (ypCR) rate. RESULTS: Sixteen patients with SBC received neoadjuvant CGD with a ypCR rate of 38% and a < ypT2 rate of 50%. Grade 3 and 4 toxicity occurred in 80% and 40% of patients, but was manageable with 81% of patients completing > 3 CGD cycles. Whole transcriptome RNA sequencing demonstrates co-clustering of SBC with conventional urothelial tumors. SBC tumors are characterized by basal-squamous and stroma rich gene signatures with frequent increased expression of immune checkpoint (CD274 (PD-L1)), chemokine (CXCL9), and T-cell (CD8A) genes. CONCLUSIONS: SBC is a chemosensitive subtype, with ypCR rate similar to urothelial bladder cancer following CGD neoadjuvant therapy. Whole transcriptome tissue analyses demonstrate increased expression of immune checkpoint and T-cell genes with therapeutic implications.

Oncologic Outcomes in Patients with Residual Upper Tract Urothelial Carcinoma Following Neoadjuvant Chemotherapy.

BACKGROUND AND OBJECTIVE: Growing evidence supports the use of neoadjuvant chemotherapy (NAC) for upper tract urothelial carcinoma (UTUC). However, the implications of residual UTUC at radical nephroureterectomy (RNU) after NAC are not well characterized. Our objective was to compare oncologic outcomes for pathologic risk-matched patients who underwent RNU for UTUC who either received NAC or were chemotherapy-naïve. METHODS: We retrospectively identified 1993 patients (including 112 NAC recipients) who underwent RNU for nonmetastatic, high-grade UTUC between 1985 and 2022 in a large, international, multicenter cohort. We divided the cohort into low-risk and high-risk groups defined according to pathologic findings of muscle invasion and lymph node involvement at RNU. Recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) estimates were calculated using the Kaplan-Meier method. Multivariable analyses were performed to determine clinical and demographic factors associated with these outcomes. KEY FINDINGS AND LIMITATIONS: Among patients with low-risk pathology at RNU, RFS, OS, and CSS were similar between the NAC and chemotherapy-naïve groups. Among patients with high-risk pathology at RNU, the NAC group had poorer RFS (hazard ratio [HR] 3.07, 95% confidence interval [CI] 2.10-4.48), OS (HR 2.06, 95% CI 1.33-3.20), and CSS (subdistribution HR 2.54, 95% CI 1.37-4.69) in comparison to the pathologic risk-matched, chemotherapy-naïve group. Limitations include the lack of centralized pathologic review. CONCLUSIONS AND CLINICAL IMPLICATIONS: Patients with residual invasive disease at RNU after NAC represent a uniquely high-risk population with respect to oncologic outcomes. There is a critical need to determine an optimal adjuvant approach for these patients. PATIENT SUMMARY: We studied a large, international group of patients with cancer of the upper urinary tract who underwent surgery either with or without receiving chemotherapy beforehand. We identified a high-risk subgroup of patients with residual aggressive cancer after chemotherapy and surgery who should be prioritized for clinical trials and drug development.

Tumor Subtyping: Making Sense of Heterogeneity with a Goal Toward Treatment.

BACKGROUND: Bladder cancers have high total mutation burdens resulting in genomic diversity and intra- and inter-tumor heterogeneity that may impact the diversity of gene expression, biologic aggressiveness, and potentially response to therapy. To compare bladder cancers among patients, an organizational structure is necessary that describes the tumor at the histologic and molecular level. These "molecular subtypes", or "expression subtypes" of bladder cancer were originally described in 2010 and continue to evolve secondary to next generation sequencing (NGS) and an increasing public repository of well-annotated cohorts. OBJECTIVE: To review the history and methodology of expression-based subtyping of non-muscle invasive (NMIBC) and muscle invasive bladder cancer (MIBC). METHODS: A literature review was performed of primary papers from PubMed that described subtyping methods and their descriptive feature including search terms of "subtype", and "bladder cancer". RESULTS: 21 papers were identified for review. Tumor subtyping developed from N = 2 to N = 6 subtyping schemes with most subtypes comprised of at least luminal and basal tumors. Most NMIBCs are luminal cancers and luminal MIBCs may be associated with less aggressive features, while one study of basal tumors identified a better clinical outcome with systemic chemotherapy. Tumors with a P53-like may have intrinsic resistance to chemotherapy. The heterogeneity of tumors, which is likely derived from stromal components and immune cell infiltration, affect subtype calls. CONCLUSION: Subtyping, while still evolving, is ready for testing in clinical trials. Improved patient selection with tumor subtyping may help with tumor classification and potentially match patient or tumor to therapy.