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Purpose:Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth.Experimental Design:Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes.Results:In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65% NE-like vs. 82% overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors.Conclusions:A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.

Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth. Experimental Design: Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes. Results: In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65% NE-like vs. 82% overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors. Conclusions: A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.

Background In PURE01 study (NCT02736266), neoadjuvant pembro resulted in 42% pT0 in patients (pts) with MIBC. pT0 pts had features suggesting pre-existing immunity or higher tumor mutational burden (TMB) may promote response. In this study, we investigated potential mechanisms for resistance to pembro, including FGFR3 genomic alterations (GA). Methods Pts enrolled in the PURE-01, which is still recruiting pts in its amended design, had predominant urothelial carcinoma histology and stage cT ≤ 4N0 MIBC. Biomarker analyses in the expanded cohort of 96 pts included PD-L1 combined positive score and comprehensive genomic profiling (FoundationCDx assay). In addition, TCGA MIBC (n = 405) and a prospective commercial cohort (PCC) of 415 MIBC pts from the clinical use of the Decipher Bladder TURB test from the GRID registry (NCT02609269) were analyzed. A single-sample genomic classifier (GC) was trained to identify FGFR3-active tumors (FGFR3+). Results In PURE01 cohort, despite a linear association of TMB with ypT0 in multivariable models (p = 0.017), there was no association between FGFR3 GA and pathological response nor with PD-L1 expression. FGFR3 GA were found in 17.6% ypT0 vs 20.7% in ypT3-4 disease (corrected p = 0.82). Applying the GC to the TCGA MIBC cohort, we found 45% of FGFR3+ cases had FGFR3 mutations vs 9% for the rest of the cohort. Applying the GC to the PCC, we found that the FGFR3+ tumors were Luminal (n = 14), Luminal Infiltrated (n = 10) or Luminal Papillary (n = 30). FGFR3+ pts showed significantly lower PD-L1 (-0.03 vs. 0.109, p Conclusions In our combined cohorts, FGFR3 GA did not correlate with response to pembro. FGFR3 GA are enriched in FGFR3+ tumors, which in turn tend to have lower immune activity, PD-L1 and PD-L2, suggesting FGFR3 activity may provide a potential tool for further discriminating the mechanisms underlying response and resistance to neoadjuvant pembro in MIBC. Clinical trial identification NCT02736266 (PURE01) NCT02609269 (GRID Registry). Legal entity responsible for the study The authors. Funding Decipher Bioscience. Disclosure A. Necchi: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Clovis; Advisory / Consultancy: Janssen. R. Madison: Full / Part-time employment: Foundation Medicine. J. Chung: Full / Part-time employment: Foundation Medicine. Y. Liu: Full / Part-time employment: Decipher Bioscience. J. Chung: Full / Part-time employment: Foundation Medicine. J.S. Ross: Full / Part-time employment: Foundation Medicine. S.M. Ali: Full / Part-time employment: Foundation Medicine. E. Davicioni: Full / Part-time employment: Decipher Bioscience. E.A. Gibb: Full / Part-time employment: Decipher Bioscience. All other authors have declared no conflicts of interest.