Search

Upper tract urothelial cancer (UTUC) are rare subsets of urothelial cancer, which typically present with more aggressive course. Molecular markers stratifying urothelial tumors as luminal subtype and non-luminal subtype tumors have been proposed to select patients who may have greater or lesser benefit from neoadjuvant systemic therapy in bladder cancer, though not yet evaluated in UTUC. Here, a single-institution study retrospectively obtained clinical and genomic information in patients with UTUC and evaluated four patient tumors using the Decipher Bladder® assay and Foundation Medicine® test. All four patients had non-luminal molecular subtype including basal (N = 4) and mixed basal/claudin-low (N = 2) subtypes. The best clinical response achieved was stable disease in a patient who had basal/claudin-low subtype with residual ypT3 after neoadjuvant chemotherapy. For the remaining three patients, all were treated with platinum-based chemotherapy for eventual metastatic disease but all three showed progressive disease with limited overall survival, highlighting their aggressive course. The non-luminal subtype and lack of FGFR alteration may partly explain the poor overall outcomes while the real-world benefit of next generation sequencing for clinical use in UTUC patients require further clarification in a larger cohort study.

The GUSTO clinical trial (Gene expression subtypes of Urothelial carcinoma: Stratified Treatment and Oncological outcomes) uses molecular subtypes to guide neoadjuvant therapies in participants with muscle‐invasive bladder cancer (MIBC). Before commencing the GUSTO trial, we needed to determine the reliability of a commercial subtyping platform (Decipher Bladder; Veracyte) when performed in an external trial laboratory as this has not been done previously. Here, we report our pre‐trial verification of the TCGA molecular subtyping model using gene expression profiling. Formalin‐fixed paraffin‐embedded tissue blocks of MIBC were used for gene expression subtyping by gene expression microarrays. Intra‐ and inter‐laboratory technical reproducibilities, together with quality control of laboratory and bioinformatics processes, were assessed. Eighteen samples underwent analysis. RNA of sufficient quality and quantity was successfully extracted from all samples. All subtypes were represented in the cohort. Each sample was subtyped twice in our laboratory and once in a separate reference laboratory. No clinically significant discordance in subtype occurred between intra‐ or inter‐laboratory replicates. Examination of sample histopathology showed variability of morphological appearances within and between subtypes. Overall, these results show that molecular subtyping by gene expression profiling is reproducible, robust and suitable for use in the GUSTO clinical trial. [ABSTRACT FROM AUTHOR]

Objective Patients and Methods Results Conclusions To further evaluate a genomic classifier (GC) in a cohort of patients undergoing radical cystectomy (RC), as long non‐coding RNA (lncRNA)‐based genomic profiling has suggested utility in identifying a distinct tumour subgroup corresponding to a favourable prognosis in patients with bladder cancer.Transcriptome‐wide expression profiling using Decipher Bladder was performed on transurethral resection of bladder tumour samples from a cohort of patients with high‐grade, clinically organ‐confined (cTa–T2N0M0) urothelial carcinoma (UC) who subsequently underwent RC without any neoadjuvant therapy (n = 226). The lncRNA‐based luminal favourable status was determined using a previously developed GC. The primary endpoint was overall survival (OS) after RC. Secondary endpoints included cancer‐specific mortality and upstaging at RC.In the study, 134 patients were clinical non‐muscle‐invasive bladder cancer (cTa/Tis/T1) and 92 patients were cT2. We identified 60 patients with luminal favourable subtype, all of which showed robust gene expression patterns associated with less aggressive bladder cancer biology. On multivariate analysis, patients with the luminal favourable subtype (vs without) were significantly associated with lower odds of upstaging to pathological (p)T3+ disease (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.12–0.82; P = 0.02), any upstaging (OR 0.41, 95% CI 0.20–0.83; P = 0.01), and any upstaging and/or pN+ (OR 0.50, 95% CI 0.25–1.00; P = 0.05). Luminal favourable bladder cancer was significantly associated with better OS (hazard ratio 0.33, 95% CI 0.15–0.74; P = 0.007).This study validates the performance of the GC for identifying UCs with a luminal favourable subtype, harbouring less aggressive tumour biology. [ABSTRACT FROM AUTHOR]

Background: To advance the use of recent discoveries in clinical setting, it is crucial to establish a consensus regarding the molecular classification of bladder cancer (BC). BC remains a significant global public health issue. It ranks as the 10th most frequently diagnosed cancer and the 13th leading cause of cancerrelated deaths globally. Efforts are underway to develop classification systems for non-muscle invasion bladder cancer (NMIBC) and muscle invasion bladder cancer (MIBC) due to the significant differences in treatment approaches. Conclusions: We conducted a search through various scientific websites, including original papers and clinical trials, to explore the classification journey of bladder cancer and the rationale for each subtype. Most of the molecular classifications are highlighted in the following manuscript aiming to be of significant value in near future in treatment strategies to improve the outcome. Further clinical trials focusing on the impact of molecular classification are urgently needed to advance the understanding and treatment of BC. [ABSTRACT FROM AUTHOR]

Abstract The GUSTO clinical trial (Gene expression subtypes of Urothelial carcinoma: Stratified Treatment and Oncological outcomes) uses molecular subtypes to guide neoadjuvant therapies in participants with muscle‐invasive bladder cancer (MIBC). Before commencing the GUSTO trial, we needed to determine the reliability of a commercial subtyping platform (Decipher Bladder; Veracyte) when performed in an external trial laboratory as this has not been done previously. Here, we report our pre‐trial verification of the TCGA molecular subtyping model using gene expression profiling. Formalin‐fixed paraffin‐embedded tissue blocks of MIBC were used for gene expression subtyping by gene expression microarrays. Intra‐ and inter‐laboratory technical reproducibilities, together with quality control of laboratory and bioinformatics processes, were assessed. Eighteen samples underwent analysis. RNA of sufficient quality and quantity was successfully extracted from all samples. All subtypes were represented in the cohort. Each sample was subtyped twice in our laboratory and once in a separate reference laboratory. No clinically significant discordance in subtype occurred between intra‐ or inter‐laboratory replicates. Examination of sample histopathology showed variability of morphological appearances within and between subtypes. Overall, these results show that molecular subtyping by gene expression profiling is reproducible, robust and suitable for use in the GUSTO clinical trial.

Upper tract urothelial cancer (UTUC) are rare subsets of urothelial cancer, which typically present with more aggressive course. Molecular markers stratifying urothelial tumors as luminal subtype and non-luminal subtype tumors have been proposed to select patients who may have greater or lesser benefit from neoadjuvant systemic therapy in bladder cancer, though not yet evaluated in UTUC. Here, a single-institution study retrospectively obtained clinical and genomic information in patients with UTUC and evaluated four patient tumors using the Decipher Bladder ® assay and Foundation Medicine ® test. All four patients had non-luminal molecular subtype including basal ( N = 4) and mixed basal/claudin-low ( N = 2) subtypes. The best clinical response achieved was stable disease in a patient who had basal/claudin-low subtype with residual ypT3 after neoadjuvant chemotherapy. For the remaining three patients, all were treated with platinum-based chemotherapy for eventual metastatic disease but all three showed progressive disease with limited overall survival, highlighting their aggressive course. The non-luminal subtype and lack of FGFR alteration may partly explain the poor overall outcomes while the real-world benefit of next generation sequencing for clinical use in UTUC patients require further clarification in a larger cohort study., Competing Interests: JBAC received Speakers’ Bureau and Advisory board fees from BMS, Astellas/Seagen Pfizer, EMD Serono, Merck KGaA; and also received advisory board fees from Pfizer, EMD Serono, Merck, AVEO, Immunomedics, Astellas/Seagen, Jannsen, Bayer, Novartis. JJdJ reports being a consultant for Veracyte. ED reports employee of Veracyte. All other authors declare that they have no conflicts of interest., (© The Author(s) 2024.)

Objective: To further evaluate a genomic classifier (GC) in a cohort of patients undergoing radical cystectomy (RC), as long non-coding RNA (lncRNA)-based genomic profiling has suggested utility in identifying a distinct tumour subgroup corresponding to a favourable prognosis in patients with bladder cancer., Patients and Methods: Transcriptome-wide expression profiling using Decipher Bladder was performed on transurethral resection of bladder tumour samples from a cohort of patients with high-grade, clinically organ-confined (cTa-T2N0M0) urothelial carcinoma (UC) who subsequently underwent RC without any neoadjuvant therapy (n = 226). The lncRNA-based luminal favourable status was determined using a previously developed GC. The primary endpoint was overall survival (OS) after RC. Secondary endpoints included cancer-specific mortality and upstaging at RC., Results: In the study, 134 patients were clinical non-muscle-invasive bladder cancer (cTa/Tis/T1) and 92 patients were cT2. We identified 60 patients with luminal favourable subtype, all of which showed robust gene expression patterns associated with less aggressive bladder cancer biology. On multivariate analysis, patients with the luminal favourable subtype (vs without) were significantly associated with lower odds of upstaging to pathological (p)T3+ disease (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.12-0.82; P = 0.02), any upstaging (OR 0.41, 95% CI 0.20-0.83; P = 0.01), and any upstaging and/or pN+ (OR 0.50, 95% CI 0.25-1.00; P = 0.05). Luminal favourable bladder cancer was significantly associated with better OS (hazard ratio 0.33, 95% CI 0.15-0.74; P = 0.007)., Conclusions: This study validates the performance of the GC for identifying UCs with a luminal favourable subtype, harbouring less aggressive tumour biology., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)