Clinical parameters outperform molecular subtypes for predicting outcome in bladder cancer: Results from multiple cohorts including TCGA.

Studies report molecular subtypes within muscle invasive bladder cancer (MIBC) predict clinical outcome. We evaluated whether subtyping by a simplified method and established classifications could predict clinical outcome.

Institutional cohort-1 (n=52; MIBC: 39), Oncomine-dataset (MIBC: 151) and The Cancer Genome Atlas (TCGA)-dataset (MIBC: 402) were subtyped by simplified panels (MCG-1; MCG-Ext) that included only transcripts common among published studies, and analyzed for predicting metastasis, cancer-specific survival (CSS), overall-survival (OS), and recurrence-free survival (RFS). TCGA-dataset was further analyzed using Lund-Taxonomy, BC-Molecular Taxonomy Group Consensus (Consensus), and mRNA-subtype (TCGA-2017) classifications.

MIBC specimens from cohort-1 and Oncomine-dataset showed intra-tumor heterogeneity for transcript/protein expression. MCG-1 subtypes did not predict outcome in univariate or Kaplan-Meier analyses. In multivariate analyses, N-stage (P≤0.007), T-stage (P≤0.04), M-stage (P=0.007) and/or age (P=0.01) predicted metastasis, CSS/OS and/or cisplatin-based adjuvant-chemotherapy response. In the TCGA-dataset, publications report that subtypes risk-stratify patients for OS. Consistently, MCG-1 and MCG-Ext subtypes associated with OS, but not RFS, in univariate and Kaplan-Meier analyses. TCGA-dataset includes low-grade specimens (21/402) and subtypes associated with tumor-grade (P=0.005). However, MIBC is rarely low-grade (<1%). Among only high-grade specimens, MCG-1 and MCG-Ext subtypes could not predict OS. Subtypes by Consensus, TCGA-2017 and Lund-Taxonomy associated with tumor-grade (P<0.0001) and OS (P=0.01-<0.0001) univariately. Regardless of classification, subtypes had ∼50%-60% sensitivity and specificity to predict OS/RFS. In multivariate analyses, N-stage and lymphovascular-invasion consistently predicted RFS (P=0.039) and OS (P=0.003).

Molecular subtypes reflect bladder tumor heterogeneity and associate with tumor-grade. In multiple cohorts/subtyping-classifications, clinical parameters outperform subtypes for predicting outcome.

The Journal of urology. 2019 May 21 [Epub ahead of print]

Daley S Morera, Sarrah S Lahorewala, Daniel Belew, Santu Ghosh, Zachary Klaassen, Andre R Jordan, Jiaojiao Wang, Martha K Terris, Roni J Bollag, Axel S Merseburger, Arnulf Stenzl, Mark S Soloway, Vinata B Lokeshwar

Department of Biochemistry and Molecular Biology, Augusta University , Augusta , GA , 30912., Division of Urology, Department of Surgery, Augusta University , Augusta , GA , 30912., Biostatistics and Data Science, Augusta University , Augusta , GA 30912., Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center (c), University of Miami-Miller School of Medicine , Miami , Florida , 33136., Department of Pathology, Bio-Repository Alliance of Georgia for Oncology (BRAG-Onc) at Georgia Cancer Center (e), Augusta University , Augusta GA , 30912., Department of Urology, University-Hospital Schleswig-Holstein, Campus Luebeck , Luebeck , Germany., Department of Urology, Eberhard Karls University Tübingen , Tübingen , Germany., Memorial Healthcare System , Aventura , FL 33180.