Molecular subtype concordance and metastatic patterns in muscle‐invasive bladder cancer

Molecular subtypes are potential prognostic and predictive tools in muscle-invasive bladder cancer (MIBC). However, subtype concordance between primary tumors and metastases, as well as subtype-specific differences in metastatic patterns, remain poorly characterized. The present study aimed to evaluate the concordance of molecular subtypes between primary tumors and matched lymph node (LN) metastases and to explore their association with metastatic patterns. Gene expression-based molecular subtypes were determined according to the five-tiered Lund Taxonomy in 182 primary tumor samples and 34 matched LN metastases from patients with MIBC who underwent upfront radical cystectomy. Subtypes identified in the primary tumors were compared with those in matched positive LNs and patterns of distant metastasis were analyzed. In addition, the association between molecular and histological subtypes was also investigated. We found an overall 62% subtype concordance between primary tumors and corresponding LN metastases, with complete concordance in the basal/squamous subtype, lower concordance in the luminal subtypes (genomically unstable: 67%; urothelial-like: 57%), and low concordance (33%) in the mesenchymal-like (Mes) subtype. Luminal subtypes were associated with LN-only metastases and less frequent distant metastases. In contrast, the Mes subtype was associated with a higher rate of distant metastases (43%), and more frequent multiorgan involvement (≥3 organs: 40%). Higher expression of the mesenchymal gene CDH2 and the neuronal-differentiation genes GNG4 and ENO2 was associated with a higher number of metastatic sites. Gene expression-based molecular subtypes may change between primary MIBCs and matched LN metastases, and these differences appear to be subtype-dependent. Mes subtype and the expression of CDH2 as well as GNG4 and ENO2 are associated with more frequent and extensive metastases, indicating highly aggressive forms of MIBC.