Molecular profiling in muscle‐invasive bladder cancer: more than the sum of its parts

Abstract

Bladder cancers are biologically and clinically heterogeneous. Recent large-scale transcriptomic profiling studies focusing on life-threatening muscle-invasive cases have demonstrated a small number of molecularly distinct clusters that largely explain their heterogeneity. Similar to breast cancer, these clusters reflect intrinsic urothelial cell-type differentiation programs, including those with luminal and basal cell characteristics. Also like breast cancer, each cell-based subtype demonstrates a distinct profile with regard to its prognosis and its expression of therapeutic targets. Indeed, a number of studies suggest subtype-specific differential responses to cytotoxic chemotherapy and to therapies that inhibit a number of targets, including growth factors (EGFR, ERBB2, FGFR) and immune checkpoint (PD1, PDL1) inhibitors. Despite burgeoning evidence for important clinical implications, subtyping has yet to enter into routine clinical practice. Here we review the conceptual basis for intrinsic cell subtyping in muscle-invasive bladder cancer and discuss evidence behind proposed clinical uses for subtyping as a prognostic or predictive test. In deliberating barriers to clinical implementation, we review pitfalls associated with transcriptomic profiling and illustrate a simple immunohistochemistry (IHC)-based subtyping algorithm that may serve as a faster, less expensive alternative. Envisioned as a research tool that can easily be translated into routine pathology workflow, IHC-based profiling has the potential to more rapidly establish the utility (or lack thereof) of cell type profiling in clinical practice. Conflict of interest statement: DrBerman has served as a paid scientific advisor to Janssen Pharmaceuticals, which manufactures erdafitinib. cancers that invade the muscular bladder wall, commonly referred to as muscle-invasive bladder cancers. This focus reflects the scarcity of molecular subtype studies identified in more superficial bladder cancers,Non-luminal-like MIBCs are often casually referred to as 'basal-like', a simplification that clearly underestimates the variety of MIBC molecular phenotypes. About two-thirds of non-luminal-like MIBCs show strong expression of basal genes including KRT5, KRT6, KRT14, CD44, CDH3, and EGFR. This molecular subtype shows relatively high levels of both stromal-

RNAseq expression patterns of canine invasive urothelial carcinoma reveal two distinct tumor clusters and shared regions of dysregulation with human bladder tumors

“…HER2 overexpression has been identified by immunohistochemistry in 57% of canine iUCs [56] and is predicted to be an upstream regulator of gene expression in canine iUCs [28]. Some growth factors, including EGFR and ERBB2, are the target of directed therapies for the treatment of iUCs in humans [57]. These findings suggest that canine iUC is an excellent platform for expanding our foundational understanding of growth factor receptor-targeted therapies.…”

Traditional Classification and Novel Subtyping Systems for Bladder Cancer

“…mRNA in frozen samples is relatively stable, while that in formalinfixed, paraffin-embedded specimens is often severely degraded (49). Because the TME contains a large number of other components, such as stromal cells and immune cells, the inappropriate purification of tissues can also affect the results of molecular subtyping (23). Of course, bladder cancer is a highly heterogeneous tumor, and even if the samples are collected from different sites of the same tumor tissue, its molecular subtyping results may be different (44).…”

“…It should also aid in the development of personalized new molecular diagnoses and treatments. In particular, the study of molecular subtyping based on genetics has made rapid progress in the study of bladder cancer and has attracted increasing attention (23)(24)(25). The development of molecular subtyping based on genomics and transcriptomes, etc., provides a new way to understand bladder cancer.…”

Immunohistochemistry-based taxonomical classification of bladder cancer predicts response to neoadjuvant chemotherapy

“…A recent study of bladder cancer histological variants has shown that BASQ tumors display greatest heterogeneity and supports that variants arise from conventional urothelial carcinomas (28). More work needs to be carried out to specifically assess the relevance of sample bias, the difference between primary tumour vs. lymph node or distant metastases (29,30) as well as the changes in tumor biology associated with tumor evolution, naturally or under therapy pressure (31). Furthermore, prospective studies should determine the optimal strategy for BASQ tumor definition, considering the more recently proposed classifiers (32).…”