Abstract:

In this Review, Meeks et al. summarize heterogeneity in bladder cancer and how it affects tumour biology and clinical care. They describe current knowledge of tumour evolution, genomic heterogeneity and different tumour subtypes, as well as morphological heterogeneity seen in variant bladder cancer histology. They also discuss the influence of heterogeneity on treatment decision making, drug development and clinical trial design. Bladder cancers have a high total mutational burden and considerable intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels that remain difficult to quantify. Heterogeneity might be driven by genomic events initiated by APOBEC enzymes and selection pressure from therapeutic interventions, which both drive tumour evolution. Bladder tumours can be categorized into different subtypes on the basis of gene expression signatures, but these molecular subtypes might be unstable and different subtypes can occur within the same tumour causing intratumoural heterogeneity. Variant tumour histologies are the morphological extreme of tumour heterogeneity and include glandular, squamous, nested, plasmacytoid, micropapillary, sarcomatoid and small-cell carcinoma. Tumour heterogeneity might affect treatment efficacy, for example, of neoadjuvant chemotherapy and immune checkpoint inhibitors, as well as targeted therapy, for example, when individual actionable mutations only occur in a fraction of the tumour. Biomarkers to select personalized treatments in precision medicine approaches will likely shape future clinical trial design, but their validity might be affected by heterogeneity. Histological and molecular analyses of urothelial carcinoma often reveal intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels. Despite the clonal initiation of the tumour, progression and metastasis often arise from subclones that can develop naturally or during therapy, resulting in molecular alterations with a heterogeneous distribution. Variant histologies in tumour tissues that have developed distinct morphological characteristics divergent from urothelial carcinoma are extreme examples of tumour heterogeneity. Ultimately, heterogeneity contributes to drug resistance and relapse after therapy, resulting in poor survival outcomes. Mutation profile differences between patients with muscle-invasive and metastatic urothelial cancer (interpatient heterogeneity) probably contribute to variability in response to chemotherapy and immunotherapy as first-line treatments. Heterogeneity can occur on multiple levels and averaging or normalizing these alterations is crucial for clinical trial and drug design to enable appropriate therapeutic targeting. Identification of the extent of heterogeneity might shape the choice of monotherapy or additional combination treatments to target different drivers and genetic events. Identification of the lethal tumour cell clones is required to improve survival of patients with urothelial carcinoma.