Molecular Subtypes as a Basis for Stratified Use of Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer—A Narrative Review

SIMPLE SUMMARY: Although it is one disease, cancer of the urinary bladder occurs in several molecular subtypes that can be identified by laboratory tests. Tumors of advanced stages are treated with surgical removal of the urinary bladder with or without addition of chemotherapy. About 50% of patients are cured by surgery and this proportion is increased slightly by the addition of chemotherapy. Still, many patients do not benefit from chemotherapy, which also comes with significant toxicity. Recent advances in the field suggest that molecular subtypes can help identify patient categories that do or do not benefit from adding chemotherapy to surgery. In this article, we review the literature and conclude that molecular subtypes are likely to have such a role in the future but that there are differences between studies that make them challenging to compare. The current evidence is insufficient to guide clinical practice. ABSTRACT: There are no established biomarkers to guide patient selection for neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer. Recent studies suggest that molecular subtype classification holds promise for predicting chemotherapy response and/or survival benefit in this setting. Here, we summarize and discuss the scientific literature examining transcriptomic or panel-based molecular subtyping applied to neoadjuvant chemotherapy-treated patient cohorts. We find that there is not sufficient evidence to conclude that the basal subtype of muscle-invasive bladder cancer responds well to chemotherapy, since only a minority of studies support this conclusion. More evidence indicates that luminal-like subtypes may have the most improved outcomes after neoadjuvant chemotherapy. There are also conflicting data concerning the association between biopsy stromal content and response. Subtypes indicative of high stromal infiltration responded well in some studies and poorly in others. Uncertainties when interpreting the current literature include a lack of reporting both response and survival outcomes and the inherent risk of bias in retrospective study designs. Taken together, available studies suggest a role for molecular subtyping in stratifying patients for receiving neoadjuvant chemotherapy. The precise classification system that best captures such a predictive effect, and the exact subtypes for which other treatment options are more beneficial remains to be established, preferably in prospective studies.