Deciphering riddles in molecular subtyping of bladder cancer

Abstract

Objective: Bladder cancer (BCa) is a prevalent malignant tumor in the urinary system. Molecular subtyping, utilizing molecular characteristics, represents a novel classification system that has demonstrated its efficacy in tumor diagnosis and treatment. Given the critical role of molecular subtyping in the BCa treatment, acquiring a comprehensive understanding is imperative for guiding treatment decisions, optimizing risk assessment systems, and ultimately improving patient prognosis.

Methods: In this review, we provide a comprehensive overview of the research progress in molecular subtyping of BCa, with a primary focus on discussing its utility in guiding various treatment modalities including neoadjuvant chemotherapy, neoadjuvant immunotherapy, and targeted therapy. In addition, this review also covers the trimodality treatment, antibody-drug conjugates, and the treatment of small cell BCa.

Results: We present a comprehensive overview of the responsiveness or resistance of different molecular subtypes of BCa to various therapeutic modalities. The basal subtype demonstrates favorable sensitivity to neoadjuvant chemotherapy across multiple classification systems, whereas the luminal infiltrated subtype exhibits potential susceptibility to immunotherapy. In terms of targeted therapy, the basal-like and the basal/squamous subtypes in some classifications have shown notable responsiveness to epidermal growth factor receptor-targeted therapy. Moreover, the luminal subtype in the University of Texas M.D. Anderson Cancer Center classification, the luminal papillary subtypes according to the Cancer Genome Atlas Research Network classification in 2017, and the luminal unstable type in the 2019 Molecular Subtyping classification show potential for the fibroblast growth factor receptor 3-targeted treatment.

Conclusion: The significance and impact of BCa molecular subtyping in guiding treatment, evaluating progression, and predicting prognosis are increasingly acknowledged. Accurate subtyping and broad application can bring good benefits to clinical decision-making, risk assessment, and prognostic evaluation.

Keywords: Bladder cancer; Molecular subtyping; Neoadjuvant chemotherapy; Neoadjuvant immunotherapy; Targeted therapy.

Figure 1

Evolving schemes of the molecular subtyping of bladder cancer. UNC, the University of North Carolina; Lund, Lund University; TCGA, the Cancer Genome Atlas; MDA, the University of Texas M.D. Anderson Cancer Center. MS, molecular subtype; SCC, squamous cell carcinoma; NE, neuroendocrine; UROMOL, Urothelial Carcinoma Molecular Classification; Sc/NE, small-cell/neuroendocrine. ^a This includes the infiltrated counterparts of each subtype in the Lund classification (2018).