Bladder Cancer: New Insights Into its Molecular Pathology - Beyond the Abstract

Bladder cancer is one of the most prevalent cancers worldwide. The majority of patients present with non-invasive bladder cancer, comprising non-invasive papillary carcinoma (Ta) and carcinoma in situ (CIS; Tis). Bladder cancer develops either via the FGFR3/RAS pathway (for Ta) or the TP53/RB1 pathway (for Tis). Non-invasive papillary carcinoma (Ta) develops from hyperplasia post FGFR3/HRAS mutation; then, it potentially progresses to invasive carcinoma after the inactivation of CDKN2A/TP53/RB1. Carcinoma that develops via this FGFR3/RAS pathway has been considered as the luminal type. CIS develops from dysplasia after the inactivation of TP53/RB1, followed by aggressive invasive carcinoma. Carcinoma that develops via the TP53/RB1 pathway has been considered as the basal type.

Recent data from The Cancer Genome Atlas (TCGA) sub-classify bladder cancers into the following five molecularly-distinct subtypes: luminal-papillary, luminal-infiltrated, luminal, basal-squamous, and neuronal. The luminal-papillary subtype (35%), characterized by a papillary morphology and FGFR3 alterations, carries the best overall survival and is predicted to have little response to neoadjuvant chemotherapy (NAC). FGFR3 inhibitors or early cystectomy is recommended for this subtype. The luminal-infiltrated subtype (19%) is enriched for a mesenchymal signature and moderately expresses immune markers (PD-L1 and CTLA4). This subtype has little response to NAC and is predicted to show a substantial response to immune checkpoint inhibitors. For the luminal subtype (6%), which displays an umbrella cell phenotype, no recommended therapies exist at present. The basal-squamous subtype (35%), which is characterized by the expressions of basal or squamous cell differentiation markers and immune markers (PD-L1 and CTLA4), has a relatively high sensitivity toward NAC and a potential to be responsive toward immune checkpoint inhibitors. For the neuronal type (5%), which is enriched for high expressions of neuroendocrine and neuronal markers, etoposide plus cisplatin-based therapy is suggested, in a similar manner to treatments for neuroendocrine cancers at other organs.

The newly identified associations of specific molecular subtypes with therapeutic strategies are not yet validated but look promising. The translation of the molecular characterization of bladder cancer to clinical application is demanded to provide clinicians with the best therapeutic strategies for patients with bladder cancer.
Molecular distinct subtypes

Written by:
Kentaro Inamura, MD, PhD, Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan


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