(UroToday.com) In bladder cancer, there are two pathways, the papillary and non-papillary pathways (Figure 1). Papillary tumors develop to low-grade tumors, which can later progress to high-grade tumors. The non-papillary tumors develop into high-grade invasive tumors.

Figure 1 – Bladder cancer pathways:

When discussing the classification of muscle-invasive bladder cancer (MIBC), it is important to be aware of the equilibrium of the urothelium. Stem cells in the basal aspect are more differentiated than the cells in the luminal aspect (Figure 2). This can be used to classify tumors into different molecular classes. Several groups have performed molecular classifications of MIBC. All of the various classification systems have the separation of the basal from the luminal tumors in common (figure 3). As these classification systems became more complicated, a more simplified classification system was formulated this year (Figure 4). The luminal papillary type of tumors has mutations in the FGFR3 with papillary morphology. In contrast, the unstable luminal type has mutations in TP53, ERCC2, and a worse prognosis than the luminal papillary subtype. The basal squamous is the largest class of tumors and often have squamous differentiation, with an inferior prognosis. The smallest class is the neuroendocrine subtype with TP53 and RB1 mutations and with a very unfavorable prognosis.

Figure 2 – Classification of MIBC:

Figure 3 – Luminal and basal tumors of MIBC:

Figure 4 – Simplified classification system of luminal and basal tumors:

The purpose of this simplified molecular classification system is several folds. It should serve as a consolidation of previous work, and it should be used as a reference for further studies and comparison, possibly helping us explain the evolution of bladder cancer. The clinical significance of this classification system shows that luminal subtypes have a superior prognosis, and neuroendocrine and basal subtypes have an inferior prognosis. This system has not yet been validated for response prediction for any of the currently used treatments for MIBC. Lastly, this classification system may help investigate the significance of various assessed biomarkers.

One such biomarker is the Xpert Bladder cancer monitor, which uses real-time polymerase chain reaction (PCR) on a urine sample, assessing various targets (UPK1B, IGF2, CRH, ANXA10, ABL1) with an operation time of 90 minutes. The targets assessed have been correlated to the various molecular tumor subtypes in the previously shown classification system (figure 5).

Figure 5 – Correlation of the molecular classification system and the various targets assessed with the Xpert Bladder Cancer Monitor test:

A recent study investigated a specific therapy targeting the actionable FGFR3 mutation or FGFR2/3 mutation1. For this trial, patients with luminal papillary were specifically selected, and they showed a confirmed response rate of 40% with a median overall survival of 13.8 months. The reasons why not all patients responded to this treatment, although they were specifically selected for their specific molecular subtype, include:

  • Variances in dynamic of progression – some patients may have had rapidly progressing disease compared to other patients who had slower progressive disease.
  • The authors used bulk profiling of one specimen, but there might have been more mutations.
  • There might have been intra-tumor heterogeneity

Nectin 4 is a surface protein expressed on the surface of cancer cells, expressed in 97% of tested cancers. In a study where NECTIN 4 was targeted in bladder cancer patients, a complete response of 12% and a confirmed objective response of 44% were noted, with a tolerable safety profile2. Nectin 4 is highly expressed in the luminal component subtype and not in the neuroendocrine subtype.

In conclusion, molecular phenotyping dramatically improves our understanding of bladder cancer. It helped us to discover molecular classes with different biological phenotypes, and it may even help us to explain the evolution of bladder cancer. The consensus subtypes should become a foundation for comparison and exploration in further studies. Lastly, the heterogeneity of tumors is a possible explanation of why the complete response rate to specific targeted molecular subtype therapies is not higher.


Presented by: Roland Seiler, MD, Associated professor at the Department of Urology at the University Hospital Bern in Switzerland

Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, @GoldbergHanan at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020.

1. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. New England Journal of Medicine 2019; 381(4): 338-48.
2. Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2019; 37(29): 2592-600.