Introduction

Different methods for molecular subtyping of muscle-invasive bladder cancer (MIBC) have been described. Our goal was to investigate the impact of molecular subtypes in the context of neoadjuvant cisplatin-based chemotherapy (NAC) and to develop a single sample model for clinical use.

Methods

Pre-NAC transurethral resection (TUR) specimens of 305 patients were profiled with the HumanExon microarray from Affymetrix. The original models (UNC, MDA, TCGA, Lund) for molecular subtyping were used to generate the subtype calls for these samples. Based on the biological and clinical significance, we developed a single sample genomic subtyping classifier (GSC) to predict modified consensus subtypes (claudin-low, basal, luminal-infiltrated and luminal). Overall survival (OS) according to subtype was analyzed and compared to OS in 376 non-NAC cases from three publicly available datasets.

Results

The subtype calls in our NAC dataset were similar to previously published ratios and biological functions confirmed the concordance between the different subtyping methods (e.g. UNC luminal, MDA luminal, TCGA cluster I). Our GSC predicted the four consensus molecular subtypes with high accuracy (AUC >0.85). Extravesical extension of residual primary tumor (pT3/4) after NAC was observed more frequently in claudin-low and luminal-infiltrated subtypes. GSC was not significantly associated with major pathologic response (i.e., ypT<2N0). Patients with luminal tumors had the best outcome in both datasets with 3-year OS rates of 77% and 75%, respectively. The prognosis of patients with luminal-infiltrated tumors was inferior to that of luminal tumors and did not improve with NAC. Patients with claudin-low tumors had poor OS irrespective of treatment regimen. Patients with GSC basal tumors had a 3-year OS rate of 49.2% (p<0.001) in the non-NAC cohort compared to 77.8% (p<0.001) in the NAC cohort._x000D_

Conclusions

The benefit of NAC varies between molecular subtypes. The poor OS of claudin-low tumors even after NAC implies that these tumors are resistant to cisplatin-based chemotherapy, and these patients should be included in protocols investigating alternative treatment options like immunotherapy. The prognosis of patients with basal tumors improved the most when treated with NAC compared to surgery alone. Our findings require validation prior to clinical implementation._x000D_

Funding

RS: Salary funded by the Swiss National Foundation. GenomeDx funded gene_x000D_ expression analysis. PB: AUA Foundation/Astellas Rising Stars in Urology Award. BvR: _x000D_ The EAU - European Urological Scolarship Programme. MSvdH: Veni grant, Netherlands_x000D_ Organisation for Scientific Research