Molecular subtypes of muscle-invasive bladder cancers (MIBC) have recently been discovered based on gene expression. We investigated the impact of different subtyping methods on response to neoadjuvant cisplatin-based chemotherapy (NAC) and developed a single sample model for subtyping.
Transcriptome-wide microarray analysis was conducted on pre-NAC transurethral resection (TUR) specimens of 223 patients with MIBC who received NAC followed by cystectomy at 5 centers. The specimens were classified according to four published methods for molecular subtype (UNC, MDA, TCGA, Lund). Overall survival (OS) for each subtype was compared between NAC patients in this study and non-NAC patients from the provisional TCGA. A genomic classifier (GSC) was trained to predict subtype in a single sample model and validated in independent NAC (2 centers) and non-NAC datasets.
The models generated subtype calls similar to previously published ratios. Concordance of a given subtype between the different methods was high. Luminal tumors had the best OS independent of NAC. Patients with tumors classified as UNC basal, MDA basal and TCGA cluster III experienced the greatest improvement in OS after NAC compared to surgery alone. Tumors assigned as UNC claudin-low had the worst OS irrespective of treatment regimen (p=0.005). GSC accurately predicted four classes (luminal, luminal-infiltrated, basal, claudin-low) and the differential impact of a basal subtype on patient OS in NAC (3-yr survival of 75.2%; p=0.001) and non-NAC (3-yr survival of 42.4%; p=0.014) cohorts could be validated.
The benefit of NAC varies between molecular subtypes. The good prognosis of luminal/cluster I tumors could not be improved with NAC, which suggests these patients may be managed best with surgery alone. The prognosis of patients with basal tumors improved the most when treated with NAC compared to surgery alone. 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. Further validation prior to clinical implementation is needed.