Molecular subtypes of urothelial carcinoma (UC) may impact the outcomes after neoadjuvant chemotherapy in muscle invasive bladder cancer (MIBC). Previous studies reported contradictory results in this setting. Here, we assessed pathological response and 3-year (yr) progression free survival (PFS) according to the consensus molecular subtypes for patients in the French prospective Vesper clinical trial (NCT01812369).
493 patients received dose-dense Methotrexate, Vinblastine, Doxorubicin and Cisplatin (dd-MVAC) or Gemcitabine and Cisplatin (GC) after randomization in the VESPER trial. This ancillary study was restricted to patients treated in neoadjuvant setting. We performed 3’ mRNA sequencing on TURB FFPE tissue, taking multiple samples when morphology and/or multiplexed GATA3 Cytokeratin 5/6 TUBB2a immunostaining highlighted distinct patterns. Consensus molecular subtype was then determined for each area from their transcriptomic profile.
Out of 296 cases, 97 presented intra-tumor immunostaining heterogeneity. For 251 cases, one single molecular subtype was detected within the tumor, including 37 luminal papillary, 60 luminal unstable, 17 luminal non specified, 53 stroma-rich, 81 basal/squamous and 3 neuroendocrine-like. 45 cases were mixed including 2 or more molecular subtypes (27 with basal/squamous component). Pathological response was not statistically different between pure molecular subtypes, but was decreased for the mixed cases (OR=0.43, 95% CI 0.19-0.96, p=0.040). Compared to luminal and stroma-rich subtypes, 3yr PFS was significantly decreased when basal/squamous subtype was detected, either pure or admixed with another molecular type (HR=2.16, 95% CI 1.46-3.20, p<1e-3). Lymphovascular invasion was also found to be a significant risk factor for 3yr PFS (HR=1.91, 95% CI 1.29-2.83, p=0.001), independently from molecular subtype.
In the VESPER trial, the basal/squamous molecular subtype (pure or mixed) is associated with a decreased 3yr PFS after neoadjuvant chemotherapy in comparison with other subtypes. These results suggest the need to develop and validate new therapeutic strategies.
Clinical trial identification
Legal entity responsible for the study
Institut National du Cancer (INCa).
All authors have declared no conflicts of interest.