Prognostic significance of pathologic response to neoadjuvant chemotherapy in muscle-invasive urothelial carcinoma of the bladder with histologic subtype

Introduction: Patients with histologic subtypes (HS) of urothelial cancers are often excluded from neoadjuvant chemotherapy (NAC) trials for muscle-invasive bladder cancer (MIBC). Additionally, there exist conflicting data regarding the inherent chemotherapeutic sensitivity of individual HS. Herein, we assess the prognostic significance of pathologic response to NAC, a common surrogate endpoint of success in NAC trials, in patients with HS versus pure urothelial carcinoma (PUC). Methods: The National Cancer Database (NCDB) was queried for patients with cT2-4N0M0 MIBC who received NAC and radical cystectomy (RC) between 2004 and 2020. Pathologic response to NAC was defined as complete (ypT0N0), partial (<ypT2N0), and no response (≥ypT2 or ypN+). Kaplan-Meier analysis and log-rank tests were performed for overall survival (OS) and Cox proportional hazard regressions were performed to test relationships between NAC response and the presence of a HS in predicting OS. Results: 5,372 patients were included, with 345 (6.4%) having HS. Nonresponse rates to NAC in HS patients were significantly higher than those with PUC (65.2% vs. 55.8%, P = 0.003). Patients with squamous and glandular differentiation exhibited the highest rates of nonresponse (79% and 72.2%, respectively). In unstratified analysis, patients with HS exhibited shorter OS (P < 0.0001). Patients with HS had uniformly worse OS even after controlling for pathologic response (P = 0.013), with the most notable discrepancy in partial responders (HR = 4.88, 95% CI 2.29-10.38, P < 0.001; 3-year OS 91% vs. 66% for partial response in PUC vs. HS, respectively). Conclusions: Patients with HS MIBC exhibit poor survival when treated with NAC followed by RC compared with PUC, even when controlling for pathologic response. These data suggest that pathologic response is a less accurate surrogate endpoint in patients with HS relative to PUC, and may suggest a role for therapeutic intensification in the adjuvant setting for patients with HS.