Identification of Molecular Subgroups of Muscle-Invasive Urothelial Bladder Cancer and Their Impact on Treatment Outcome.

Purpose: Neoadjuvant chemotherapy (NACT) improves muscle-invasive bladder cancer (MIBC) survival. However, its efficacy is limited to a group of patients. This study explored CK5/6 and GATA3 for molecular subtyping and their prediction to response in patients with MIBC.

Methods: This is a prospective study that includes 50 patients with TCC bladder. All Patients received 4 cycles neoadjuvant gemcitabine/ cisplatin then guided to further treatment according to the response to NACT. Responders (CR & PR) went for CCRTH whereas non-responders (SD & PD) went surgery if resectable or second line chemotherapy if non-resectable. The baseline TUR pathology specimens were examined for histopathological feature and CK5/6 and GATA3 and divided into 4 molecular subgroups.

Results: The patients were divided into four molecular subgroups: luminal (n=12/26.7%), basal (n=8/17.8%), double-positive (n=21/26.7%), and double-negative (n=4/8.9%). There was no clinicopathological difference seen among the 4 molecular subgroups. The PFS was higher in patients with GATA3 positive (24 months) than GATA3 negative (17 months). Yet, it did not reach a statistically significant value (P = 0.1605). On the other hand, PFS was not affected by either CK5/6 status or different molecular subgroups. The OS was better in the luminal subgroup than the basal (20.8 months versus 16.16 months respectively, While the double positive showed the highest OS of 26 months(P=0.0352).

Conclusion: GATA3 and CK5/6 IHC can classify MIBCs into four subtypes. These subtypes predicted treatment outcomes, however, were not correlated with the response to NACT. GATA3-positive tumors, luminal and double-positive subtypes tend to have higher OS and PFS. CK5/6 positivity did not impact the treatment outcome.