Comparison of molecular profiles of upper tract urothelial carcinoma vs. urinary bladder cancer in the era of targeted therapy: a narrative review

BACKGROUND AND OBJECTIVE: Although upper tract urothelial carcinoma (UTUC) shares the histological appearance of urinary bladder cancer (UBC), molecular studies suggest that UTUC and UBC represent two distinct disease entities. However, treatment approaches for UTUC are virtually extrapolated from the evidence on UBC. As targeted drugs—immune-checkpoint inhibitors, fibroblast growth factor receptor inhibitors, and antibody-drug conjugates—target specific molecules, gaining more knowledge about the target-molecular profiles of each drug can help formulate optimal treatment strategies for UTUC. METHODS: This narrative review summarized the subgroup analyses of clinical trials of FDA-approved targeted drugs to explore the differential effects of each targeted drug when administered for UTUC compared to UBC. We focused on the differences in mutation frequency, RNA expression subtype, and therapeutic target protein expressions (specifically PD-L1, Nectin-4, and Trop-2) between UTUC and UBC and discussed their relationship with the efficacy of each targeted drug. KEY CONTENT AND FINDINGS: A clinical trial of nivolumab in an adjuvant setting (CheckMate 274) implied that immune-checkpoint inhibitors might be less efficacious in UTUC than in UBC. Genomic and transcriptomic studies suggest that UTUC has a high frequency of FGFR3 mutations and predominantly shows the luminal papillary subtype, which is immunologically cold with low T-cell infiltration. These findings are consistent with a possible lower response rate to immunotherapy in UTUC than that in UBC. Clinical trials of enfortumab vedotin in a third-line setting (EV201 and EV301) implied that enfortumab vedotin might be less efficacious in UTUC than in UBC. Previous immunohistochemical analyses suggest that UTUC might have a slightly lower rate of Nectin-4 positivity than UBC, indicating that enfortumab vedotin was less efficacious in UTUC than in UBC. CONCLUSIONS: Clinical differences in the effects of targeted drugs for UTUC and UBC may highlight the molecular differences between these diseases. The treatment strategy should be optimized based on further investigation of the molecular characteristics of UTUC.