Clinical features, genomic alterations, and survival outcomes for variant histology urothelial carcinoma.

e16549 Background: Twenty-five percent of urothelial tumors exhibit variant histology. Each variant exhibits unique genomic composition and has a distinct clinical course. While there is emerging work describing the clinical and genomic features of variant histology, the integration of both with their impact on clinical outcomes remains less studied. Here, we describe the clinical features, genomic alterations, and outcomes of a real-world cohort of variant urothelial histology. Methods: This was a retrospective review of patients with variant histology urothelial carcinoma who underwent genomic sequencing and were treated at our institution between 2016-2023. Genomic data was derived from standard of care CLIA-next generation sequencing. Demographics and outcomes were derived from chart review. Kaplan-Meier method was used for progression free survival (PFS) and overall survival (OS). Results: 78 patients (pts) were included. Median age was 68.6 (33.7-90.7). 69.2% were male. Variant histology included 15 pts with squamous cell component, 14 pts with plasmacytoid component, 13 pts with micropapillary component, 8 pts with adenocarcinoma. The remaining variant histologies are listed in table 1. 10 pts (12.8%) had more than one variant histology present. 60 pts (76.9%) had metastatic disease; 24 (40%) of them with de novo metastatic disease. Metastatic sites were distant lymph nodes (LN) in 37 pts, lung in 25 pts, bone in 22 pts, and liver in 14 pts. The table lists genomic findings by variant histology. Overall, 2-yr PFS was 29% and 2-yr OS was 69.4%. Median PFS was 0.3 yrs for plasmacytoid vs. 0.4 for adenocarcinoma vs. 0.7 for micropapillary vs. 0.8 for squamous. Median OS was 1.5 yrs for plasmacytoid vs. 2.9 for adenocarcinoma vs. 3 for micropapillary vs. not evaluable for squamous. Conclusions: In this cohort of patients with variant urothelial histology, the most common genomic alterations were TERT and TP53 mutations. Several targetable alterations including KRAS, PIK3CA, and TSC1 were detected across various histology subtypes and suggest a potential avenue for further therapeutic research. Though not statistically significant, PFS and OS were shorter for patients with plasmacytoid and adenocarcinoma variants. [Table: see text]