Next-generation sequencing of bladder and upper tract micropapillary variant urothelial carcinoma patients and associated clinical outcomes.

Abstract

828 Background: Micropapillary variant urothelial carcinoma (MPUC) is a histologically and genotypically defined variant of urothelial carcinoma (UC), with more aggressive disease course and presenting at a more advanced stage. Previous literature has revealed MPUC to have a distinct molecular and genetic profile which may be driving this disease, notably higher rates of ERBB2 mutations compared to UC. Our study investigated the relationship between MPUC tumor genetic changes and associated clinical and pathological outcomes. Methods: Retrospective chart review of the electronic medical record (EMR) at a single institution was performed for the years 2015 to 2025 to identify patients with a history of micropapillary variant urothelial carcinoma confirmed on surgical pathology. Patients with either tumor genomic profiling, or blood-based next-generation sequencing (NGS) were identified, and their NGS reports analyzed for specific genomic alterations, tumor mutational burden, and mutation type. Clinical and pathology data were retrieved from EMR. Statistical analysis was then performed using Cox-proportional hazards test and Chi squared analyses for univariate analysis, and Kaplan-Meir curves were generated for overall, progression-free, and recurrence-free survival. Results: A cohort of 192 men and 43 women were identified, 37 with NGS reports available. Most common gene mutations were TERT (81%), TP53 (62%), RB1 (35%), ARID1A (32%), and ERBB2 (27%). 69% of the cohort was alive at the time of review. Median overall survival and recurrence free survival were 55 months and 28.5 months respectively. There were no statistically significant differences in overall or recurrence free survival in patients with aberrant ERBB2 versus those without (p=0.99, p=0.98). Univariate analysis results are shown in Table 1- notably age at MPUC diagnosis, initial tumor stage, and both N and M stage at time of MPUC diagnosis were significant for increased risk of death. Conclusions: MPUC tumors harbor unique genetic profiles, distinct from UC and other variants possibly driving the shorter times to recurrence and overall survival. High levels of ERBB2 mutations are seen in MPUC patients, with potentially high levels of the downstream protein HER2 as a cause for this more aggressive phenotype. Further work is underway on the entire cohort using FISH staining for HER2 to examine the degree of activity and associated clinical outcomes in MPUC patients, as a potential for future drug target in this population. Baseline pathology and associated mortality. Variable Total Hazard Ratio 95% Confidence Interval P-value Age (Continuous) 235 1.03 1.01-1.06 0.01 Tumor stage 1.89 1.13-3.17 0.02  ≤ T1 95  ≥T2 140 Lymphovascular Invasion 1.39 0.86-2.23 0.17  Yes 89  No 146 Concomitant CIS 2.15 0.93-4.97 0.07  Yes 12  No 223 N-Stage 2.22 1.08-4.56 0.03  N0 188  N1+ 47 M-Stage 1.82 1.13-2.89 0.01  M0 153  M1+ 82