Real world genomics in metastatic urothelial carcinoma (mUC).
Authors: Wu Sulin , Kyasaram Ravi Kumar , Wu Chen-Han Wilfred , Fu Pingfu , Margevicius Seunghee P. , Garcia Jorge A. , Barata Pedro C. , Mendiratta Prateek , Brown Jason R 
Published: June 2023

e16583

Background: Next generation sequencing (NGS) has therapeutic value in mUC. Beyond FGFR3 alteration and tumor mutational burden, genetic testing can identify novel predictive and prognostic biomarkers. In clinical practice, variability is introduced between assays due to genomic coverage, sequencing depth, timing, and tissue used. Methods: A single-institution retrospective database of patients (pts) diagnosed with mUC between 2013 and 2022 was generated. Clinicopathologic features and NGS results, including mutations, fusions, and copy number alterations, were abstracted from pt records. Progression free survival was calculated from start of first-line (1L) treatment (PFSFLT) and of 1L/maintenance/2L immunotherapy (PFSIO) to date of disease progression or death, censored at last follow up for pts alive without progression. Overall survival (OS) was calculated from diagnosis date of mUC to the date of death or censored at last follow up. Association between two categorical factors was estimated by chi-square test. Time-to-event data were analyzed by Kaplan-Meier method with log-rank test and Cox model. Results: 251 records were reviewed, of which 79 unique mUC pts with somatic NGS testing were identified. Pts were predominantly male (70.9%), white (86.1%), past/present smokers (65.8%), with bladder primary site (78.5%) and urothelial histology (72.2%). NGS was performed on 37 (46.8%) primary and 42 (53.2%) metastatic specimens, including 57 solid tumor (72.2%), 12 liquid biopsy (15.2%), and 10 (12.7%) with both. NGS was performed prior to or during 1L treatment for 61 pts (77.2%) and later for 18 pts (22.8%). Median TMB, where measured (n = 43), was 9 mut/Mb (2-40). The most prevalent genes with pathogenic variants identified were TP53 (37, 46.8%), TERT (32, 40.5%), PIK3CA (22, 27.8%), FGFR3 (18, 22.8%), ARID1A (16, 20.3%), CDKN2A/B (13, 16.5%) and ERBB2 (13, 16.5%). Several TP53 (45) and ARID1A variants (19) were observed, and fewer TERT (3) and FGFR3 (6) variants were seen. Among prevalent mutant genes, TP53 and TERT were most commonly concordant (68.4%, p = 0.0068). TERT was significantly co-mutated with ARID1A (64.6% concordant, p = 0.00479) and exclusive with mutant PIK3CA (41.8% concordant, p = 0.012). ERBB2 and FGFR3 alterations were mutually exclusive. ERBB2 alterations significantly correlated with lack of metastasis to lung, liver, or bone (p = 0.00355), though no genes predicted metastasis to those sites. ERBB2 alterations also correlated with improved PFSIO (HR 0.3, 95% CI 0.09-0.99, p = 0.049), but not with PFSFLT. FGFR3 mutation is associated with inferior OS (HR 1.88., 95% CI: 1.03 – 3.43, p = 0.04), especially for male pts (HR 2.85, 95% CI: 1.26-6.51, p = 0.013). Conclusions: A diverse array of NGS testing was performed on mUC pts, collected at varying timepoints. Despite inherent heterogeneity, these results yielded prognostic and predictive information for ERBB2 and FGFR3 alterations to be further studied in larger cohorts.