Clinically advanced urothelial bladder cancer (CAUBC) in young onset bladder cancer (YOUC) patients: A genomic landscape study.

666 Background: CAUBC (any patients with node positive, metastasis positive or inoperable T4 disease) arising in YOUC is a challenging disease with significant need for improvements in systemic therapy especially for patients with surgically incurable disease. Methods: 9,411 cases of CAUBC underwent comprehensive genomic profiling (CGP) to examine all classes of genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and trinucleotide mutational signatures were determined from the sequencing data. HRDsig status was calculated using a broad set of genome-wide copy number features (PMID 37769224). PD-L1 was determined by IHC using the Dako 22C3 tumor proportional score (TPS) system. Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery. Results: 291 (3.1%) CAUBC developed in YOUC patients under the age of 50 (CAUBC<50). The GA and biomarkers were compared with 9,120 CAUBC that developed in patients 50 years of age and older (CAUBC>50). The male gender preponderance in the CAUBC>50 was greater than in the CAUBC<50 cases (75.1% vs 69.4%; p=.069). The GA/tumor were higher in the CAUBC>50 (8.0 vs 7.0; p<.0001). Genomic ancestry distribution revealed significantly more Admixed American cases in the CAUBC<50 (8.9% vs 5.2%; P=.033) and more European cases in the CAUBC>50 (85.3% vs 74.9%; P<.0001). MSI high status was extremely uncommon (range 0.3% to 0.8%; NS). The frequency of TMB > 10 mutations/Mb was higher in the CAUBC>50 patients (35.1% vs 28.5%; P=.048). An APOBEC trinucleotide signature was more frequent in the CAUBC>50 patients (32.5% vs 25.8%; p=.041). PD-L1 low expression (1-49% TPS) was available in small subsets of cases and was similar in both groups (21.5% vs 28.5%; p=.84). GA in KMD6A (26.6% vs 14.8%; p=.0001), ERBB2 (18.4% vs 16.8%; p=.85.), ERBB3 (6.3% vs 6.5%; p=.91) MTAP (25.0% vs 20.3%; p=.27) and TERT (78.0% vs 68.4%; p=.005) were more frequent in CAUBC>50 cases and GA in HRAS (4.8% vs 2.1%; p=.11) and CCND1 (16.2% vs 13.1%; p=.35) were more frequent in the CAUBC<50 cases. GA in FGFR1 (4.1% vs 5.2%; p=.71), FGFR3 (14.1% vs 17.9%; p=.31), PIK3CA (20.3% vs 21.3%; p=.91) and PTEN (6.5% vs 4.5%; p=.31) were similar in both groups. Conclusions: In review of the CGP data, in contrast with CAUBC arising in older patients > 50 years of age, CAUBC arising in YOUC patients <50 years features a unique patten of biomarker and GA distribution that has potential to influence therapy selection and guide future clinical trials. CAUBC 0-49 years CAUBC >50 years P-value Sex (% male) 69.4% 75.1% .069 AMR ancestry 8.9% 5.2% .033 EUR ancestry 74.9% 85.3% <.0001 FGFR3 14.1% 17.9% NS KDM6A 14.8% 26.6% .0001 MTAP 20.3% 25.0% NS TERT 68.4% 78.0% .005 TMB>10 mut/Mb 28.5% 35.1% .048 APOBEC Signature 25.8% 32.5% .041