Frequency and impact of a genome-wide homologous recombination deficiency signature (HRDsig+) on the genomic landscape of clinically advanced urothelial bladder carcinoma (CAUBC).

845 Background: CAUBC (metastatic and surgically incurable advanced UBC) is a challenging with significant need for improvement in systemic therapies. We aimed to explore HRD sig status and related biomarkers, including other GA, to generate hypothesis and inform clinical trial designs for these patients. Methods: 8825 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. 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: 387 (4.4%) of CAUBC cases featured a positive HRDsig status (HRDsig+). The median age (62-63) was similar in the HRDsig+ and HRDsig- groups and both groups were predominantly male (75-77%). The GA/tumor frequencies were similar (5-6). MSI-high status was extremely low in both groups (0.8% vs 0%). The median TMB (10 vs 6.3; P<.0001) and frequency of TMB > 10 mutations/Mb (50.9% vs 34.8%; P=0.016) was higher in the HRDsig+. Trinucleotide mutational signature distribution, PD-L1 low (1-49% TPS) and PD-L1 high (≥50% TPS) expression were similar in both groups. As anticipated, GA in genes associated with HRD including BRCA1 (9.0% vs 1.6%; P<0.0001), BRCA2 (17.1% vs 2.5%; P<0.0001), ATM (9.6% vs 5.3%; P=0.0003) and RAD21 (8.5% vs 3.4%; P<0.0001) were more frequent in the HRDsig+ cases. In the HRDsig- group, 83.7%/87.0% of BRCA1 / BRCA2 mutated CAUBC were mono-allelic, likely non-driver GA, respectively. FGFR3 GA were significantly more frequent in the HRDsig- CAUBC (18.1% vs 10.9%; P=0.001). GA in ERBB2 (17.8-18.5%) and ERBB3 (6.2-7.8%) were similar in both groups. MTOR pathway related mutations, including PTEN (4.5-6.2%) and PIK3CA (18.6-21.7%) were similar in both groups. GA in TERT were more frequent in the HRDsig- group (78.9% vs 57.6%; P<0.0001) and GA in TP53 were more frequent in the HRDsig+ cases (72.1% vs 60.5%; P<0.0001). Conclusions: With a 4.4% frequency, HRDsig+ status is a relatively uncommon biomarker in CAUBC. This finding may inform clinical trial designs, for example with PARP inhibitors and other ‘HRD-targeting’ agents. Limitations include the retrospective nature, potential selection bias and lack of clinical outcomes annotation. Genomic differences between HRDsig- and HRDsig+ CAUBC groups. CAUBC HRDsig- CAUBC HRDsig+ P value EUR Ancestry 85.2% 78.6% 0.003 ATM 5.3% 9.6% 0.003 BRCA1 1.6% 9.0% <.0001 BRCA2 2.5% 17.1% <.0001 FGFR3 18.1% 10.9% 0.001 RAD21 3.4% 8.5% <.0001 TP53 60.5% 72.1% <.0001 RB1 2.7% 5.4% <.0001 TMB≥10 mut/Mb 34.8% 50.9% 0.016