A study of the homologous recombination deficiency signature (HRDSig) status of advanced esophageal squamous cell carcinoma (AESCC) by utilizing comprehensive genomic profiling (CGP).

485 Background: The role of poly-ADP-ribose polymerase (PARP) inhibitors is currently under investigation as a potential therapeutic option for AESCC. Homologous recombination deficiency signature status (HRDSig) positivity has been shown to predict biallelic loss of BRCA1/2 which may simultaneously portend a worse prognosis and a sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. In this study, we attempt to characterize the genomic alterations present in AESCC based on HRDSig status utilizing comprehensive genomic profiling (CGP) techniques. Methods: 2,029 cases of AESCC underwent comprehensive genomic profiling with an examination of all genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and genomic trinucleotide signatures were determined from the sequencing data. HRDSig status was calculated using a broad set of genome-wide copy number features (PMID 37769224). Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery. Results: 154 (7.6%) of the 2029 AESCC cases featured a positive HRDSig status (HRDSig+). The age (66-67) and gender (58%-63% male) distribution were similar in the HRDSig+ and HRDSig- AECSS cases as was the frequency of GA/tumor (9 for both). The median TMB was higher in the HRDSig+ (6.3 vs 3.8; P<.0001) as was frequency of TMB > 10 mutations/Mb (19.5% vs 10.0%; P=.004). An APOBEC trinucleotide signature was also more frequent in the HRDSig+ AESCC (11.0% vs 5.4%; P=.05). As anticipated, GA in genes associated with HRD including BRCA1 (10.4% vs 1.4%; P<.0001) and BRCA2 (14.3% vs 2.0%; P<.0001) was present. MTOR pathway activating mutations were also more frequent in the HRDSig+ AESCC group including PTEN (13.0% vs 7.3%; P=.06). Conclusions: With a 7.6% frequency, HRDSig+ status is a relatively rare event in AESCC. CGP with determination of HRDSig status in AESCC may prove useful in tailoring PARP inhibitor-based treatment regimens and may potentially uncover other genomic alterations that can aid in designing targeted therapy combinations in future. Characteristics of comprehensive genomic profiling of clinically advanced esophageal squamous cell carcinoma by HRDSig status. AESCC HRDSig- (n=1875) AESCC HRDSig+ (n=154) P-value Pathogenic genomic alterations BRCA1 1.4% (26) 10.4% (16) 0.00 BRCA2 2.0% (36) 14.3% (22) 0.00 PTEN 7.3% (137) 13.0% (20) 0.06 COSMIC trinucleotide signature APOBEC 5.4% (101) 11.0% (17) 0.05 Tumor mutational burden (TMB) Median TMB (range) (IQR) 3.8 (0-85) (2.5-6.3) 6.3 (0-61) (3.8-8.8) 0.00 TMB≥10 mut/Mb 10.0% (188) 19.5% (30) 0.00