Exploration of novel biomarkers and novel therapies for immune checkpoint inhibitors (ICIs) in genetic variants of esophageal squamous cell carcinoma (ESCC): A study of 1,059 Japanese cases.

495 Background: In Japan, cancer genome profiling (CGP) tests will be covered by insurance in 2019, and more than 1,000 ESCC cases have been accumulated in the national database. ICIs are currently the key drugs for esophageal cancer, and MSI and TMB status can work as biomarkers for ICIs in solid tumors. Therefore, to improve the prognosis of esophageal squamous cell carcinoma (ESCC), we aim to search for gene variants that may predict the efficacy of ICIs and explore the possibility of new treatment from genetic data accumulated in the Japanese nation-wide C-CAT database. Methods: We retrospectively analyzed 1,059 ESCC cases from C-CAT data accumulated from June 2019 to February 2024. We used the registered clinical and genetic information to examine gene variants and carcinogenic pathways that could serve as biomarkers for ICIs. Results: Of the 1059, 152 (14.4%) had TMB-H and 3 (0.3%) had MSI-H, with a median TMB of 5.0 Muts/Mb (range: 0-268). XPO1 and TP53 were found to be positively and negatively correlated as genes affecting TTF in nivolumab monotherapy (FDR P value < 0.01). TMB has the potential to be a biomarker for ICI, but TMB was significantly higher in the group with variants in the ARID family ( ARID2 , ARID1A plus ARID5B ) (median TMB 5.0 vs 8.0 Muts/Mb, P<0.001). In addition, 709 patients (66.9%) had any variants in three pathways (TP53, RTK and cell cycle), which are thought to be involved in the carcinogenesis of ESCC. PIK/Akt/mTOR and epigenetic modulation pathways were also found to be abnormal in many cases, and abnormalities in the epigenetic modification pathway were found to contribute significantly to TMB-H (FDR P value<0.01, Logarithmic value=19.2). Conclusions: This is the first case-specific report on the relationship between mutations in the ARID family and TMB in ESCC and the signalling pathways leading to carcinogenesis. In the present study, the association between the ARID family and TMB, and between abnormalities in the epigenetic modification pathway and TMB, which has been previously reported in other cancer types but not in esophageal cancer, suggests that multiple pathological mutations including these may be new biomarkers for ICI in 1059 Japanese patients. Furthermore, multiple pathways are often involved in ESCC carcinogenesis at the same time, and a separate, combined approach that takes these into account may be necessary in the development of new drugs.