Correlations Of Dna Damage Response Gene Alterations With Response To Immune Checkpoint Inhibitors Are Different In Solid Tumors.

Abstract Background: The DNA damage response (DDR), which is frequently disrupted in cancer, is a signal transduction pathway that responds to DNA damage and DNA replication blocks. Genomic alterations in DDR genes are associated with increased genomic instability and higher tumor mutational burden (TMB). A better understanding of DDR alterations will not only expand our knowledge of cancer development but also led to new cancer treatments. TMB has different predictive values among multiple cancer types. We hypothesized that the prediction values of DDR alterations for response to immune checkpoint inhibitors (ICIs) are also varied. In the present work, we explored the associations between DDR alterations and ICIs efficacy in different solid tumors. Methods: In a cohort of 3396 patients at our center were enrolled. The following tumor types are included: NSCLC (n=1080), colorectal cancer (n=509), gastric cancer (n=269), bile duct cancer (n=122), pancreatic cancer (n=199), hepatocellular carcinoma (n=309), glioma (n=778), melanoma (130). Targeted next-generation sequencing and PD-L1 immunohistochemistry (22C3 antibody) were performed. The ICIs treatment cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was also selected. Results: Across all 3396 patients, the mutational frequencies of DDR genes were 23.4%. Hepatocellular carcinoma, colorectal cancer, and NSCLC were the tumor types in which DDR alterations were most frequent-30.4%, 30.1% , and 29.1%, respectively. About 7.6% of patients have high microsatellite instability (MSI-H) in the DDR alterations group, while 0.2% of patients display MSI-H in the control group (P < 0.0001). For all patients, the median TMB was significantly higher in the DDR alterations group (8.92 vs 4.69 muts/Mb, P < 0.0001). Furthermore, 39.7% of patients had PD-L1 expression (TPS≥10%) in the DDR alterations group and 29.9% of patients had PD-L1 expression in the control group (P = 0.016). For the entire MSKCC cohort, patients in the DDR alterations group had significantly longer median overall survival after ICIs therapy (34 vs 15 months, P < 0.0001). However, DDR alterations display divergent predictive roles in different cancer types. DDR alterations are associated with ICIs efficacy in melanoma (P = 0.0007), colorectal cancer (P = 0.0012), NSCLC (P = 0.0224), bladder cancer (P = 0.0439), and breast cancer (P = 0.0451). There were no associations between DDR alterations and benefit from ICIs in renal cell carcinoma, glioma, esophagogastric, and head and neck cancers. Conclusions: Our data indicated that DDR alterations are associated with increased TMB, MSI-H, and higher PD-L1 expression. Furthermore, DDR alterations were associated with better response to ICIs in pan-cancer analysis. It's worth noting that DDR alterations can predict patient responses to ICIs in some cancer types, but not in all types of cancer. Citation Format: Tao Li, Yanling Niu, Tonghui Ma, Danhua Wang, Dong-Dong Jia. Correlations of DNA damage response gene alterations with response to immune checkpoint inhibitors are different in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1640.