Therapeutic effect of DDR pathway with different functional annotations for immune checkpoint inhibitor

2611 Background: DNA damage response and repair (DDR) pathway-related gene mutations have been reported to predict the efficacy of immune checkpoint inhibitor (ICI). However, therapeutic effect of DDR pathway with different functional annotations is not fully studied. Here we explore the relationship of DDR pathway with different functional annotations and clinical outcomes in public cohorts of immunotherapy and chemotherapy. Methods: Genetic testing and clinical outcomes data were obtained from the public clinical cohorts across 10 tumor types. 232 DDR pathway-related gene were assigned to eight pathway according to the literature. Nine predictive models for the mutation pathogenicity were included in the analysis, of which at least five returned positive results were defined as deleterious mutations. All annotations were according to the American College of Medical Genetics (ACMG) standards and guidelines. To explore the association between DDR pathways and ICI, DDR pathway mutation is grouped. Patients, who harbored mutations in two or more DDR pathways and meanwhile had deleterious mutation in at least one DDR pathway, were enrolled in group A. Patients, who harbored deleterious mutations in only one DDR pathway or had only uncertain significance mutations, were enrolled in group B. Patients with no DDR gene mutations were enrolled in Group C. We analyzed relation of the group and survival outcomes in four public cohorts. Results: Of 4 clinical cohort analyzed, the group A treated with ICI has the best PFS or OS outcomes. However, the comparison of group B and group C is not coincide across different cohorts. Treatment is the key factor that influents the relation of DDR pathway mutations and clinical outcomes. As shown in POPLAR/OAK cohort, patients in group C has the best PFS (p=0.0381) or OS (p=0.0350) outcome when treated with chemotherapy, but patients in group A has the best PFS (p=0.0083) or OS (p=0.0222) outcome when treated with ICI. Conclusions: When treated with ICI, patients with at least one deleterious mutation and another deleterious or uncertain significance mutation has the best PFS or OS outcomes, but not for chemotherapy. Our study suggested that DDR pathway with deleterious mutations might be a potential predictive factor for immunotherapy.[Table: see text]