Prognostic Impact of DDR Mutations (mt) in IDH Mutant High-Grade Gliomas (HGG).

2066 Background: The oncometabolite 2-hydroxyglutarate (2HG) produced by IDH1/2 mt in HGG has profound effects on numerous pathways including DNA damage repair (DDR). We investigated the prognostic effect of DDR mt in IDH mutant vs. wild type (wt) tumors in a large cohort using a real-world database. Methods: A total of 4894 HGG tumors tested at Caris Life Sciences (Phoenix, AZ) with NextGen sequencing of DNA (592-gene panel or whole exome sequencing) were included in the study. DDR alteration was defined as a pathogenic mutation in one of > 20 DDR genes. Patient survival was obtained by insurance claims data and calculated from the initiation of tissue collection (rwOS). Cox proportional hazards model was used to calculate hazard ratios (HR) and log-rank tests to calculate p values, which were adjusted for multiple comparisons. Significance was set at p<0.05. Results: In the 1121 HGG carrying either IDH1 or 2 mutations, 100 carried a DDR mutation (8.9%) . When comparing DDR mutant (mt) vs. wild type (wt), no difference was seen in patient age (median 39 vs. 38 yrs; p = 0.8); gender (female 45% vs. 42%, p = 0.9), race or ethnicity (p > 0.1). The most frequent mutations were seen in MSH6 (24% of the DDR mt), ATM (18%), MLH1 (15%), MSH2 (13%), MSH3 (10%) and BRCA2 (10%). When comparing the rwOS of DDR mt vs. wt, a significantly shorter survival was seen (24m vs. 51m, HR = 1.87, 95% CI [1.41-2.48], p < 0.001); the effect persisted in the subset of tumors collected prior to temozolomide treatment (26m vs. 64m, HR = 1.92 [1.35-2.74], p < 0.001). In contrast, in IDH wt tumors, patients with (N = 223) or without DDR mutation (N = 3550) showed similar survival (17.5m vs. 20.6m, p = 0.1). In the IDH mutant cohort, DDR mt was associated with an increased tumor mutational burden (TMB) compared to DDR wt tumors (median = 6 vs. 4 mutations/mb, by Wilcoxon). Multivariate analysis within the IDH mutant tumors indicated that both TMB and DDR status were independently associated with poorer rwOS, with TMB showing an adjusted HR of 1.01 per unit increase (p = 0.005) and DDR status with an adjusted HR of 1.59 (p = 0.028). Conclusions: In a large real-world database, we demonstrate IDH mt HGG with a DDR mutation exhibit significantly poorer survival compared to DDR wt. This is not seen in IDH wt, where survivals of the two groups are similar. These results stand in sharp contrast to reported prognostic effect of DDR mutation in many other solid tumors. The data suggest that DDR mutations in the context of 2HG accumulation in IDH mt HGG may be an indicator of profound genomic instability that confers severe negative impact on patient survival. Clinicians managing high-grade gliomas should consider the presence of DDR mutations in IDH mutant patients as a poor prognostic category in this overall favorable prognostic group and consider therapeutic approaches accordingly.