Analysis of POLE mutation and tumor mutational burden (TMB) across 80,853 tumors: Implications for immune checkpoint inhibitors (ICPIs)

Abstract

Background: Mutations of the DNA polymerase epsilon (POLE) can lead to a hypermutated tumor phenotype, in the absence of microsatellite instability (MSI). Exceptional responses to ICPIs in POLE-mutated endometrial adenocarcinoma (EA), colorectal (CRC), and glioblastoma (GBM) are described, but detailed pan-tumor POLE analyses are lacking. Methods: We prospectively analyzed 80,853 primarily advanced solid tumors using hybrid-capture based comprehensive genomic profiling. TMB (mutations/Mb) was calculated from 1.11Mb of sequenced DNA (PMID: 28420421). Known genomic alterations (kGA) were defined as those reported as somatic in the COSMIC database or with published evidence indicating loss of function. Results: POLE GA were identified in 5.0%of cases: melanoma (10%), duodenal adeno (DA, 7.8%), uterus carcinosarcoma (CS, 6.9%), EA (6.4%), unknown primary carcinoma (CUP, 6.3%), NSCLC (6.1%), CRC (5.1%), prostate adeno (5.0%), and GBM (4.6%). Most POLE GA were variants of unknown significance (VUS). POLE kGA were found in only 259 (0.3%) total cases, including ovary or uterus CS (2.2%), DA (1.3%), EA (1.2%), CRC (0.7%), GBM (0.6%), and CUP (0.6%). Patients with POLE kGA had a median age of 58 yrs (range 7-95); 53% were male. Median TMB in cases with POLE kGA, VUS and wild-type was 31, 9 and 3.6, respectively (each p<0.0001). Of cases with POLE kGA, 54% had high TMB (>20), while 28% had low TMB (<5). The most common POLE kGA were R446Q (n=77), P286R (n=41), V411L (n=29) and L424X (n=17). R446Q, which is uncharacterized, was associated with low TMB (p<0.0001) and predominantly germline, while P286R and V411L were associated with high TMB (each p<0.0001), predominantly somatic, and enriched in CRC and EA. Inactivating GA in mismatch repair genes co-occurred with POLE kGA in 28% of cases; these cases had low MSI (7% vs. 5% for all kGA POLE cases), but very high TMB (median 230). PD-L1 IHC and outcomes will be presented for a subset of cases. Conclusions: POLE GA are found across tumor types, but functionally significant GA may be less frequent than previously reported, particularly in advanced tumors. Identification of specific POLE GA associated with a hypermutated phenotype may be important to identify likely responders to ICPIs.