e13050 Background: DNA polymerase epsilon and polymerase delta encoded by the POLE and POLD1 gene are the major components participating in DNA replication, which both carry a proofreading (exonuclease) domain allowing error correction during replication. In case of POLE/POLD1 mutation, a deficient DNA repair activity results in a hypermutated phenotype of cancer, which would be a promising biomarker for immune checkpoint inhibitors (ICPIs). However, the prevalence of POLE and POLD1 in Chinese patients (pts) with solid tumors remained unknown. Methods: Targeted panel sequencing of 450 cancer genes were performed on FFPE tissues and matched blood samples obtained from 6313 Chinese pts with 23 different types of solid tumors. In our cohort, 41% were female pts with a median age of 56-year-old (range: 1-91), while 59% were male with a median age of 59-year-old (range: 1-96). The major cancer types were NSCLC (29%), HCC (11%), CRC (11%), gastric cancer (GC, 7%), soft tissure sarcoma (6%), pancreatic cancer (5%), intrahepatic cholangiocarcinoma (5%), and others. Somatic genomic alterations (sGAs) including single base substitutions, short and long insertions/deletions (indels), copy number alterations (CNA), rearrangements, TMB and MSI status were assessed by NGS. Results: Clinical relevant genomic alterations (CRGAs) were defined as known loss-of-function mutations, truncations, mutations on splicing sites and confirmed somatic mutations in COSMIC. CRGAs of POLE and POLD1 accounted for 2.1% and 1.3% of Chinese solid tumors respectively. Tumors with highest frequency of POLE CRGAs in Chinese cohort were endometrial cancer (8.3%), urothelial cancer (4.8%), CRC (4.3%), GC (3.2%), breast cancer (2.9%), cancer of unknown primary (CUP, 2.5%), ovarian cancer (2.1%) and NSCLC (2.0%), which tumors with highest frequency of POLD1 CRGAs were endometrial cancer (8.3%), urothelial cancer (4.8%), GC (3.0%), CRC (2.8%), SCLC (2.1%), HCC (1.9%), cervical cancer (1.6%), CUP (1.2%) and pancreatic cancer (1.2%). In addition, 1.6% and 1.2% of Chinese solid tumors harbored variants of unknown significance of POLE and POLD1, respectively. Conclusions: For the first time, our study reported prevalence of somatic mutations of POLE and POLD1 in large samples of Chinese population. Comparing with large cohort study of western population (ESMO 2017, 1170P), more CRGAs of POLE were identified in Chinese solid tumors (2.1% vs. 0.6%, p < 0.0001) indicating ethnic differences of ICPIs potential candidates between Chinese and western populations.
Effects of Co-occurring Genomic Alterations on Survival in Patients with KRAS-Mutant Pancreatic Cancer
