Zhengbo Song1, Guoping Cheng2, Chunwei Xu3, Wenxian Wang4, Yang Shao5, Yiping Zhang6. 1. Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China. Electronic address: songzb@zjcc.org.cn. 2. Department of Pathology, Zhejiang Cancer Hospital, Hangzhou 310022, China. 3. Department of Pathology, Fujian Cancer Hospital, Hangzhou 350014, China. 4. Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China. 5. Geneseeq Biotechnology Inc., Nanjing 210061, China. 6. Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China. Electronic address: zjzlyy16@163.com.
Abstract
BACKGROUND: Mutations in polymerase ε (POLE), a DNA polymerase involved in DNA replication and repair, have been investigated in endometrial cancers and response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) immunotherapy. However, the frequency of POLE gene mutation in patients with non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS: We assessed POLE mutation in 319 patients with NSCLC by next-generation sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA mismatch repair proteins (MMR), and the abundance of CD8-positive tumor infiltrating lymphocytes (TILs) were assayed by immunohistochemistry. Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and compared among groups using log-rank tests. RESULTS: Nine of the 319 patients (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without POLE mutation, respectively (P = 0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and PMS2), and CD8-positive TILs were evaluated in all nine patients. No microsatellite instability was detected, but seven patients had high levels of CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.
BACKGROUND: Mutations in polymerase ε (POLE), a DNA polymerase involved in DNA replication and repair, have been investigated in endometrial cancers and response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) immunotherapy. However, the frequency of POLE gene mutation in patients with non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS: We assessed POLE mutation in 319 patients with NSCLC by next-generation sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA mismatch repair proteins (MMR), and the abundance of CD8-positive tumor infiltrating lymphocytes (TILs) were assayed by immunohistochemistry. Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and compared among groups using log-rank tests. RESULTS: Nine of the 319 patients (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without POLE mutation, respectively (P = 0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and PMS2), and CD8-positive TILs were evaluated in all nine patients. No microsatellite instability was detected, but seven patients had high levels of CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.