POLE/POLD1 Mutations Across Cancer Types and Association With Immune Checkpoint Inhibitor Therapy Outcomes

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In a research letter published in JAMA Oncology, Wang et al identified the frequency of mutations in DNA polymerase epsilon (POLE) and delta 1 (POLD1) genes across cancer types and found that these mutations were associated with better survival outcomes among patients receiving immune checkpoint inhibitor therapy.

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Study Details

All 47,721 patients included in the analysis and POLE/POLD1 mutation data were selected from the cBioPortal database. POLE/POLD1 alterations considered in the analysis included all nonsynonymous mutations including missense, frame-shift, nonsense, nonstop, splice site, and translation start site changes. 

Frequency of Mutations and Outcomes With Immune Checkpoint Inhibitor Therapy

Among the 47,721 patients, the overall frequencies of POLE/POLD1 mutations were 2.79% and 1.37% of patients, respectively. Among the 23 cancer types assessed, those with the highest frequencies of POLE/POLD1 mutations or both were nonmelanoma skin cancer (16.6%, 34 of 205 patients), endometrial cancer (14.8%, 189 of 1,273), melanoma (14.7%, 210 of 1,426), colorectal cancer (7.4%, 197 of 2,674), bladder cancer (7.2%, 113 of 1,568), esophagogastric cancer (7.2%, 185 of 2,586), lung cancer (5.9%, 293 of 4,974), and cervical cancer (5.3%, 28 of 524). Tumor mutational burden of patients with POLE/POLD1 mutations was markedly greater vs those without mutations in most cancer types.

POLE/POLD1 Mutations

  • Cancer types with the highest frequencies of POLE/POLD1 mutations were nonmelanoma, endometrial, colorectal, bladder, esophagogastric, lung, and cervical cancers and melanoma.
  • Presence of POLE/POLD1 mutations was associated with improved survival in patients receiving immune checkpoint inhibitors.

In an immune checkpoint inhibitor treatment cohort including 1,527 patients with wild-type and 117 with mutated POLE/POLD1, median overall survival was 34 months among patients with vs 18 months in those without mutations (χ2 = 8.4, P = .004). In multivariate analysis adjusting for cancer types and microsatellite instability (MSI) status, POLE/POLD1 mutations were an independent factor associated with survival benefit from immune checkpoint inhibitor treatment (hazard ratio = 1.41, P = .047). According to the investigators, no significant difference in overall survival among patients receiving immune checkpoint inhibitors was observed between those with MSI-high status and patients with POLE/POLD1 mutations with non–MSI-high status.

The investigators concluded, “In this study, we conducted [an] analysis using a large data set and found that POLE/POLD1 mutations are promising potential predictive biomarkers for positive immune checkpoint inhibitor outcomes.”

Rui-Hua Xu, MD, PhD, of the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, is the corresponding author of the JAMA Oncology article.

Disclosure: The study was supported by the National Key Research and Development Program of China, Natural Science Foundation of Guangdong Province, National Natural Science Foundation of China, and others. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.