POLE Mutation Associated With Microsatellite Instability and High Tumor Mutational Burden Confers Exquisite Sensitivity to Immune Checkpoint Inhibitor Therapy in Non–Small Cell Lung Cancer: A Case Report and Genomic Database Analysis

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  DNA polymerase epsilon (POLE) mutations have emerged as a potential predictive biomarker for response to immunotherapy in advanced solid tumors, but are uncommon in non–small cell lung cancer (NSCLC). Here we present a patient with POLE-mutated NSCLC with high tumor mutational burden (TMB) and microsatellite instability (MSI), who experienced a complete response to a chemoimmunotherapy regimen that included an immune checkpoint inhibitor. Publicly available genomic sequencing databases were also queried for the prevalence of POLE mutations in NSCLC.
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  We describe the case of a 68-year-old male never smoker who was diagnosed with cT3 N0 M0 adenocarcinoma of the lung with a hypermutated phenotype characterized by a pathogenic POLE mutation, MSI-high, and very high TMB (572 mutations/megabase) as determined by next generation sequencing. Following completion of 4 cycles of neoadjuvant nivolumab with carboplatin and pemetrexed, the patient underwent left upper lobectomy and mediastinal lymph node dissection, and was found to have had a complete pathologic response.
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  Analysis of DNA sequencing databases confirmed that pathogenic POLE mutations, while very uncommon in NSCLC, appear to be associated with a hypermutated phenotype resulting in high TMB. This clinical vignette illustrates the potential for profound response to immunotherapy in NSCLCs harboring this phenotype. Further work is necessary to characterize POLE mutational status as a potential beneficial predictive biomarker.