Clinical and Molecular Characterization of <i>POLE</i> Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers.

Abstract

DNA polymerase epsilon is critical to DNA proofreading and replication. Mutations in <i>POLE</i> have been associated with hypermutated tumors and antitumor response to immune checkpoint inhibitor (ICI) therapy. We present a clinicopathologic analysis of patients with advanced cancers harboring <i>POLE</i> mutations, the pattern of co-occurring mutations, and their response to ICI therapy within the context of mutation pathogenicity. We conducted a retrospective analysis of next-generation sequencing data at MD Anderson Cancer Center to identify patient tumors with <i>POLE</i> mutations and their co-occurring mutations. The pathogenicity of each mutation was annotated using InterVar and ClinVar. Differences in therapeutic response to ICI, survival, and co-occurring mutations were reported by <i>POLE</i> pathogenicity status. Four hundred fifty-eight patient tumors with <i>POLE</i> mutations were identified from 14,229 next-generation sequencing reports; 15.0% of <i>POLE</i> mutations were pathogenic, 15.9% benign, and 69.1% variant of unknown significance. Eighty-two patients received either programmed death 1 or programmed death ligand-1 inhibitors as monotherapy or in combination with cytotoxic T-cell lymphocyte-4 inhibitors. Patients with pathogenic <i>POLE</i> mutations had improved clinical benefit rate (82.4% <i>v</i> 30.0%; <i>P</i> = .013), median progression-free survival (15.1 <i>v</i> 2.2 months; <i>P</i> < .001), overall survival (29.5 <i>v</i> 6.8 months; <i>P</i> < .001), and longer treatment duration (median 15.5 <i>v</i> 2.5 months; <i>P</i> < .001) compared to those with benign variants. Progression-free survival and overall survival remained superior when adjusting for number of co-occurring mutations (≥ 10 <i>v</i> < 10) and/or microsatellite instability status (proficient mismatch repair <i>v</i> deficient mismatch repair). The number of comutations was not associated with response to ICI (clinical benefit <i>v</i> progressive disease: median 13 <i>v</i> 11 comutations; <i>P</i> = .18). Pathogenic <i>POLE</i> mutations were associated with clinical benefit to ICI therapy. Further studies are warranted to validate <i>POLE</i> mutation as a predictive biomarker of ICI therapy.