Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers

Benjamin Garmezy, Jinesh Gheeya, Heather Y. Lin, Yuefan Huang, Taebeom Kim, Xianli Jiang, Kyaw Z. Thein, Patrick G. Pilié, Fadl Zeineddine, Wanlin Wang, Kenna R. Shaw, Jordi Rodon, John Paul Shen, Ying Yuan, Funda Meric-Bernstam, Ken Chen, Timothy A. Yap

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

PURPOSE DNA polymerase epsilon is critical to DNA proofreading and replication. Mutations in POLE 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 POLE mutations, the pattern of co-occurring mutations, and their response to ICI therapy within the context of mutation pathogenicity. METHODS We conducted a retrospective analysis of next-generation sequencing data at MD Anderson Cancer Center to identify patient tumors with POLE 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 POLE pathogenicity status. RESULTS Four hundred fifty-eight patient tumors with POLE mutations were identified from 14,229 next-generation sequencing reports; 15.0% of POLE 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 POLE mutations had improved clinical benefit rate (82.4% v 30.0%; P = .013), median progression-free survival (15.1 v 2.2 months; P, .001), overall survival (29.5 v 6.8 months; P, .001), and longer treatment duration (median 15.5 v 2.5 months; P, .001) compared to those with benign variants. Progression-free survival and overall survival remained superior when adjusting for number of co-occurring mutations (≥ 10 v, 10) and/or microsatellite instability status (proficient mismatch repair v deficient mismatch repair). The number of comutations was not associated with response to ICI (clinical benefit v progressive disease: median 13 v 11 comutations; P = .18). CONCLUSION Pathogenic POLE mutations were associated with clinical benefit to ICI therapy. Further studies are warranted to validate POLE mutation as a predictive biomarker of ICI therapy.

Original languageEnglish (US)
Article numbere2100267
JournalJCO Precision Oncology
Volume6
DOIs
StatePublished - 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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