Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers. (2nd February 2022)

• Record Type: Journal Article
• Authors: Garmezy, Benjamin; Gheeya, Jinesh; Lin, Heather Y.; Huang, Yuefan; Kim, Taebeom; Jiang, Xianli; Thein, Kyaw Z.; Pilié, Patrick G.; Zeineddine, Fadl; Wang, Wanlin; Shaw, Kenna R.; Rodon, Jordi; Shen, John Paul; Yuan, Ying; Meric-Bernstam, Funda; Chen, Ken; Yap, Timothy A.
• Is Part Of: JCO precision oncology. Volume 6(2022)
• Publication Date: 2022-02-02
• Subjects: Precision Medicine; Neoplasms; Pharmacogenetics; Molecular Targeted Therapy; Personalized medicine; Oncology; Pharmacogenomics; Periodical; Periodicals; 616.994
• DOI: 10.1200/PO.21.00267
• Languages: English
• ISSNs: 2473-4284

Abstract

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. Abstract :