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

Author:

Garmezy Benjamin1ORCID,Gheeya Jinesh2ORCID,Lin Heather Y.3ORCID,Huang Yuefan4,Kim Taebeom4ORCID,Jiang Xianli4ORCID,Thein Kyaw Z.5ORCID,Pilié Patrick G.6,Zeineddine Fadl7,Wang Wanlin5,Shaw Kenna R.8ORCID,Rodon Jordi5ORCID,Shen John Paul7ORCID,Yuan Ying3ORCID,Meric-Bernstam Funda58ORCID,Chen Ken4ORCID,Yap Timothy A.589

Affiliation:

1. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

2. The University of Texas Health Science Center at Houston, Houston, TX

3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX

4. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX

5. Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX

6. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

7. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

8. Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX

9. The Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX

Abstract

PURPOSEDNA 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.METHODSWe 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.RESULTSFour 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).CONCLUSIONPathogenic 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.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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