DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden.

Cell Reports Medicine
David HsiehchenHao Zhu

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but prediction of their benefit is challenging. Neoantigens generated through impaired non-mismatch DNA repair may result in greater ICI activity. By analyzing 1,661 ICI-treated patients, we show that deletions and mutations in nucleotide excision repair (NER) and homologous repair (HR) pathways are predictors of ICI benefit independent of tumor mutation burden and tumor type. NER and HR mutations are also associated with objective response rates to ICIs in esophagogastric and non-small-cell lung cancers. In a cohort of 40,181 unique patients, NER and HR mutations are present in 3.4% and 13.9% of cancers, respectively. These results indicate that NER and HR gene mutations occur in a subpopulation of cancer patients and may aid patient selection for ICI therapy. Assessing NER and HR mutations in the context of other biomarkers may yield powerful predictors of ICI activity across different cancer types.

Citations

Dec 12, 2020·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Dong PanChuan-Yuan Li
Mar 23, 2021·Oncotarget·Tess A O'Meara, Sara M Tolaney
May 8, 2021·Hematology/oncology Clinics of North America·Brendan J GuercioJonathan E Rosenberg
Jun 2, 2021·Future Oncology·Rachel RoyfmanJohn Nemunaitis
Aug 12, 2021·Nature Reviews. Cancer·Roman M ChabanonSophie Postel-Vinay

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Clinical Trials Mentioned

NCT04042831
NCT03207347
NCT03209401

Software Mentioned

GraphPad Prism
SPSS Statistics

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