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. 2020 Jun 23;1(3):100034.
doi: 10.1016/j.xcrm.2020.100034.

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

David Hsiehchen  1   2 , Antony Hsieh  3 , Robert M Samstein  4   5 , Tianshi Lu  6 , Muhammad S Beg  1 , David E Gerber  1   7 , Tao Wang  6 , Luc G T Morris  8   9 , Hao Zhu  10
Affiliations

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

David Hsiehchen et al. Cell Rep Med. .

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.

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Conflict of interest statement

DECLARATION OF INTERESTS R.M.S. and L.G.T.M. are inventors on a provisional patent application (62/569,053) filed by MSKCC, relating to the use of TMB in cancer immunotherapy. D.E.G. reports advisory or consulting roles for Bristol-Myers Squibb, Karyopharm, and Catalyst and receives research funding from AstraZeneca, Ber-GenBio, Karyopharm, and 3V Biosciences. L.G.T.M. receives laboratory research funding from AstraZeneca. H.Z. owns Ionis Pharmaceuticals stock worth less than $10,000. H.Z. has an active collaboration with Alnylam Pharmaceuticals and Twenty-Eight Seven Therapeutics. All other authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
DNA Repair Gene Mutations Are Associated with Longer Overall Survival in ICI-Treated Patients (A) Unadjusted Kaplan-Meier survival curves for NER mutant (Mut) and wild-type (WT) patients treated with ICIs. (B) Unadjusted Kaplan-Meier survival curves for HR Mut and WT patients treated with ICIs. (C) Unadjusted and adjusted hazard ratios (HRs) for overall survival with 95% confidence intervals (95% CI) associated with NER and HR mutations. The adjusted Cox regression model included TMB, type of ICI administered, and tumor type.
Figure 2
Figure 2
NER and HR Mutations Are Independent and Additive Predictors of ICI Response (A) Kaplan-Meier survival curves for ICI-treated patients with no mutations (WT), NER or HR mutations, or NER and HR mutations. (B) Kaplan-Meier survival curves for non-MMRd ICI patients with no mutations (WT), NER or HR mutations, or NER and HR mutations.
Figure 3
Figure 3
Association between Objective Response Rates to ICIs and NER and HR Mutations The proportions of NER and HR Mut or WT cancers are shown for patients who had a complete or partial response (Responder) and for patients who did not (non-responder) in separate cohorts of patients with esophagogastric adenocarcinoma (EGA) or non-small-cell lung cancer (NSCLC).
Figure 4
Figure 4
Landscape of NER and HR Mutations across Different Cancers (A) Waterfall plot of NER and HR mutations across 40,181 unique cancers. (B) Frequency of NER and HR mutations and median TMB by cancer type.
See this image and copyright information in PMC

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