@article{06bb2d0a3eb14562a7d9ead0213e8e6d,
title = "DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden",
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.",
keywords = "DNA repair, cancer biomarkers, immunotherapy, survival",
author = "David Hsiehchen and Antony Hsieh and Samstein, {Robert M.} and Tianshi Lu and Beg, {Muhammad S.} and Gerber, {David E.} and Tao Wang and Morris, {Luc G.T.} and Hao Zhu",
note = "Funding Information: This work was supported by an AACR Translational Immuno-Oncology Award (to R.M.S.); NIH grants 2UM1CA186644-06 (to M.S.B.), K24CA201543-01 (to D.E.G.), CCSG 5P30CA142543 (to T.W.), R01DE027738 (to L.G.T.M), R01DK111588 (to H.Z.), and R01CA190525 (to H.Z.); and a Cancer Prevention and Research Institute of Texas grant RP190208 (to T.W.). Funding Information: This work was supported by an AACR Translational Immuno-Oncology Award (to R.M.S.); NIH grants 2UM1CA186644-06 (to M.S.B.), K24CA201543-01 (to D.E.G.), CCSG 5P30CA142543 (to T.W.), R01DE027738 (to L.G.T.M), R01DK111588 (to H.Z.), and R01CA190525 (to H.Z.); and a Cancer Prevention and Research Institute of Texas grant RP190208 (to T.W.). Conceptualization, D.H. A.H. and H.Z.; Investigation, D.H. R.M.S. T.L. T.W. L.G.T.M. and H.Z.; Resources, D.H. R.M.S. T.W. M.S.B. D.E.G. T.W. L.G.T.M. and H.Z.; Formal Analysis, D.H. T.L. and T.W.; Writing ?Original Draft, D.H. A.H. and H.Z.; Writing ? Review & Editing, R.M.S. M.S.B. D.E.G. T.W. and L.G.T.M. 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, BerGenBio, 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. Funding Information: 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, BerGenBio, 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. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = jun,
day = "23",
doi = "10.1016/j.xcrm.2020.100034",
language = "English (US)",
volume = "1",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "3",
}