Tumor mutational burden (TMB) has emerged as a promising biomarker of immunotherapy response across multiple cancer types; however, clinical outcomes among patients with low TMB tumors are heterogeneous. Herein, we demonstrate that tumor aneuploidy provides independent prognostic value among patients with lower TMB (<80th percentile) tumors treated with immunotherapy. A higher aneuploidy score is associated with poor prognosis following immunotherapy among tumors with low TMB, but not those with high TMB. Importantly, aneuploidy scores can be calculated from existing clinical targeted sequencing infrastructure, facilitating deployment of aneuploidy scores as a clinical biomarker.
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All data are available from the cBioPortal study found at https://www.cbioportal.org/study/summary?id=tmb_mskcc_2018 and the GENIE v.7.1 release: https://www.synapse.org/#!Synapse:syn7222066/wiki/405659. Aneuploidy scores and FGA values for each sample are provided in the GitHub repository referenced below. Source data are provided with this paper.
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This work was supported by the Ludwig Cancer Research Foundation (S.P.P. and R.R.W.), a Career Development Award from the LUNGevity Foundation (S.P.P.), an Ullman Scholarship in Translational Cancer Immunology from the University of Chicago Comprehensive Cancer Center (UCCCC) (S.P.P.), a Cancer Spotlight Grant (S.P.P.) from the UCCCC, a Fight Against Cancer Grant from the United-4 A Cure Foundation (S.P.P.) and a National Institutes of Health NCI-SOAR Grant 1R25CA240134-01 (L.F.S.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
L.F.S. declares no competing interests. R.R.W. reports having stock and other ownership interests with Boost Therapeutics, ImmVira LLC, Reflexion Pharmaceuticals, Coordination Pharmaceuticals Inc., Magi Therapeutics and Oncosenescence; serving in a consulting or advisory role for Aettis Inc., AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., NanoProteagen, NKMax America Inc., Shuttle Pharmaceuticals and Highlight Therapeutics, S.L.; having research grants with Varian and Regeneron; and receiving compensation including travel, accommodations or expense reimbursement from AstraZeneca, Boehringer Ingelheim Ltd. and Merck Serono S.A. S.P.P. has patents outside of the submitted work.
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Spurr, L.F., Weichselbaum, R.R. & Pitroda, S.P. Tumor aneuploidy predicts survival following immunotherapy across multiple cancers. Nat Genet 54, 1782–1785 (2022). https://doi.org/10.1038/s41588-022-01235-4
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