Abstract
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.
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Data availability
Data will be made available upon reasonable request with the permission of Caris Life Sciences. Raw sequencing data are owned by Caris Life Sciences and cannot be shared due to patient privacy and protected proprietary information. Access to aggregated data can be requested by contacting the corresponding author, including a brief description of the requirements and intended use. Requests will be discussed with the Caris data access team and a response given within 4 weeks. External datasets used in this study are available from the following public resources: gnomAD, gnomad.broadinstitute.org; International Genome Sample Resource (1000 Genomes Project), www.internationalgenome.org; dbSNP, www.ncbi.nlm.nih.gov/snp. Source data are provided with this paper.
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Acknowledgements
D.H. is supported by a Cancer Prevention and Research Institute of Texas Early Clinical Investigator Award (RP200549) and the Josephine Hughes Sterling Foundation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper. D.S.B.H. is supported by the Dr. Miriam and Sheldon Adelson Medical Research Foundation. The remaining authors received no specific funding for this work.
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D.H. and H.Z. conceptualized the study. M.M., M.E., A.E., J.X. and D.H. performed data analyses. A.S., W.E.-D., E.S.A., S.L.G., M.J.H., H.B., D.S.B.H., S.V.L., P.C.M., R.R.M., T.W.-D., J.M., G.W.S., D.S., H.Z. and D.H. contributed to the assembly of the CARIS cohort. M.M. and D.H. drafted the paper, and all authors participated in the review and editing of the paper.
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A.E., J.X., G.W.S. and D.S. are employees of Caris Life Sciences. S.L.G. serves a paid consultant and advisor to Pfizer, Daiichi Sankyo, Eli Lilly, AstraZeneca, Genentech, SeaGen, Novartis and Menarini and has stock ownership in HCA Healthcare. E.S.A. serves as a paid consultant and advisor to Janssen, Astellas, Sanofi, Dendreon, Bayer, BMS, Amgen, Constellation, Blue Earth, Exact Sciences, Invitae, Curium, Pfizer, Merck, AstraZeneca, Clovis and Eli Lilly; has received research support (to his institution) from Janssen, J&J, Sanofi, BMS, Pfizer, AstraZeneca, Novartis, Curium, Constellation, Celgene, Merck, Bayer and Clovis; and is the co-inventor of a patented AR-V7 biomarker technology that has been licensed to Qiagen. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 TMB cutoffs associated with ICI benefit retain predictive value across demographics.
Subset analyses of patients stratified by age groups and self-reported sex show that the association between TMB cutoffs and outcomes are similar across demographics. Forest plots depict hazard ratios (squares) and error bars indicate 95% confidence intervals.
Extended Data Fig. 2 Associations between overall survival and TMB at the 75th percentile for individual cancer types are independent of the sequencing platform used.
Hazard ratios of overall survival in the ICI cohort using a TMB threshold at the 75th percentile for individual cancer types were separately calculated for cases analyzed by the 592-gene panel or exome sequencing. Forest plots depict hazard ratios (squares) and error bars indicate 95% confidence intervals.
Extended Data Fig. 3 Immune correlates between TMB-high and TMB-low cancers using the earliest cutoff at which ICIs are predictive.
PD-L1 positive cell frequency, T-cell inflammatory score, and CD8 + T cell frequency are compared between TMB-high cancers and TMB-low cancers using the earliest cutoff at which ICIs are associated with OS benefit. Biomarkers enriched in TMB-high and TMB-low cancers using a false discovery rate of 0.05 are highlighted.
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Muquith, M., Espinoza, M., Elliott, A. et al. Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers. Nat Cancer (2024). https://doi.org/10.1038/s43018-024-00752-x
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DOI: https://doi.org/10.1038/s43018-024-00752-x