Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival
Abstract Background Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer typ...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-03-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13073-020-00729-2 |
| _version_ | 1817977551150120960 |
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| author | Mary A. Wood Benjamin R. Weeder Julianne K. David Abhinav Nellore Reid F. Thompson |
| author_facet | Mary A. Wood Benjamin R. Weeder Julianne K. David Abhinav Nellore Reid F. Thompson |
| author_sort | Mary A. Wood |
| collection | DOAJ |
| description | Abstract Background Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized. Methods Using a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential. Results We find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes. Conclusions We find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma. |
| first_indexed | 2024-04-13T22:17:56Z |
| format | Article |
| id | doaj.art-020f9dccb61e4868af0dd53ce442a9c8 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-04-13T22:17:56Z |
| publishDate | 2020-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-020f9dccb61e4868af0dd53ce442a9c82022-12-22T02:27:22ZengBMCGenome Medicine1756-994X2020-03-0112111610.1186/s13073-020-00729-2Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survivalMary A. Wood0Benjamin R. Weeder1Julianne K. David2Abhinav Nellore3Reid F. Thompson4Computational Biology Program, Oregon Health & Science UniversityComputational Biology Program, Oregon Health & Science UniversityComputational Biology Program, Oregon Health & Science UniversityComputational Biology Program, Oregon Health & Science UniversityComputational Biology Program, Oregon Health & Science UniversityAbstract Background Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized. Methods Using a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential. Results We find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes. Conclusions We find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma.http://link.springer.com/article/10.1186/s13073-020-00729-2Tumor mutational burdenTMBNeoepitopesNeoepitope burdenNeoantigensSplice junctions |
| spellingShingle | Mary A. Wood Benjamin R. Weeder Julianne K. David Abhinav Nellore Reid F. Thompson Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival Genome Medicine Tumor mutational burden TMB Neoepitopes Neoepitope burden Neoantigens Splice junctions |
| title | Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival |
| title_full | Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival |
| title_fullStr | Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival |
| title_full_unstemmed | Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival |
| title_short | Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival |
| title_sort | burden of tumor mutations neoepitopes and other variants are weak predictors of cancer immunotherapy response and overall survival |
| topic | Tumor mutational burden TMB Neoepitopes Neoepitope burden Neoantigens Splice junctions |
| url | http://link.springer.com/article/10.1186/s13073-020-00729-2 |
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