Tumor mutational burden is a determinant of immune-mediated survival in breast cancer
Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer....
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2018-10-01
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Online Access: | http://dx.doi.org/10.1080/2162402X.2018.1490854 |
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doaj-5c1e86749b8f4e34bf035b1f784d1f982020-11-25T02:50:48ZengTaylor & Francis GroupOncoImmunology2162-402X2018-10-0171010.1080/2162402X.2018.14908541490854Tumor mutational burden is a determinant of immune-mediated survival in breast cancerAlexandra Thomas0Eric D. Routh1Ashok Pullikuth2Guangxu Jin3Jing Su4Jeff W. Chou5Katherine A. Hoadley6Cristin Print7Nick Knowlton8Michael A. Black9Sandra Demaria10Ena Wang11Davide Bedognetti12Wendell D. Jones13Gaurav A. Mehta14Michael L. Gatza15Charles M. Perou16David B. Page17Pierre Triozzi18Lance D. Miller19Wake Forest Baptist Medical CenterWake Forest School of MedicineWake Forest School of MedicineWake Forest Comprehensive Cancer CenterWake Forest School of Medicine, Medical Center BoulevardWake Forest Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillThe University of AucklandThe University of AucklandSchool of Biomedical Sciences, University of OtagoWeill Cornell Medical CollegeSidra Medical and Research CenterSidra Medical and Research CenterEA Genomics, Division of Q SolutionsRutgers Cancer Institute of New JerseyRutgers Cancer Institute of New JerseyUniversity of North Carolina at Chapel HillProvidence Cancer Center, Earle A. Chiles Research InstituteWake Forest Baptist Medical CenterWake Forest Comprehensive Cancer CenterMounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.http://dx.doi.org/10.1080/2162402X.2018.1490854breast cancermutational burdenimmune subtypesprognosissurvival |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alexandra Thomas Eric D. Routh Ashok Pullikuth Guangxu Jin Jing Su Jeff W. Chou Katherine A. Hoadley Cristin Print Nick Knowlton Michael A. Black Sandra Demaria Ena Wang Davide Bedognetti Wendell D. Jones Gaurav A. Mehta Michael L. Gatza Charles M. Perou David B. Page Pierre Triozzi Lance D. Miller |
spellingShingle |
Alexandra Thomas Eric D. Routh Ashok Pullikuth Guangxu Jin Jing Su Jeff W. Chou Katherine A. Hoadley Cristin Print Nick Knowlton Michael A. Black Sandra Demaria Ena Wang Davide Bedognetti Wendell D. Jones Gaurav A. Mehta Michael L. Gatza Charles M. Perou David B. Page Pierre Triozzi Lance D. Miller Tumor mutational burden is a determinant of immune-mediated survival in breast cancer OncoImmunology breast cancer mutational burden immune subtypes prognosis survival |
author_facet |
Alexandra Thomas Eric D. Routh Ashok Pullikuth Guangxu Jin Jing Su Jeff W. Chou Katherine A. Hoadley Cristin Print Nick Knowlton Michael A. Black Sandra Demaria Ena Wang Davide Bedognetti Wendell D. Jones Gaurav A. Mehta Michael L. Gatza Charles M. Perou David B. Page Pierre Triozzi Lance D. Miller |
author_sort |
Alexandra Thomas |
title |
Tumor mutational burden is a determinant of immune-mediated survival in breast cancer |
title_short |
Tumor mutational burden is a determinant of immune-mediated survival in breast cancer |
title_full |
Tumor mutational burden is a determinant of immune-mediated survival in breast cancer |
title_fullStr |
Tumor mutational burden is a determinant of immune-mediated survival in breast cancer |
title_full_unstemmed |
Tumor mutational burden is a determinant of immune-mediated survival in breast cancer |
title_sort |
tumor mutational burden is a determinant of immune-mediated survival in breast cancer |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2018-10-01 |
description |
Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification. |
topic |
breast cancer mutational burden immune subtypes prognosis survival |
url |
http://dx.doi.org/10.1080/2162402X.2018.1490854 |
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