@article{8bd2470183d34780a30cf9721584b7c6,
title = "Tumor mutational burden is a determinant of immune-mediated survival in breast cancer",
abstract = "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.",
keywords = "breast cancer, immune subtypes, mutational burden, prognosis, survival",
author = "Alexandra Thomas and Routh, {Eric D.} and Ashok Pullikuth and Guangxu Jin and Jing Su and Chou, {Jeff W.} and Hoadley, {Katherine A.} and Cristin Print and Nick Knowlton and Black, {Michael A.} and Sandra Demaria and Ena Wang and Davide Bedognetti and Jones, {Wendell D.} and Mehta, {Gaurav A.} and Gatza, {Michael L.} and Perou, {Charles M.} and Page, {David B.} and Pierre Triozzi and Miller, {Lance D.}",
note = "Funding Information: This study was supported by funds from the American Cancer Society (RSG-12-198-01-TBG; L.D.M., E.D.R. and A.P.), the Mary Kirkpatrick Professorship for Breast Cancer Research (L.D.M.), the NCI Breast SPORE program (P50-CA58223-09A1; C.M.P.), RO1-CA195740-01 (C.M.P.), the Breast Cancer Research Foundation (C.M.P.), the Maurice Wilkins Centre, New Zealand (C. P. and N.K.) and Breast Cancer Cure NZ (C.P.). The Biostatistics Shared Resource and the Bioinformatics Shared Resource, supported by the Wake Forest Baptist Comprehensive Cancer Center{\textquoteright}s NCI Cancer Center Support Grant award number P30CA012197, also contributed to this work. The content is solely the responsibility of the authors and does not represent the official views of the National Cancer Institute. L.D.M. and A.T. conceived of and designed the study. All authors contributed to aspects of the data analysis and interpretation and the writing of the manuscript. We thank the Cancer Genome Atlas Research Network and the Molecular Taxonomy of Breast Cancer International Consortium for collecting, analyzing and sharing data used in this study. Funding Information: This study was supported by funds from the American Cancer Society (RSG-12-198-01-TBG; L.D.M., E.D.R. and A.P.), the Mary Kirkpatrick Professorship for Breast Cancer Research (L.D.M.), the NCI Breast SPORE program (P50-CA58223-09A1; C.M.P.), RO1-CA195740-01 (C. M.P.), the Breast Cancer Research Foundation (C.M.P.), the Maurice Wilkins Centre, New Zealand (C. P. and N.K.) and Breast Cancer Cure NZ (C.P.). The Biostatistics Shared Resource and the Bioinformatics Shared Resource, supported by the Wake Forest Baptist Comprehensive Cancer Center{\textquoteright}s NCI Cancer Center Support Grant award number P30CA012197, also contributed to this work. The content is solely the responsibility of the authors and does not represent the official views of the National Cancer Institute. Publisher Copyright: {\textcopyright} 2018, {\textcopyright} 2018 The Author(s). Published by Taylor & Francis.",
year = "2018",
month = oct,
day = "3",
doi = "10.1080/2162402X.2018.1490854",
language = "English (US)",
volume = "7",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",
number = "10",
}