Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
JournalOncoImmunology
DOIs
Publication statusAccepted/In press - 1 Jan 2018

Fingerprint

Tumor Burden
Breast Neoplasms
Survival
Neoplasms
Atlases
Regulator Genes
Immune System
Immunity
Therapeutics
Chromosomes
Genome

Keywords

  • breast cancer
  • immune subtypes
  • mutational burden
  • prognosis
  • survival

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

Thomas, A., Routh, E. D., Pullikuth, A., Jin, G., Su, J., Chou, J. W., ... Miller, L. D. (Accepted/In press). Tumor mutational burden is a determinant of immune-mediated survival in breast cancer. OncoImmunology. https://doi.org/10.1080/2162402X.2018.1490854

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer. / Thomas, Alexandra; Routh, Eric D.; Pullikuth, Ashok; Jin, Guangxu; Su, Jing; Chou, Jeff W.; Hoadley, Katherine A.; Print, Cristin; Knowlton, Nick; Black, Michael A.; Demaria, Sandra; Wang, Ena; Bedognetti, Davide; Jones, Wendell D.; Mehta, Gaurav A.; Gatza, Michael L.; Perou, Charles M.; Page, David B.; Triozzi, Pierre; Miller, Lance D.

In: OncoImmunology, 01.01.2018.

Research output: Contribution to journalArticle

Thomas, A, Routh, ED, Pullikuth, A, Jin, G, Su, J, Chou, JW, Hoadley, KA, Print, C, Knowlton, N, Black, MA, Demaria, S, Wang, E, Bedognetti, D, Jones, WD, Mehta, GA, Gatza, ML, Perou, CM, Page, DB, Triozzi, P & Miller, LD 2018, 'Tumor mutational burden is a determinant of immune-mediated survival in breast cancer', OncoImmunology. https://doi.org/10.1080/2162402X.2018.1490854
Thomas, Alexandra ; Routh, Eric D. ; Pullikuth, Ashok ; Jin, Guangxu ; Su, Jing ; Chou, Jeff W. ; Hoadley, Katherine A. ; Print, Cristin ; Knowlton, Nick ; Black, Michael A. ; Demaria, Sandra ; Wang, Ena ; Bedognetti, Davide ; Jones, Wendell D. ; Mehta, Gaurav A. ; Gatza, Michael L. ; Perou, Charles M. ; Page, David B. ; Triozzi, Pierre ; Miller, Lance D. / Tumor mutational burden is a determinant of immune-mediated survival in breast cancer. In: OncoImmunology. 2018.
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