Dual roles for immune metagenes in breast cancer prognosis and therapy prediction

Angela Alistar, Jeff W. Chou, Srikanth Nagalla, Michael A. Black, Ralph D'Agostino, Lance D. Miller

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background: Neoadjuvant chemotherapy for breast cancer leads to considerable variability in clinical responses, with only 10 to 20% of cases achieving complete pathologic responses (pCR). Biological and clinical factors that determine the extent of pCR are incompletely understood. Mounting evidence indicates that the patient's immune system contributes to tumor regression and can be modulated by therapies. The cell types most frequently observed with this association are effector tumor infiltrating lymphocytes (TILs), such as cytotoxic T cells, natural killer cells and B cells. We and others have shown that the relative abundance of TILs in breast cancer can be quantified by intratumoral transcript levels of coordinately expressed, immune cell-specific genes. Through expression microarray analysis, we recently discovered three immune gene signatures, or metagenes, that appear to reflect the relative abundance of distinct tumor-infiltrating leukocyte populations. The B/P (B cell/plasma cell), T/NK (T cell/natural killer cell) and M/D (monocyte/dendritic cell) immune metagenes were significantly associated with distant metastasis-free survival of patients with highly proliferative cancer of the basal-like, HER2-enriched and luminal B intrinsic subtypes.Methods: Given the histopathological evidence that TIL abundance is predictive of neoadjuvant treatment efficacy, we evaluated the therapy-predictive potential of the prognostic immune metagenes. We hypothesized that pre-chemotherapy immune gene signatures would be significantly predictive of tumor response. In a multi-institutional, meta-cohort analysis of 701 breast cancer patients receiving neoadjuvant chemotherapy, gene expression profiles of tumor biopsies were investigated by logistic regression to determine the existence of therapy-predictive interactions between the immune metagenes, tumor proliferative capacity, and intrinsic subtypes.Results: By univariate analysis, the B/P, T/NK and M/D metagenes were all significantly and positively associated with favorable pathologic responses. In multivariate analyses, proliferative capacity and intrinsic subtype altered the significance of the immune metagenes in different ways, with the M/D and B/P metagenes achieving the greatest overall significance after adjustment for other variables.Conclusions: Gene expression signatures of infiltrating immune cells carry both prognostic and therapy-predictive value that is impacted by tumor proliferative capacity and intrinsic subtype. Anti-tumor functions of plasma B cells and myeloid-derived antigen-presenting cells may explain more variability in pathologic response to neoadjuvant chemotherapy than previously recognized.

Original languageEnglish (US)
Article number80
JournalGenome Medicine
Volume6
Issue number10
DOIs
StatePublished - Oct 28 2014
Externally publishedYes

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Breast Neoplasms
Plasma Cells
B-Lymphocytes
Tumor-Infiltrating Lymphocytes
Neoplasms
Natural Killer Cells
Dendritic Cells
Drug Therapy
Monocytes
Therapeutics
T-Lymphocytes
Transcriptome
Genes
Neoadjuvant Therapy
Biological Factors
Antigen-Presenting Cells
Microarray Analysis
Meta-Analysis
Immune System
Leukocytes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Alistar, A., Chou, J. W., Nagalla, S., Black, M. A., D'Agostino, R., & Miller, L. D. (2014). Dual roles for immune metagenes in breast cancer prognosis and therapy prediction. Genome Medicine, 6(10), [80]. https://doi.org/10.1186/s13073-014-0080-8
Alistar, Angela ; Chou, Jeff W. ; Nagalla, Srikanth ; Black, Michael A. ; D'Agostino, Ralph ; Miller, Lance D. / Dual roles for immune metagenes in breast cancer prognosis and therapy prediction. In: Genome Medicine. 2014 ; Vol. 6, No. 10.
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Dual roles for immune metagenes in breast cancer prognosis and therapy prediction. / Alistar, Angela; Chou, Jeff W.; Nagalla, Srikanth; Black, Michael A.; D'Agostino, Ralph; Miller, Lance D.

In: Genome Medicine, Vol. 6, No. 10, 80, 28.10.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dual roles for immune metagenes in breast cancer prognosis and therapy prediction

AU - Alistar, Angela

AU - Chou, Jeff W.

AU - Nagalla, Srikanth

AU - Black, Michael A.

AU - D'Agostino, Ralph

AU - Miller, Lance D.

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Y1 - 2014/10/28

N2 - Background: Neoadjuvant chemotherapy for breast cancer leads to considerable variability in clinical responses, with only 10 to 20% of cases achieving complete pathologic responses (pCR). Biological and clinical factors that determine the extent of pCR are incompletely understood. Mounting evidence indicates that the patient's immune system contributes to tumor regression and can be modulated by therapies. The cell types most frequently observed with this association are effector tumor infiltrating lymphocytes (TILs), such as cytotoxic T cells, natural killer cells and B cells. We and others have shown that the relative abundance of TILs in breast cancer can be quantified by intratumoral transcript levels of coordinately expressed, immune cell-specific genes. Through expression microarray analysis, we recently discovered three immune gene signatures, or metagenes, that appear to reflect the relative abundance of distinct tumor-infiltrating leukocyte populations. The B/P (B cell/plasma cell), T/NK (T cell/natural killer cell) and M/D (monocyte/dendritic cell) immune metagenes were significantly associated with distant metastasis-free survival of patients with highly proliferative cancer of the basal-like, HER2-enriched and luminal B intrinsic subtypes.Methods: Given the histopathological evidence that TIL abundance is predictive of neoadjuvant treatment efficacy, we evaluated the therapy-predictive potential of the prognostic immune metagenes. We hypothesized that pre-chemotherapy immune gene signatures would be significantly predictive of tumor response. In a multi-institutional, meta-cohort analysis of 701 breast cancer patients receiving neoadjuvant chemotherapy, gene expression profiles of tumor biopsies were investigated by logistic regression to determine the existence of therapy-predictive interactions between the immune metagenes, tumor proliferative capacity, and intrinsic subtypes.Results: By univariate analysis, the B/P, T/NK and M/D metagenes were all significantly and positively associated with favorable pathologic responses. In multivariate analyses, proliferative capacity and intrinsic subtype altered the significance of the immune metagenes in different ways, with the M/D and B/P metagenes achieving the greatest overall significance after adjustment for other variables.Conclusions: Gene expression signatures of infiltrating immune cells carry both prognostic and therapy-predictive value that is impacted by tumor proliferative capacity and intrinsic subtype. Anti-tumor functions of plasma B cells and myeloid-derived antigen-presenting cells may explain more variability in pathologic response to neoadjuvant chemotherapy than previously recognized.

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