title: Dual roles for immune metagenes in breast cancer prognosis and therapy prediction.
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.
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157 USA ; The Comprehensive Cancer Center of Wake Forest University, Medical Center Blvd, Winston Salem, NC 27157 USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Alistar
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157 USA.
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Chou
authors.affiliation: Department of Medicine, Jefferson Medical College, 1015 Chestnut Street, Suite 1321, Philadelphia, PA 19107 USA.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Nagalla
authors.affiliation: Department of Biochemistry, Otago School of Medical Sciences, University of Otago, 710 Cumberland Street, Dunedin, 9054 New Zealand.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Black
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157 USA ; The Comprehensive Cancer Center of Wake Forest University, Medical Center Blvd, Winston Salem, NC 27157 USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: D'Agostino
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157 USA ; The Comprehensive Cancer Center of Wake Forest University, Medical Center Blvd, Winston Salem, NC 27157 USA.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller