Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study

Hum Pathol. 2013 Oct;44(10):2055-63. doi: 10.1016/j.humpath.2013.03.010. Epub 2013 May 21.


Tumor-infiltrating lymphocytes (TILs) convey clinically relevant information for primary breast cancers (PBCs). However, limited data characterizing the immunobiology of metastatic breast cancers (MBCs) are available. Here, we examine TILs in surgically resected MBCs relative to their matched PBCs. Tissue microarrays of PBCs and MBCs were labeled for CD3 (total T cells), CD4 (helper T cells), CD8 (cytotoxic T cells), FoxP3 (regulatory T cells), and CD20 (B cells) to characterize TILs. Expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 (HER-2) classified the tumors as luminal (ER(+)/PR(+)/HER-2(-)), triple negative (ER(-)/PR(-)/HER-2(-)), or HER-2(+) (ER(-)/PR(-)/HER-2(+)). These analyses reveal 5 novel findings. First, MBCs overall contained fewer TILs (mean, 35.1 CD3(+) TILs/high-power field [hpf]) than their matched PBCs (mean, 23.6 CD3(+) TILS/hpf), with fewer CD20(+) cells than CD3(+) cells in PBC and MBC (P = .0247). Second, the number of CD3(+), CD8(+), CD4(+), and FoxP3 TILs was decreased in triple-negative MBCs relative to matched PBCs, whereas only CD8(+) TILs were decreased in luminal MBCs relative to matched PBCs. Third, triple-negative MBCs contain fewer TILS (mean, 16 CD3(+) TILs/hpf) than luminal MBCs (mean, 21.7 CD3(+) TILs/hpf). Fourth, brain metastases contained fewer TILs relative to MBC from other sites. Finally, in this series, a CD8(+)/FoxP3(+) T-cell ratio of 3 or greater in PBCs was associated with improved overall survival from diagnosis, whereas a CD8(+)/FoxP3(+) T-cell ratio less than 3 in MBCs at first relapse was associated with improved overall survival. These findings suggest that evaluating the immunologic microenvironment of both PBCs and MBCs may yield important clinical information to guide breast cancer prognosis and therapy.

Keywords: Breast cancer; FoxP3; Regulatory T cells (Treg); Tumor-infiltrating lymphocytes (TILs).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Carcinoma, Ductal, Breast / immunology
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / mortality
  • Carcinoma, Ductal, Breast / secondary*
  • Female
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Immunophenotyping
  • Lymphocyte Subsets / metabolism
  • Lymphocyte Subsets / pathology*
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology*
  • Maryland / epidemiology
  • Mastectomy
  • Middle Aged
  • Pilot Projects
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Estrogen / metabolism*
  • Receptors, Progesterone / metabolism*
  • Survival Rate
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology
  • Tissue Array Analysis
  • Tumor Microenvironment


  • Biomarkers, Tumor
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Receptor, ErbB-2