Breast Cancer Research and Treatment

, Volume 139, Issue 2, pp 477–488 | Cite as

Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers

  • Chi-Chen Hong
  • Song Yao
  • Susan E. McCann
  • Ree Y. Dolnick
  • Paul K. Wallace
  • Zhihong Gong
  • Lei Quan
  • Kelvin P. Lee
  • Sharon S. Evans
  • Elizabeth A. Repasky
  • Stephen B. Edge
  • Christine B. Ambrosone
Epidemiology

Abstract

Immune signatures in breast tumors differ by estrogen receptor (ER) status. The purpose of this study was to assess associations between ER phenotypes and circulating levels of cytokines that co-ordinate cell-mediated [T-helper type 1 (Th1)] and humoral [T-helper type 2 (Th2)] immunity. We conducted a case–case comparison of 523 women with newly diagnosed breast cancer to evaluate associations between 27 circulating cytokines, measured using Luminex XMap technology, and breast cancer phenotypes [ER vs. ER+; triple negative breast cancer (TNBC) vs. luminal A (LumA)]. Ratios of Th1 to Th2 cytokines were also evaluated. Levels of interleukin (IL)-5, a Th-2 cytokine, were higher in ER than in ER+ tumors. The highest tertile of IL-5 was more strongly associated with ER (OR = 2.33, 95 % CI 1.40–3.90) and TNBCs (OR = 2.78, 95 % CI 1.53–5.06) compared to ER+ and LumA cancers, respectively, particularly among premenopausal women (OR = 4.17, 95 % CI 1.86–9.34, ER vs. ER+; OR = 5.60, 95 % CI 2.09–15.01, TNBC vs. LumA). Elevated Th1 cytokines were also detected in women with ER and TNBCs, with women in the highest tertile of interferon α2 (OR = 2.39, 95 % CI 1.31–4.35) or tumor necrosis factor-α (OR = 2.27, 95 % CI 1.21–4.26) being twice as likely to have TNBC versus LumA cancer. When cytokine ratios were examined, women with the highest ratios of Th1 cytokines to IL-5 levels were least likely to have ER or TNBCs compared to ER+ or LumA cancers, respectively. The strongest associations were in premenopausal women, who were up to 80 % less likely to have TNBC than LumA cancers (IL-12p40/IL-5, OR = 0.19, 95 % CI 0.07–0.56). These findings indicate that immune function is associated with ER and TNBC and may be most relevant among younger women, who are likely to be diagnosed with these aggressive phenotypes.

Keywords

Estrogen negative breast cancer Triple negative breast cancer Cytokines Immune function 

Abbreviations

AJCC

American Joint Committee on Cancer

BRCA1

Breast cancer type 1 susceptibility protein

CCL2

Chemokine (C–C motif) ligand 2

CCL7

Chemokine (C–C motif) ligand 7

CCL11

Chemokine (C–C motif) ligand 11

CK

Cytokeratin

CXCL10

Chemokine (C–X–C motif) ligand 10

DBBR

Data Bank and Biorepository

EGFR+

Epidermal growth factor receptor positive

ER

Estrogen receptor

ER+

Estrogen receptor positive

ER

Estrogen receptor negative

G-CSF

Granulocyte-colony stimulating factor

GM-CSF

Granulocyte macrophage-colony stimulating factor

HER2

Human epidermal growth factor receptor 2 negative

IFN

Interferon

IHC

Immunohistochemistry

IL

Interleukin

IL1RA

Interleukin-1 receptor antagonist

IP-10

Interferon gamma-induced protein 10

IRB

Institutional Review Board

LumA

Luminal A

MCP

Monocyte chemotactic protein

MDC

Macrophage-derived chemokine

MIP-1

Macrophage inflammatory protein-1

QC

Quality control

RPCI

Roswell Park Cancer Institute

TAMS

Tumor-associated macrophages

Th1

T-helper type 1

Th2

T-helper type 2

Th17

T-helper type 17

TNBC

Triple negative breast cancer

TNF

Tumor necrosis factor

Supplementary material

10549_2013_2549_MOESM1_ESM.pdf (132 kb)
Table 1Descriptive statistics of 27 cytokines and all ratios examined in 530 women with invasive breast cancer. Specific cutpoints used to define low, medium, and high circulating cytokine levels are provided along with detectable assay limits, interplate coefficient of variations for each cytokine measured, and proportion of samples below the detectable limit. Effect of sample storage and season of blood draw on cytokine levels are also shown. (PDF 133 kb)
10549_2013_2549_MOESM2_ESM.pdf (165 kb)
Table 2Associations between circulating immune markers and risk of ER breast cancer among women with invasive breast cancer (PDF 166 kb)
10549_2013_2549_MOESM3_ESM.pdf (599 kb)
Table 3Associations between circulating immune markers and risk of triple negative versus LumA breast cancer (PDF 599 kb)
10549_2013_2549_MOESM4_ESM.pdf (55 kb)
Table 4Spearman partial correlations between cytokines and/or their ratios significantly associated with ER or TNBCs (PDF 56 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Chi-Chen Hong
    • 1
  • Song Yao
    • 1
  • Susan E. McCann
    • 1
  • Ree Y. Dolnick
    • 3
  • Paul K. Wallace
    • 3
  • Zhihong Gong
    • 1
  • Lei Quan
    • 1
  • Kelvin P. Lee
    • 4
  • Sharon S. Evans
    • 4
  • Elizabeth A. Repasky
    • 4
  • Stephen B. Edge
    • 2
  • Christine B. Ambrosone
    • 1
  1. 1.Department of Cancer Prevention and ControlRoswell Park Cancer InstituteBuffaloUSA
  2. 2.Department of Surgical OncologyRoswell Park Cancer InstituteBuffaloUSA
  3. 3.Department of Flow & Image CytometryRoswell Park Cancer InstituteBuffaloUSA
  4. 4.Department of ImmunologyRoswell Park Cancer InstituteBuffaloUSA

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