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

  • Epidemiology
  • Published:
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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.

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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

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Acknowledgments

Funding for this research was provided by the Breast Cancer Research Foundation (PI: Christine Ambrosone). Dr. Song Yao was the recipient of a fellowship from the Department of Defense Breast Cancer Research Program (W81XWH-08-1-0223). Funding bodies for this study did not play any role in the collection, analysis, interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication. The Roswell Park Cancer Institute Databank and Biorepository, the Clinical Data Network and Flow & Image Cytometry Department are CCSG Shared Resources (NIH P30 CA016056-27).

Conflicts of interest

The authors have no potential conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Chi-Chen Hong, Song Yao, Susan E. McCann, Zhihong Gong, Lei Quan & Christine B. Ambrosone

  2. Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA

    Stephen B. Edge

  3. Department of Flow & Image Cytometry, Roswell Park Cancer Institute, Buffalo, NY, USA

    Ree Y. Dolnick & Paul K. Wallace

  4. Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA

    Kelvin P. Lee, Sharon S. Evans & Elizabeth A. Repasky

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  1. Chi-Chen Hong
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  2. Song Yao
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  3. Susan E. McCann
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  4. Ree Y. Dolnick
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  7. Lei Quan
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  12. Christine B. Ambrosone
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Correspondence to Chi-Chen Hong.

Additional information

Chi-Chen Hong and Song Yao contributed equally to this study and should be considered as first co-authors.

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Table 1

Descriptive 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)

Table 2

Associations between circulating immune markers and risk of ER− breast cancer among women with invasive breast cancer (PDF 166 kb)

Table 3

Associations between circulating immune markers and risk of triple negative versus LumA breast cancer (PDF 599 kb)

Table 4

Spearman partial correlations between cytokines and/or their ratios significantly associated with ER− or TNBCs (PDF 56 kb)

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Hong, CC., Yao, S., McCann, S.E. et al. Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers. Breast Cancer Res Treat 139, 477–488 (2013). https://doi.org/10.1007/s10549-013-2549-3

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