Abstract 52: Pretreatment levels of circulating Th1 and Th2 cytokines and their ratios are associated with ER-negative and triple-negative breast cancers.
Authors: Hong Chi-Chen , Yao Song , McCann Susan , Dolnick Ree Y. , Wallace Paul K. , Gong Zhihong , Quan Lei , Repasky Elizabeth A. , Evans Sharon , Edge Stephen B. , Lee Kelvin , Ambrosone Christine B. 
Published: August 2013

Abstract
Purpose: Immune signatures differ between estrogen receptor negative (ER−) and ER positive (ER+) breast tumors. The purpose of this study was to assess associations between ER phenotypes and circulating cytokine levels that co-ordinate cell-mediated and humoral immunity.
Patients and Methods: We conducted a case-case comparison of 523 women with incident invasive breast cancer to evaluate associations between 27 circulating cytokines measured prior to surgery and/or adjuvant treatment using Luminex XMap technology and breast cancer phenotypes (ER−versus ER+ ; triple negative breast cancer (TNBC) versus luminal A). Ratios of T helper (Th) 1 to Th2 cytokines were also evaluated since different functional subsets of T helper cells regulate each other, often through antagonistic activity. Case-case comparisons were performed using unconditional logistic regression to examine associations between cytokine measures and odds of ER−versus ER+ tumors and TNBC versus luminal A cancers.
Results: Both ER− and TNBCs were associated with high levels of circulating IL-5, a Th2 cytokine specific in driving eosinophil-dependent inflammatory diseases typically associated with allergic diseases such as asthma. Overall, women in the highest tertile compared to the lowest had approximately 2.5-fold increased odds of being diagnosed with ER− breast cancer or TNBC. Associations were strongest among premenopausal women, showing over 4-fold increased odds of ER−breast cancer (OR=4.17, 95% CI: 1.86 to 9.34) and over 5.5-fold increased odds of TNBC (OR=5.60, 95% CI: 2.09-15.01). Both ER-and TNBCs were associated with more pronounced Th1 immune activation, with women in the highest tertile of IFNα2 (OR=2.39, 95% CI: 1.31, 4.35) or TNFα (OR=2.27, 95% CI: 1.21, 4.26) being twice as likely to have TNBC. Relationships were again stronger among premenopausal women, with those in the highest tertile of IFNα2 being &gt; 4 times more likely to have ER−(OR=4.11, 95% CI: 1.70, 9.92) and TNBC (OR=4.55, 95% CI: 1.58, 12.34). Several cytokine ratios indicating a strong Th1/IL5 balance were inversely associated with both ER− and TNBC. Women in the highest tertile were approximately 2 to 2.5 times less likely to have ER− breast cancer and 2.5 to 3 times less likely to have TNBC. Associations were strongest among premenopausal women, who were approximately 3 times less likely to have ER− disease and up to 5-times less likely to have TNBC (IL-12p40/IL-5, OR=0.19, 95% CI, 0.07 to 0.56).
Conclusion: These findings, taken together, support the hypothesis that immune function is associated with development of ER− and TNBC, and that immune pathways might be physiologically most relevant among younger women who are most likely to be diagnosed with these aggressive phenotypes, and point to the possibility that these breast cancer patients may benefit from immunotherapies such as IFNα2, which increase Th1 versus Th2 balance, or eosinophil or IL-5-targeted therapies that have been developed to neutralize IL-5 or target IL-5R for the treatment of eosinophilic diseases.
Citation Format: Chi-Chen Hong, Song Yao, Susan McCann, Ree Y. Dolnick, Paul K. Wallace, Zhihong Gong, Lei Quan, Elizabeth A. Repasky, Sharon Evans, Stephen B. Edge, Kelvin Lee, Christine B. Ambrosone. Pretreatment levels of circulating Th1 and Th2 cytokines and their ratios are associated with ER-negative and triple-negative breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 52.