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

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.