title: Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers.
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.
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Chi-Chen.Hong@RoswellPark.org
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Hong
authors.forename: Song
authors.initials: S
authors.lastname: Yao
authors.forename: Susan E
authors.initials: SE
authors.lastname: McCann
authors.forename: Ree Y
authors.initials: RY
authors.lastname: Dolnick
authors.forename: Paul K
authors.initials: PK
authors.lastname: Wallace
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Gong
authors.forename: Lei
authors.initials: L
authors.lastname: Quan
authors.forename: Kelvin P
authors.initials: KP
authors.lastname: Lee
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Evans
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Repasky
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Edge
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011960:Receptors, Estrogen; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000097:blood / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D011960:Receptors, Estrogen