Association of Circulating Eosinophils With Systemic Immune Activation and Reduced Recurrence in Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer

Purpose Hormone receptor–positive/human epidermal growth factor receptor 2–negative (HER2–) breast cancer, the most common subtype, lacks simple, noninvasive biomarkers for recurrence. We evaluated circulating eosinophil count as a clinically applicable biomarker for recurrence in this population. Methods Associations between preoperative eosinophil count and patient outcomes were evaluated in a multimodal discovery cohort (N = 472) and validated via propensity score overlap weighting in an independent expanded cohort (N = 23,170). We assessed the additive value of eosinophils in patients with 21-gene recurrence scores (RSs; n = 2,973) and their predictive role for adjuvant cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in high-risk patients (n = 3,471). Mechanisms were investigated using integrated multiomics, spatial digital pathology, and in vivo preclinical models. Results Higher circulating eosinophil counts correlated with significantly improved recurrence-free and distant metastasis-free survival in the discovery cohort. Genomic analysis associated these elevated counts with lower human leukocyte antigen homozygosity and increased intratumoral immune activation. Functionally, eosinophils were associated with antitumor effects, with evidence of CD8 + T-cell involvement. These findings were further validated in vivo, where eosinophil adoptive transfer significantly reduced tumor burden in both the EMT6 (BALB/c) and E0771 (C57BL/6) mouse models. Spatial profiling demonstrated that tumor-infiltrating eosinophils predominantly coaggregated with lymphocytes. These clinical associations were then validated in the independent expanded cohort through multivariable and propensity score–weighted analyses. Critically, eosinophil levels provided additive prognostic value beyond the 21-gene RS and, among high-risk patients, predicted the subset that would derive greater benefit from CDK4/6 inhibition. Conclusion Circulating eosinophil count serves as a potential clinically applicable, liquid biopsy biomarker that independently prognosticates recurrence risk and predicts CDK4/6 inhibitor benefit, reflecting systemic immune activation in hormone receptor–positive/HER2– breast cancer.