Abstract
BACKGROUND: Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is associated with aggressive tumor biology and a distinct immune microenvironment. Although the absolute lymphocyte count (ALC) in peripheral blood is widely used as a routine indicator of systemic immune function, its relationship with HER2 status remains insufficiently explored. METHODS: This retrospective study investigated the association between pretreatment peripheral ALC and HER2 status in a cohort of breast cancer patients. Multivariate logistic regression, random forest modeling, and restricted cubic spline (RCS) analyses were employed to assess this relationship. Subgroup analyses were conducted across major clinical and pathological variables to evaluate their robustness. In parallel, tumor immune infiltration profiles were analyzed using the TIMER 2.0 platform. RESULTS: A robust and consistent inverse association was observed between ALC and HER2-positive status across all analytical approaches. In fully adjusted logistic regression models, higher ALC was independently associated with lower odds of HER2 positivity (OR= 0.53, 95% CI: 0.37-0.77, P<0.001), with consistent effects across all examined subgroups. Further immune profiling using the TIMER 2.0 platform demonstrated that ERBB2 (HER2) expression was negatively correlated with the infiltration of key anti-tumor lymphocytes, including CD8⁺ T cells, activated memory CD4⁺ T cells, and natural killer (NK) cells, while showing relative enrichment of immature B cells and non-regulatory CD4⁺ T cells. Collectively, these findings suggest that HER2-overexpressing tumors are associated with concurrent systemic immune alterations and a locally suppressed tumor immune microenvironment. CONCLUSION: Peripheral blood ALC levels are negatively correlated with HER2 expression in breast cancer. Given its accessibility and cost-effectiveness, ALC may serve as a complementary systemic immune indicator for contextual assessment of HER2-related immune characteristics and immune heterogeneity at the population level.