HER2 Expression and Axillary Metastasis in Treatment-Naïve Early Breast Cancer

The clinical significance of human epidermal growth factor receptor 2 (HER2)-low breast cancer remains controversial, particularly in early-stage, treatment-naïve patients. Because neoadjuvant therapy may alter tumor biology and nodal status, we specifically evaluated patients who underwent upfront surgery without prior systemic treatment. We also investigated whether the recently recognized HER2-ultralow subgroup exhibited differences in axillary metastatic involvement.

In this multicenter observational study, we retrospectively analyzed 407 patients with hormone receptor-positive early-stage breast cancer who underwent upfront surgery between 2017 and 2023 without neoadjuvant therapy. Patients were categorized as HER2-ultralow (immuno-histochemistry [IHC] 0), HER2-low (IHC 1+ or 2+ with fluorescence in situ hybridization [FISH] negative), or HER2-positive (IHC 3+ or 2+ with FISH positive). Groups were compared for sentinel lymph node (SLN) positivity. Multivariable logistic regression and receiver operating characteristic (ROC) analyses were used to identify predictors of axillary metastasis.

SLN positivity rates were similar across the HER2-ultralow (29.0%, n = 288), HER2-low (30.6%, n = 80), and HER2-positive groups (31.3%, n = 39) (p = 0.941). HER2 expression was not an independent predictor of SLN positivity. Lymphovascular invasion (LVI) was the strongest determinant (odds ratio = 5.42; 95% confidence interval: 3.13-9.39; p < 0.001). Larger tumor size and higher proliferative activity were independently associated with increased axillary involvement. ROC analysis showed higher discrimination for LVI (AUC = 0.68) than Ki-67 (AUC = 0.53) and tumor size (AUC = 0.61). Exploratory survival analyses demonstrated no statistically significant differences among groups; however, these findings should be interpreted cautiously because of the limited follow-up duration and low number of events.

In hormone receptor-positive early-stage breast cancer treated with upfront surgery, HER2 expression was not independently associated with axillary metastasis risk in this treatment-naïve cohort. Classical pathological factors, particularly lymphovascular invasion, larger tumor size, and higher proliferative activity, remained the principal determinants of axillary involvement.