Dual cutoffs of estrogen receptor positivity define prognostic and predictive subgroups in breast cancer

Estrogen receptor (ER) expression informs treatment decisions in breast cancer, and the percentage of ER-positive cells may further influence clinical behavior. We analyzed four HER2-negative cohorts by integrating immunohistochemistry-based ER quantification with transcriptomic and immune profiling. The proportion of ER-positive cells was the strongest predictor of recurrence. Recurrence risk peaked around 45% ER positivity and decreased beyond this point, supporting 50% as a meaningful prognostic cutoff. Tumors with ER ≥ 50% demonstrated favorable survival, whereas ER <50% showed molecular features similar to triple-negative disease, including proliferative and metabolic pathway activation and p53/DNA repair signaling. Immune profiling identified immune depletion in ER-high tumors, B cell and macrophage enrichment in ER-low tumors, and strong immune activation in triple-negative tumors. In neoadjuvant chemotherapy cohorts, lower ER percentages were associated with greater chemosensitivity, and 14% distinguished response likelihood. These results indicate that continuous ER expression provides prognostic and therapeutic insight beyond current threshold-based classification.