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

TL;DR

This study shows that different levels of estrogen receptor positivity in breast cancer can predict survival and treatment response, suggesting new thresholds for better classification and treatment decisions.

Contribution

The study identifies dual estrogen receptor cutoffs (50% and 14%) that define distinct prognostic and predictive subgroups in breast cancer.

Findings

ER ≥ 50% is associated with favorable survival and distinct molecular features.

ER < 50% tumors show biology similar to triple-negative breast cancer with active proliferation and metabolism.

ER < 14% is a strong predictor of response to neoadjuvant chemotherapy.

Abstract

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.

•ER ≥ 50% defines a prognostic threshold for breast cancer survival•ER <50% tumors show intermediate biology and active proliferation/metabolism•ER <14% optimally predicts response to neoadjuvant chemotherapy•Dual ER cutoffs enable biology-informed classification and tailored therapy for ER-low BC

ER ≥ 50% defines a prognostic threshold for breast cancer survival

ER <50% tumors show intermediate biology and active proliferation/metabolism

ER <14% optimally predicts response to neoadjuvant chemotherapy

Dual ER cutoffs enable biology-informed classification and tailored therapy for ER-low BC

Health sciences

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