# 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.

## Key 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