Past, present, and future perspectives in estrogen-receptor-low breast cancer

Estrogen receptor (ER)-low breast cancer, defined as 1-10% ER expression on immunohistochemistry, has emerged as a distinct reporting category since the 2020 ASCO/CAP guidelines. This rare subgroup remains poorly characterized, which raises major diagnostic and therapeutic challenges.

This narrative review summarizes the different perspectives on ER-low breast cancer, including definitions, pathological assessments, clinicopathological, molecular, and immune features, prognosis, current treatment strategies, and emerging research directions.

ER-low breast cancers comprise a biologically heterogeneous but clinically meaningful entity whose features and behaviors seem closer to ER-negative/triple-negative breast cancer than to ER-positive disease, with similarities observed in molecular subtype distribution, immune ecosystem, chemotherapy sensitivity, and prognosis. At the same time, the benefits of endocrine therapy appear uncertain, limited, and variable, subject to factors such as the degree of ER expression, progesterone receptor status, and residual disease after neoadjuvant treatment. Emerging data suggest that immunotherapy may be particularly relevant in this subgroup, with pathologic complete response rates approaching those observed in triple-negative breast cancer in some neoadjuvant studies. However, ER-low tumors are underrepresented in prospective randomized trials, and treatment recommendations are still largely extrapolated from broader hormone receptor-positive or triple-negative populations.

ER-low breast cancer challenges the traditional binary classification of hormone receptor-positive/-negative disease. Diagnostic variability, biological heterogeneity, and therapeutic ambiguity justify the need for standardized pathological assessment, biomarker-driven stratification, and dedicated prospective trials to refine management and improve outcomes.