Endocrine therapy in early-stage estrogen Receptor-Low breast cancer: a systematic review and Meta-Analysis

Background: Tumors with ≥1% estrogen receptor (ER) expression by immunohistochemistry (IHC) are classified as hormone receptor-positive. While this definition includes ER-low tumors (ER 1-9%), the clinical benefit of endocrine therapy (ET) in ER-low early-stage breast cancer (BC) remains uncertain. Methods: This is a systematic review and meta-analysis of studies in early-stage ER-positive, HER2-negative BC reporting (i) ET efficacy within ER-low tumors and/or (ii) outcomes comparing ER-low versus ER-rich disease. Ovid MEDLINE, Embase, and conference abstracts were searched through January 2025. Endpoints were disease-free survival (DFS) and overall survival (OS). Random-effects meta-analyses were performed to derive pooled hazard ratios (HRs) with 95% confidence intervals (95% CI). Heterogeneity was assessed with the I² statistic. Results: Of 8,982 records screened, 17 studies were included, comprising 10,232 patients with ER-low tumors and 58,662 with ER-rich disease. Among the ER-low group, receipt of ET was associated with a reduction of 33% in the risk of relapse or death (HR 0.67, 95% CI 0.54-0.85, I²=0%) and of 22% in the risk of death (HR 0.78, 95% CI 0.68-0.90; I²=19.2%). Compared with ER-rich disease, ER-low tumors had inferior outcomes for both DFS (HR 2.18, 95% CI 1.58-3.00; I²=78%) and OS (HR 2.08, 95% CI 1.30-3.31; I²=95.8%). Conclusions: In patients with ER-low tumors, ET use was associated with improved outcomes. These findings support consideration of ET in early-stage ER-low disease and the inclusion of these patients in trials evaluating novel ET-based therapies, alongside therapeutic approaches appropriate to their higher baseline risk of relapse.