Abstract PS3-07-19: Impact of Endocrine Therapy in Estrogen Receptor-Low Breast Cancer: A Systematic Review and Meta-Analysis

Abstract Background: The current threshold for estrogen receptor (ER) positivity in breast cancer (BC) is ≥1% of positively stained cancer cells by immunohistochemistry. However, tumors with ER-low expression (ER 1-9%) share biological features with triple-negative breast cancer (TNBC), including gene-expression profiles, immune features, and response rates to neoadjuvant chemotherapy and immunotherapy. The clinical benefit of endocrine treatment (ET) in this subgroup of patients remains uncertain. Methods: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. We searched Ovid MEDLINE and Embase (last updated February 2, 2025) for randomized trials and observational studies including patients with non-metastatic ER-positive (≥1%)/HER2-negative BC, presenting estimates of ET efficacy or effectiveness within the ER-low subgroup, or enabling outcome comparisons between ER-low and ER≥10% tumors. Manual citation screening was also performed to identify additional eligible studies. Two reviewers independently screened studies and extracted data. Random-effects meta-analyses were performed to derive pooled hazard ratios (HR) with 95% confidence intervals (95% CI) for overall (OS), disease-free survival (DFS) in the two ER strata, and to assess the association between ET use and outcomes within the ER-low group. Heterogeneity was assessed with the I2 statistic. Egger’s test was used to evaluate publication bias. Sensitivity analyses included leave-one-out and exclusion of reconstructed data or surrogate endpoints. Results: Of 8,982 records screened, 17 studies were included, comprising 9,711 patients with ER-low tumors and 58,660 with ER≥10% tumors. In pooled analyses, patients with ER-low tumors had worse DFS (HR 2.18 [95% CI: 1.58-3.00]; I2 = 78%) and OS (HR 2.08 [95% CI: 1.30-3.31]; I2 = 96%) compared to those with ER≥10% tumors. Among patients with ER-low tumors, receipt of endocrine therapy was associated with improved DFS (HR 0.74 [95% CI: 0.55-1.00]; I2 = 25%) and OS (HR 0.80 [95% CI: 0.70-0.92]; I2 = 21%). No significant publication bias was detected by Egger’s test. Sensitivity analyses confirmed the robustness of the findings. Conclusions: Our systematic review and metanalysis showed that patients with ER-low breast cancer experience a significantly worse prognosis compared to those with ER>10%, and derive a survival benefit from ET. These results suggest that, in addition to therapeutic strategies appropriate for such high-risk profile - such as chemotherapy - the potential benefit of adjuvant endocrine therapy should not be overlooked and ought to be part of the clinical discussion for patients with early-stage ER-low tumors. Citation Format: D. Massa, E. Chiappe, V. Delucchi, F. Girardi, E. Blondeaux, M. La Commare, V. Guarneri, M. Lambertini, M. Dieci. Impact of Endocrine Therapy in Estrogen Receptor-Low Breast Cancer: A Systematic Review and Meta-Analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-19.