Abstract PS1-10-14: Defining the prognosis of estrogen receptor low-positive de novo metastatic breast cancer

Abstract Background: Recent studies have reported the prognosis and heterogeneity of estrogen receptor (ER) low-positive early-stage breast cancer. Survival and treatment outcomes have not been reported for patients with ER low-positive, metastatic breast cancer. The primary objective of this study was to compare overall survival (OS) among patients with ER low-positive de novo metastatic breast cancer (dnMBC), ER-negative dnMBC, and ER-positive dnMBC. The secondary objective was to determine if progesterone receptor (PR) status can define two prognostic groups among ER low-positive dnMBC patients. Methods: A retrospective cohort of patients with dnMBC was created using data from the National Cancer Database (NCDB). Adults diagnosed with human epidermal receptor 2 (HER2) negative dnMBC between 2018-2021 were included. The primary exposures were ER status, based on immunohistochemistry and defined as negative, <1%, low-positive, 1-10%, or positive, 11-100%, and PR status (negative, <1% and positive, 1-100%). Cox regression models were used to compare OS by ER-PR status in age-adjusted and multivariable models adjusting for metastatic disease sites, race, ethnicity, comorbidities, insurance, and treatment receipt (see Table for ER-PR status classification). An exploratory survival analysis by first-course treatment (chemotherapy and/or endocrine therapy) was conducted among ER low-positive patients. We distinguished cytotoxic chemotherapy from cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) receipt based on timing of endocrine and chemotherapy treatment. Results: Among 27,672 HER2-negative dnMBC patients, 2.5% were ER low-positive, 20.8% ER negative, and 76.7% ER positive. Patients with ER low-positive dnMBC had a similar OS to those with ER negative dnMBC in multivariable analysis [hazard ratio, 95% confidence interval [HR(95%CI)]: 1.04 (0.94-1.14)], while patients with ER positive dnMBC had improved OS [HR(95%CI)]: 0.50 (0.48-0.52)] (see Table below). Patients with ER low-positive PR positive dnMBC had superior OS to patients with ER negative dnMBC in multivariable analysis [HR(95%CI): 0.84 (0.71-1.00)]. In contrast, patients with ER low-positive, PR negative dnMBC did not have improved OS compared to ER negative patients. ER low-positive patients, irrespective of PR status, who received chemotherapy and endocrine therapy (with or without CDK4/6i) or endocrine therapy with CDK4/6i alone had improved or similar OS compared to ER low-positive patients who received chemotherapy alone. Conclusions and Relevance: Our findings suggest PR positivity identifies a subgroup among ER low-positive dnMBC patients with superior OS than ER negative patients. Further, first-line treatments incorporating endocrine therapy may be an option for patients with ER low-positive dnMBC. This promising finding warrants further investigation. Citation Format: M. Klugman, M. Aboumrad, R. Chen, C. H. Marshall, J. V. Canzoniero, A. C. Wolff, K. Visvanathan. Defining the prognosis of estrogen receptor low-positive de novo metastatic breast cancer [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 PS1-10-14.