Abstract Neoadjuvant chemotherapy (NACT) plays a critical role in managing locally advanced breast cancer by reducing tumor burden before surgery and allowing for early initiation of systemic treatment. In estrogen receptor-positive/HER2-negative (ER+/HER2−) tumors, response to NACT is limited and unpredictable. Identifying predictors of response is essential to optimize treatment and minimize toxicity. The main aim of this study is to investigate clinicopathological factors associated with residual cancer burden (RCB). Secondary objectives included evaluating body mass index (BMI) and surgical outcomes. We conducted a retrospective single-center study at Girona’s Catalan Institute of Oncology, including ER+/HER2− breast cancer patients (stage I-III) treated with anthracycline- and/or taxane-based NACT between 2010 and 2023. Clinical and pathological data - age, BMI, estrogen and progesterone receptor (ER, PR) status, nodal stage, surgical procedures- were analyzed. Associations with RCB were analyzed using chi-square tests and linear regression analysis. A total of 111 patients with stage II-III breast cancer were included (mean age 47.6 years; BMI 25.8 kg/m2). Surgery involved mastectomy in 52.3% and axillary dissection in 74.8% of cases, with 17.5% converted to mastectomy after NACT. Only 13 (11.7%) achieved a favorable pathological response (RCB 0-1). Tumors with low ER expression (1-10%) were significantly more likely to respond to NACT (p=0.034). In contrast, BMI and menopausal status were not significantly associated with RCB. Advanced clinical nodal status (cN3) was strongly associated with chemoresistant tumors (p=0.030), while older age (p=0.058) and larger tumor size (cT4) (p=0.089) showed a non-significant trend toward worse outcomes. PR and HER2 expression and Ki67 index did not show significant associations with RCB in this cohort. Our findings highlight lower ER expression and limited nodal burden as predictive biomarkers of improved response to NACT in ER+/HER2− breast cancer. Considering the low response rate, these results support a more tailored therapeutic approach and underscore the need for predictive tools in optimizing patient selection within this biologically heterogeneous subgroup. Citation Format: A. Brotons, H. Pla, R. Fort, A. Roqué-Lloveras, S. del Barco, C. Montañés-Ferrer, J. Paz, A. Ribera, Í. López-Rovira, E. Polonio-Alcalá, F. León, I. Oliveras, I. Ramos, J. Ribas, E. Vila, J. Ferrer, M. Negre, J. Martínez-Sancho, G. Viñas. Residual Cancer Burden in ER+/HER2− Breast Cancer: Predictive Role of Hormone Receptor Expression and Clinical Stage 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 PS3-10-17.
Brotons et al. (2026) studied this question.