Abstract PS3-11-18: Neoadjuvant Response in HER2+ Early Breast Cancer: A Comparative Study Between HER2-Enriched and Luminal HER2 Subtypes

Abstract Introduction: HER2-positive breast cancer represents approximately 15–20% of all breast tumors and is characterized by amplification of the ERBB2 gene, associated with aggressive biological behavior. However, this group includes biologically distinct subtypes based on hormone receptor (HR) status. Tumors lacking HR expression (HER2-enriched) typically show increased sensitivity to neoadjuvant therapy (NAT), while HR-positive tumors (Luminal HER2) often exhibit lower rates of pathological complete response (pCR), despite favorable long-term outcomes in some cases. We aimed to compare pathological complete response (pCR) and survival outcomes between Luminal HER2 (HER2+/HR+) and HER2-enriched (HER2+/HR−) breast cancer subtypes following neoadjuvant therapy (NAT) in the real world setting. Methods: All HER2-positive breast cancer treated with NAT and surgery from 2007 to 2018, who received at least 1 dose of neoadjuvant trastuzumab, in a single center were analyzed. Tumors were classified as Luminal HER2 or HER2-enriched based on immunohistochemistry. Endpoints included pCR, defined as absence of invasive disease in breast and axilla (ypT0/is ypN0), relapse-free survival (RFS) and overall survival (OS). Associations between categorical variables were assessed using chi-square and Fisher’s exact tests. Survival was estimated using Kaplan-Meier curves and factors associated with RFS were evaluated in a multivariate analysis. Bilateral p-values 0.05 were considered significant. Results: Among the 301 patients, 196 (65.1%) were HER2+/HR+ and 105 (34.9%) HER2+/HR-.The median age was 45 years vs. 52 years (p.001), 68.2% vs. 39% were premenopausal (p.001), 82.7% vs.94.3% had ductal histology (p=0.008), 40.8% vs. 52.5% had grade III tumors (p=0.09), 19.4% vs. 6.7% had HER2+2/FISH-amplified (p=0.003), 62.2% vs. 60% had cT3/4 (p=0.75), 73.5% vs.80% had cN+ (p=0.26) and 59.7% vs. 62.9% had clinical stage III (p=0.76), in the HER2+/HR+ vs. HER2+/HR-, respectively. Most patients in both groups were treated with anthracyclines plus taxanes (89.7%) and trastuzumab (62.5%). Thirty four percent of patients received trastuzumab plus pertuzumab, and only 9 patients didn’t receive anti-HER2 NAT, but all of those received adjuvant anti-HER2 blockade. One hundred fifty-eight patients (52.5%) achieved pCR, significantly higher in the HER2+/HR- group (65/105, 61.9%) compared to HER2+/HR+ (93/196, 47.4%) (p = 0.017). After a median follow up of 74 months, no significant difference in RFS was observed between subtypes (5-year RFS 79.2% vs. 76.3% in HER2+/HR+ vs. HER2+/HR-, p=0.47) or in OS (5-year OS 89.2% vs. 86.1% in in HER2+/HR+ vs. HER2+/HR-, p=0.65). On univariate analysis RFS was associated with higher cT (HR 1.33 95%CI 1.00 – 1.76, p=0.045), cN+ (HR 2.0 95%CI 1.03 – 3.92, p=0.041), pCR (HR 0.28 95%CI 0.16 – 0.48, p.001), but not HER2+/HR- subtype (HR 1.19, 95%CI 0.73 – 1.94, p=0.48). On a multivariate analysis of these factors, only cN (HR 1.33, 95%CI 1.0 – 1.77, p=0.049) and pCR (HR 0.29, 95%CI 0.17 – 0.51, p=.001) persisted as significant factors for RFS. Conclusion: HER2-enriched breast cancers showed a significantly higher pCR rate to neoadjuvant systemic therapy compared to Luminal HER2 tumors. However, this improved short-term response did not translate into superior recurrence-free survival. Clinical tumor burden remained the strongest prognostic factor. These findings highlight the importance of biological subtype in predicting treatment response and support its use in guiding neoadjuvant strategies. Citation Format: L. Coelho de Mattos, B. Nelli Barbatto, L. Pivetta Genovez, L. Rodrigues Garcia, M. Assis da Escócia Fernandes, M. Celeste Tavares, S. Moraes Sanches, M. Goldner Cesca, F. Peterson Cavalher, L. de Moura Leite. Neoadjuvant Response in HER2+ Early Breast Cancer: A Comparative Study Between HER2-Enriched and Luminal HER2 Subtypes 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 PS3-11-18.