Abstract PS3-11-14: Impact of HER2 amplification and Estrogen Receptor Expression on Pathologic Complete Response to Dual Blockade in HER2-Positive Breast Cancer

Abstract Background: HER2-positive breast cancer (BC) accounts for 15-20% of cases and is defined by HER2 gene amplification and overexpression. Neoadjuvant chemotherapy (NAC) combined with HER2-targeted agents, particularly trastuzumab and pertuzumab, has improved outcomes. However, accessible biomarkers to guide treatment remain limited. Methods: A retrospective cohort of 446 stage I-III HER2-positive BC patients treated with NAC and trastuzumab ± pertuzumab from 2010 to 2023 was analyzed. The primary endpoint was pathological complete response (pCR; ypT0/isN0). HER2 was assessed via IHC (2+ vs. 3+), HER2/CEP17 ratio, and HER2 copy number, analyzed both continuously and by tertiles. Estrogen receptor (ER) was categorized as low (≤10%) or high (10%). Other covariates included Ki-67, stage, BMI, and institution. Multivariable logistic regression evaluated pCR predictors. Analyses were stratified by pertuzumab use, with interaction terms tested. Propensity score modeling with inverse probability of treatment weighting (IPTW) adjusted for treatment selection bias. Internal consistency was assessed by bootstrap resampling (1,000 iterations). Results: The pCR rate was 51.8%. Independent pCR predictors included HER2 IHC 3+ (OR 4.54), HER2 amplification (medium: OR 3.11; high: OR 3.34), HER2/CEP17 ratio (mid: OR 2.57; high: OR 3.60), ER-low (OR 2.22), and higher Ki-67 (OR 1.011 per %). In pertuzumab-treated patients, HER2 amplification and HER2/CEP17 ratio were strongest (amplification high vs. low: OR 9.04; ratio high vs. low: OR 10.70), while HER2 IHC 3+ was more predictive without pertuzumab. ER-low tumors showed greatest benefit from dual blockade (OR 4.79). ER-pertuzumab interaction was significant (p0.001). IPTW models confirmed ER and HER2 biomarkers as independent predictors. In ER ≤10% and medium/high HER2 amplification (32.6% of patients), pertuzumab significantly increased pCR (94.7% vs. 66.7%; p=0.013). Conclusions: Quantitative HER2 amplification and low ER expression are robust predictors of pCR in early HER2-positive BC. These biomarkers may help personalize neoadjuvant strategies and guide pertuzumab use. Citation Format: F. N. Acevedo, B. V. Walbaum, F. Gaete, P. Peñaloza, M. Olivares, L. Medina, M. Abud, R. Gejman, P. Zoroquiain, F. Dominguez, M. Camus, C. Vargas, M. Navarro, C. Pinto, M. Manzor, c. G. sanchez. Impact of HER2 amplification and Estrogen Receptor Expression on Pathologic Complete Response to Dual Blockade in HER2-Positive 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 PS3-11-14.