Abstract PS4-10-04: Her2 expression is associated with pathologic complete response to neoadjuvant chemo-immunotherapy among patients with stage 1-3 triple negative breast cancer

Abstract Introduction: The emergence of novel antibody-drug conjugates has brought significant attention to HER2-low breast cancer as a critical predictive biomarker. However, despite its therapeutic relevance, evidence supporting HER2-low breast cancer as a distinct biological subtype remains limited. We recently demonstrated that HER2-low triple-negative breast cancer (TNBC) exhibits a unique immune-evasive epigenetic and transcriptomic profile compared to HER2-zero, strongly suggesting that it represents a molecularly distinct entity. Based on these findings, this study aimed to assess the clinical response to standard of care neoadjuvant chemotherapy and immunotherapy (chemo-IO) in patients with early-stage TNBC based on HER2 status. Patients/Methods: We identified adult (age 18 and older) female patients with stage 1-3 TNBC treated with chemo-IO at two cancer centers over 3 years (6/2021-5/2024). HER2 status was stratified in two classification schemes: 1- Binary, HER2-zero (Immunohistochemistry [IHC] 0) versus HER2-low (IHC 1+ or 2+, FISH non-amplified); and 2- ordinal, based on IHC scores (0, 1+, or 2+). The primary endpoint was the pathologic complete response (pCR) rate by HER2 status. Univariate and multivariate logistic regression models were used to estimate the association between patient and tumor factors and pCR. To estimate the underlying population pCR rates more robustly and account for sampling variability, we conducted a bootstrap analysis (1,000 iterations), generating confidence intervals for the pCR rates in each subgroup. Results: We identified 165 patients (HER2-zero, n=50; HER2-low, n=115); those categorized as HER2-low were stratified into IHC 1+ (n=72) and IHC 2+ (n=43). The median age was 55 years [IQR 45-64]. Most patients were post-menopausal (60%), had clinical T2 or greater tumors (81%), or were node-positive (45%). No differences in patient or tumor characteristics were noted between groups except for race and ethnicity (p=0.001); patients of self-reported Black race had the highest proportion of HER2-low TNBC (88.4%) compared to White (66.7%), Asian (71.4%), and Hispanic (44.4%) patients. Rates of pCR notably differed by HER2 status with HER2-low TNBC tumors exhibiting lower rates of pCR (53.9%) compared to HER2-zero (66.0%). Increasing HER2 expression levels also correlated with lower rates of pCR (HER2 0: 66.0%, HER2 1+: 55.6%, HER2 2+: 51.2%). A bootstrap simulation confirmed the robustness of these estimates (HER2-zero: 65.6%, 95% CI 51.9-78.5%; HER2-1+: 55.6%, 95% CI 44.3-67.5%; HER2-2+: 51.0%, 95% CI 36.1-65.9%). Conclusions: While our analysis was underpowered to detect statistically significant differences due to the modest sample size, the observed 12.1% absolute decrease in pCR for HER2-low TNBC tumors suggests a clinically meaningful trend. Our results provide clinical evidence that HER2-low TNBC may be a distinct subtype less responsive to standard of care chemo-IO. These results underscore the need for expanded patient cohorts to further validate these associations and guide the development of tailored therapeutic strategies for this purported unique TNBC subgroup. Citation Format: J. L. Baker, S. M. Thomas, V. Rey, I. Eng, D. M. Marzese, M. Ensenyat-Mendez, H. L. Siu-Yuan, M. L. DiNome. Her2 expression is associated with pathologic complete response to neoadjuvant chemo-immunotherapy among patients with stage 1-3 triple negative 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 PS4-10-04.