HER2-Low Versus HER2-Zero Breast Cancer in the Neoadjuvant Setting: Pathological Complete Response and Exploratory...

Background and Objectives: The HER2-low designation has emerged as a clinically actionable category in breast cancer following the approval of trastuzumab deruxtecan for HER2-low metastatic disease. However, the clinical relevance of HER2-low expression in the neoadjuvant chemotherapy (NAC) setting remains uncertain. This study aimed to evaluate pathological complete response (pCR) as the primary endpoint and overall survival (OS) and disease-free survival (DFS) as exploratory secondary endpoints across HER2-low, HER2-zero, and HER2-positive subgroups in a NAC-treated cohort. Materials and Methods: This single-center retrospective cohort study included 118 patients with histopathologically confirmed invasive breast cancer who received NAC at our institution between January 2010 and March 2021. Patients were classified as HER2-zero (IHC 0, n = 66), HER2-low (IHC 1+ or IHC 2+/FISH-non-amplified, n = 17), or HER2-positive (IHC 3+ or IHC 2+/FISH-amplified, n = 35). pCR was defined as ypT0/Tis ypN0. Univariate analyses used χ² or Fisher's exact tests; multivariable logistic and Cox regression were performed for adjusted analyses, and Kaplan-Meier survival curves were compared by log-rank, Breslow, and Tarone-Ware tests. Results: The overall pCR rate was 24.6%, differing significantly across HER2 subgroups (HER2-positive 45.7%, HER2-low 29.4%, HER2-zero 12.1%; p = 0.001). After multivariable adjustment for age, ER, PR, and tumor grade, HER2-positive status retained an independent association with pCR (OR 4.37, 95% CI 1.46-13.10, p = 0.008), whereas HER2-low status did not (OR 2.65, 95% CI 0.60-11.75, p = 0.201). At a median follow-up of 48.8 months, neither OS (log-rank p = 0.567) nor DFS (log-rank p = 0.901) differed significantly across HER2 subgroups, and HER2 subgroup status was not independently associated with survival in exploratory Cox models. Conclusions: In this NAC-treated cohort, the unadjusted pCR advantage of HER2-low over HER2-zero tumors was not retained after adjustment for hormone receptor expression and tumor grade, and no HER2 subgroup-specific survival difference was demonstrated. Within the standard NAC framework, HER2-low disease did not show a pCR or survival pattern clearly distinct from HER2-zero disease after adjustment; the small HER2-low subgroup and wide confidence intervals preclude firm conclusions, and an exploratory hormone receptor-stratified analysis indicated that the apparent pooled HER2-low advantage was confined to the hormone receptor-negative subgroup. Future prospective studies powered for hormone receptor-stratified analyses are warranted.