Association of HER2-low expression with response to neoadjuvant chemotherapy in hormone receptor-positive early breast cancer

Introduction The clinical significance of HER2-low expression in early hormone receptor (HR)–positive breast cancer remains uncertain. While HER2-low tumors have gained therapeutic relevance through antibody–drug conjugates (ADCs) in metastatic disease, their predictive implications and association with treatment response in early-stage settings are not clearly defined. This study aimed to evaluate whether HER2-low expression influences radiologic and pathologic responses to dose-dense anthracycline- and taxane-based neoadjuvant chemotherapy (NACT) compared with HER2-zero (IHC 0) breast cancer. Methods We retrospectively analyzed 142 women with HR-positive, HER2-negative early breast cancer treated at University Hospital “Tsaritsa Yoanna” between 2018 and 2025. Patients were classified as HER2-low (IHC 1 + or 2 +/ISH–, n = 100) or HER2-zero (IHC 0, n = 42). Baseline clinicopathologic characteristics, radiologic objective response rate (ORR), and pathologic complete response (pCR) were compared. Statistical analyses included t-tests, chi-square tests, and multivariable linear regression adjusted for age, Ki-67 index, and tumor stage. Results Mean tumor reduction after NACT was − 30.8 ± 30.1% in HER2-low and − 36.1 ± 26.9% in HER2-zero (p = 0.325). pCR rates were comparable (6.0% vs 9.5%), and HER2 status was not an independent predictor of response (β = 5.32, p = 0.322). No clinicopathologic variable emerged as an independent predictor of treatment response in multivariable analyses. Subgroup analyses demonstrated no consistent differences in response across menopausal, proliferative, or histologic subsets. Conclusions HER2-low status did not significantly impact radiologic or pathologic response to dose-dense anthracycline- and taxane-based NACT in HR-positive early breast cancer, though it remains clinically relevant amid emerging ADC-based strategies.