Pathologic Complete Response to Neoadjuvant Chemotherapy in HER2-Low Versus HER2-Zero Breast Cancer: A Retrospective Cohort Study

Abstract PURPOSE Breast cancers with low human epidermal growth factor receptor 2 expression (HER2-low), defined as immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization, constitute a distinct subgroup of HER2-negative disease. While HER2-low status is clinically relevant in metastatic breast cancer, its impact on response to neoadjuvant chemotherapy and survival outcomes in early-stage disease remains unclear. We evaluated the association between HER2-low expression, pathological complete response (pCR), and survival outcomes in early-stage HER2-negative breast cancer. PATIENTS AND METHODS We retrospectively analyzed 934 women with stage II–III HER2-negative breast cancer treated with neoadjuvant chemotherapy between 2016 and 2021. Tumors were classified as HER2-zero (IHC 0) or HER2-low (IHC 1 + or IHC 2 + with negative in situ hybridization). The primary endpoint was pCR, defined as absence of residual invasive disease in the breast and axillary lymph nodes at surgery. Secondary endpoints included 5-year disease-free survival (DFS) and overall survival (OS). Hormone receptor status (estrogen receptor [ER] and progesterone receptor [PR]) and menopausal status were recorded. Multivariable logistic regression identified predictors of pCR, and Survival outcomes were evaluated using Kaplan–Meier estimation, with between-group differences assessed using log-rank testing. RESULTS Approximately half of the tumors were HER2-low, and most patients had hormone receptor–positive disease. HER2-low tumors demonstrated significantly lower pCR rates than HER2-zero tumors. ER and PR positivity independently predicted reduced likelihood of pCR across both HER2 subgroups.After a median follow-up of five years, no significant differences in DFS or OS were observed between groups. CONCLUSION HER2-low breast cancer is associated with reduced responsiveness to neoadjuvant chemotherapy, particularly in hormone receptor–positive disease, without adverse effects on 5-year survival. Clinical Trial number: Not applicable