Predictors of Response to Neoadjuvant Therapy in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer and Pathological Evaluation of HER2 Heterogeneity.

Human epidermal growth factor receptor 2 (HER2) gene amplification and heterogeneity influence anti-HER2 therapy efficacy, but quantitative assessment of HER2 expression heterogeneity remains scarce. This study evaluates HER2 protein heterogeneity and its effect on neoadjuvant therapy (NAT) outcomes in HER2-positive breast cancer. In total, 295 patients with HER2-positive breast cancer treated with neoadjuvant anti-HER2 therapy were included. HER2 expression was quantified by the percentage of HER2-stained cells across intensities, and heterogeneity was assessed using quadratic entropy. The overall pathological complete response (pCR) rate was 51.86%. Patients with HER2 heterogeneity showed a 24.5% pCR rate, significantly <62.5% in patients with HER2 homogeneity (P < .001). HER2 heterogeneity quadratic entropy (HER2-HQE) correlated with the percentage of HER2 immunohistochemistry (IHC) 3+ tumor cells and hormone receptor (HR) status (P < .001). Residual cancer burden (RCB) was significantly associated with HR status, tumor stage, lymph node stage, HER2 IHC 3+ cell percentage, and HQE grade (P ≤ .017). No correlation was found with age, histologic grade, or Ki67 index. In the HER2 IHC 3+ ≥95% subgroup, neither pCR rate nor RCB grade after NAT was associated with traditional clinicopathological parameters, even HER2-HQE and HR status (P ≥ .154). The American Joint Committee on Cancer anatomical stage significantly improved post-NAT for low/intermediate HER2-HQE subgroups (P < .001) but not for high HQE cases. In summary, HER2 heterogeneity and HR status are key predictors of anti-HER2 NAT outcomes. Higher HER2-HQE is associated with increased RCB. Quantifying HER2 heterogeneity via HQE and percentage of HER2 IHC 3+ may help optimize therapeutic strategies in clinical practice.