Dynamic Evolution of HER2 Expression Following Neoadjuvant Therapy and Its Association With Treatment Response and Prognosis in Breast Cancer: A Large‐Scale Retrospective Study

BACKGROUND: HER2 status in heterogeneous breast cancer (BC) can change dynamically during treatment, and is associated with prognosis and clinical decisions. Understanding the patterns of these changes may inform risk stratification and treatment planning. METHODS: This retrospective study analyzed 3748 BC patients with residual disease following neoadjuvant therapy (NAT) (2015-2021). HER2 status was assessed according to ASCO/CAP guidelines and pathological response by the Miller-Payne grading system. Multinomial logistic regression and Cox models identified factors linked to HER2 conversion and its association with treatment response and survival outcomes. RESULTS: HER2 status post-NAT showed 22.9% overall discordance (11.2% loss; 11.7% gain), predominantly between HER2-0 and HER2-low. Multivariate analysis revealed that age ≥ 50 years was associated with reduced likelihood of HER2 gain (adjusted OR 0.69, p < 0.001), whereas HR-positivity was associated with increased likelihood (adjusted OR 1.35, p = 0.027). Intratumoral calcification (adjusted OR 0.75, p = 0.006) and clinical stage III (adjusted OR 0.77, p = 0.016) were associated with decreased risk of HER2 loss. Conversion from HER2-0 to HER2-low status was significantly associated with poorer pathological response (adjusted OR 0.47, p = 0.011) and independently predicted inferior RFS (adjusted HR 1.33, p = 0.009) and OS (adjusted HR 1.40, p = 0.032). The adverse prognostic impact of HER2 evolution was particularly pronounced in HR-positive patients (interaction p < 0.05). CONCLUSION: Dynamic alterations in HER2 status following NAT are significantly associated with treatment response and survival outcomes. For patients without pathological complete response, reassessment of HER2 status after NAT may help identify those with distinct prognostic profiles and who are potential candidates for emerging antibody-drug conjugate therapies.