Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in human epidermal growth factor receptor 2-positive (HER2+) breast cancer is associated with improved survival. This study evaluated the association of disease extent at presentation and response to NAC with overall survival (OS) in HER2+ breast cancer.

Patients with clinical stage I to III HER2+ breast cancer (2013–2020) who underwent NAC and received HER2-targeted therapy were identified from the National Cancer Database. Overall survival was assessed by clinical stage at presentation and chemotherapy response, stratified by hormone receptor (HR) status using multivariable Cox proportional hazards regression.

The study included 57,671 patients. Among the patients with pCR, OS at 5 years was 98% for stage I, 97% for stage II, and 91% for stage III disease (p < 0.001). Among patients with residual disease, OS at 5 years was 95% for stage I, 91% for stage II, and 80% for stage III disease (p < 0.001). Multivariable analysis showed that stage III HR–/HER2+ disease with pCR did not have OS different from stage I breast cancer with residual disease (hazard ratio, 1.17; p = 0.34). Stage II HR+/HER2+ disease with pCR did not have OS different from stage I breast cancer with residual disease (hazard ratio, 0.94; p = 0.61), and stage III disease with pCR had worse OS (hazard ratio, 1.90; p < 0.001).

Among the patients who had HER2+ breast cancer treated with NAC, the clinical stage at presentation was associated with OS for those with pCR and residual disease. Patients with stage III HER2+ breast cancer and those with stage II HR+/HER2+ breast cancer who achieve pCR could benefit from further studies that evaluate potential escalation of adjuvant therapies.