Distinct Evolutionary Dynamics of HER2-Ultralow Versus HER2-Null from Residual to Metastatic Disease in Non-pCR Breast Cancer

PurposeIn breast cancer (BC) patients without pathological complete response (pCR) after neoadjuvant therapy, residual disease drives recurrence.The HER2 spectrum now includes HER2-low and HER2-ultralow.HER2-low tumors are eligible for HER2-targeted antibody-drug conjugates (ADCs), while T-DXd is approved for HR-positive HER2-ultralow metastatic BC after endocrine therapy.Evolution patterns of HER2-ultralow versus HER2-null from residual to metastatic disease remain unclear. Materials and MethodsWe retrospectively studied 488 non-pCR patients with refined HER2 classification; 92 with HER2-0 residual disease formed the analytic cohort for HER2-ultralow/HER2-null comparison.HER2 status was tested in paired residual and metastatic lesions.Logistic regression was used to identify factors linked to HER2 evolution. ResultsIn the 92-patient HER2-0 analytic cohort, HER2-ultralow (46.7% of HER2-0) converted more frequently to HER2-low than HER2-null (51.2% vs 30.6%, p=0.045).This difference remained statistically significant in the multivariable logistic regression model.In the full 517-patient contextual cohort, HER2 expression gain in recurrent/metastatic lesions was independently associated with poorer post-recurrence survival (PRS) (adjusted HR=1.74, p=0.009).In the 488patient primary cohort, conversion from HER2-0 to HER2-low was also associated with poorer PRS (adjusted HR=2.18, p<0.001).The broader HER2 expression evolution in the full 517-patient cohort and the primary 488-patient refined HER2 cohort was consistent with the core finding from the 92-patient HER2-0 analytic cohort and supported its biological plausibility.