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Updated: May 15, 2026
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Distinct Evolutionary Dynamics of HER2-Ultralow Versus HER2-Null from Residual to Metastatic Disease in Non-pCR
Shunan Wang1,2,3,4, Jingjing Liu1,2,3,4, Tong Liu1,2,3,4
1The Third Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
Purpose:
In 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 Methods:
We 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.
Results:
In 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 488-patient 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.
Conclusion:
HER2-ultralow shows distinct evolution and high HER2-low conversion potential, affecting ADC eligibility. Routine HER2-0 subclassification and metastatic HER2 reassessment appear clinically useful and warrant prospective validation.
