Targeting HER2 heterogeneity in breast cancer

Published:September 01, 2021DOI:


      • Low/heterogeneous expression of HER2 impacts benefit from anti-HER2 therapies.
      • Newer HER2-targeted therapies may be effective against HER2-low tumors.
      • Important to refine definition of HER2 expression status to optimize treatment.
      • Validation of techniques to detect HER2 heterogeneity required.
      • Novel treatments effective against HER2 heterogeneous tumors needed.


      The identification of Human epidermal growth factor receptor 2 (HER2) as a target in breast cancer and the subsequent development of HER2-targeted therapies has revolutionized the treatment of patients with HER2-positive breast cancer. However, there is an increasing awareness of how frequently tumors have low or heterogeneous expression of HER2. It is now recognized that this impacts the degree of benefit from HER2-targeted therapies. With the advent of novel and more potent antibody drug conjugates, targeting HER2 in traditional HER2-negative tumors with “HER2-low” expression is becoming possible. It is essential to refine the nomenclature around HER2 expression to enable clinicians to optimize treatment for patients across the HER2 expression spectrum in breast cancer. HER2 heterogeneity can be detected by conventional IHC, gene expression profiling or other methods and numerous studies have documented the correlation between the presence of HER2 heterogeneity and shorter disease-free survival (DFS) and overall survival (OS). Validation of techniques to identify HER2 heterogeneity in the clinic and concurrent development of agents to effectively treat tumors with non-uniform HER2 expression is needed.


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