Unlocking the Resistance to Anti-HER2 Treatments in Breast Cancer: The Issue of HER2 Spatial Distribution

Simple Summary Breast cancer is the most common cancer in women. Approximately 15% of breast cancers harbour an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein and are thus classified as HER2-positive. However, HER2 protein expression could be heterogeneous, showing different patterns of spatial distribution. This feature, also called "spatial heterogeneity" may potentially affect treatment, response, and assessment of HER2 status, ultimately impacting the best treatment strategy. The activity of some new pharmacological agents, belonging to the group of antibody-drug conjugates, may represent an opportunity for overcoming this issue. In this review, we summarize the available evidence on HER2 heterogeneity and spatial distribution and how they may affect current available treatment choices. Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the variability in the distribution and expression of the HER2 protein within a single tumour. Spatial heterogeneity may potentially affect treatment, response, assessment of HER2 status and consequently, may impact on the best treatment strategy. Understanding this feature can help clinicians to predict response to HER2-targeted therapies and patient outcomes, and to fine tune treatment decisions. This review summarizes the available evidence on HER2 heterogeneity and spatial distribution and how this may affect current available treatment choices, exploring possible opportunities for overcoming this issue, such as novel pharmacological agents, belonging to the group of antibody-drug conjugates.