HER2-Low Breast Cancer-Current Knowledge and Future Directions

Abstract

The concept of binary classification of HER2 status has recently been challenged following the DESTINY-Breast trial data showing a clinically meaningful response to antibody-drug conjugates (ADCs) in invasive breast cancer expressing low levels of HER2. HER2-low breast cancer is defined as an immunohistochemistry (IHC) score of 1+ and 2+ without HER2 gene amplification. While HER2-low breast cancer does not represent a biological entity, it encompasses both hormone receptor-positive and triple-negative breast cancer. Differences exist between this group and HER2-null breast cancer. In this review, we provide an update on HER2-low and HER2-ultralow breast cancer, including background trial data, the evolution of HER2-low expression, current clinical guidelines, quality issues, and future directions.

Keywords: HER2-low; HER2-ultralow; T-DXd; antibody–drug conjugate; artificial intelligence; breast cancer.

Figure 1

HER2 immunohistochemistry showing the current 4 immunohistochemical categories in breast ductal carcinomas. Scores 1+ and 2+ that are non-amplified by in situ hybridisation are regarded as HER2-low.

Figure 2

Trastuzumab deruxtecan (T-DXd)—antibody–drug conjugate. T-Dxd binds to HER2 on tumour cells, triggering receptor-mediated endocytosis. Inside the cell, lysosomal proteases cleave the linker, releasing the topoisomerase I inhibitor payload, which induces DNA damage and apoptosis. The membrane-permeable payload also diffuses into neighbouring cells, exerting a bystander effect that enhances the antitumor response.

Figure 3

Pathway for AI analysis of HER2-stained slide. (A). H&E stained slide of core biopsy with invasive cancer. (B). Heat map with area of invasive cancer identified. (C). Digital HER2-stained slide. (D). HER2 membrane staining pattern and intensity quantified for each invasive tumour cell. Blue circles are cells with no staining. Green circles are cells with faint membrane staining. Yellow circles are cells with moderate incomplete membrane staining. E. Overall HER2 score based on percentage of cells with each staining intensity.