Refining the definition of HER2-low class in invasive breast cancer

Abstract

Background: Emerging evidence indicates that breast cancer (BC) patients whose tumours express HER2 protein without HER2 gene amplification (HER2-low), can benefit from antibody-drug conjugates (ADC). However, the current definition of HER2-low BC remains incomplete with low rates of concordance. This study aims to refine HER2-low definition with emphasis on distinguishing HER2 score 0 from score 1+ to identify patients who are eligible for ADC.

Methods: A BC cohort (n = 363) with HER2 IHC scores 0, 1+ and 2+ (without HER2 gene amplification) and available HER2 mRNA was included. HER2 staining intensity, pattern and subcellular localisation were reassessed. Artificial neural network analysis was applied to cluster the cohort and to distinguish HER2 score 0 from 1+. Reproducibility and reliability of the refined criteria were tested.

Results: HER2 IHC score 1+ was refined as membranous staining in invasive cells as either: (1) faint intensity in ≥ 20% of cells regardless the circumferential completeness, (2) weak complete staining in ≤ 10%, (3) weak incomplete staining in > 10% and (4) moderate incomplete staining in ≤ 10%. Based on this, 63% of the HER2-negative cases were reclassified as positive (HER2-low). The refined score showed perfect observer agreement compared to the moderate agreement in the original clinical scores. Similar results were generated when the refined score was applied on the independent BC cohorts. A proposal to refine the definition of other HER2 classes is presented.

Conclusion: This study refined the definition of HER2-low BC based on correlation with HER2 mRNA and distinguished between HER2 IHC score 1+ and score 0 tumours.

Keywords: ANN; HER2 low; HER2 mRNA; breast cancer; refining.

Figure 1

Flowchart summarising cohort selection and different steps carried out.

Figure 2

A, Schematic illustration of different scenarios of human epidermal growth factor receptor 2 (HER2) expression in breast cancer and the corresponding score from different existing guidelines. B, Recommended HER2 scoring algorithm based on immunohistochemistry (IHC)‐stained slides.

Figure 3

1, An illustrated diagram and photomicrographs showing different human epidermal growth factor receptor 2 (HER2) membranous staining patterns and intensities. Faint complete (1A); faint incomplete (2B); weak complete (3C); weak incomplete (4D); moderate complete (5E), moderate incomplete (6F). 2, Graphical description highlighting degree of intratumoral heterogeneity HER2) low category. 2A, HER2 immunohistochemistry (IHC)‐stained slide showing different staining intensities within the same tumour; 2B, pie chart showing that 60% of HER2 1+ cases were scored based on heterogenous mixed expression patterns, while only 40% were scored based on single homogenous staining. Moderate staining was present in addition to other staining patterns and not in the HER2 1+ category alone. Sparkline graphs show multiple combinations of heterogenous patterns in example of HER2 score 1+ (2C), and another example of HER2 score 2+ (2D).