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

Abstract

Refining the definition of HER2-low class in invasive breast cancerBackground: 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.

Pathological identification of HER2-low breast cancer: Tips, tricks, and troubleshooting for the optimal test

“…The ANN model configured HER2 IHC score 1 + as membranous staining in invasive cells either as faint intensity in ≥20% of cells regardless of the circumferential completeness, weak complete staining in ≤10%, weak incomplete staining in >10% and moderate incomplete staining in ≤10%. This model showed statistical significance with Oncotype DX scores and a perfect intra- and inter-observer agreement (kappa value = 0.8 and 0.9, respectively) ( Atallah et al, 2022 ). Such methodologies have shown promising outcomes for a more accurate and reproducible HER2-low assessment compared to the currently available methods.…”

“…The findings of such trials could contribute to the understanding of clear-cut limits of HER2 expression required for ADC treatment strategy using the available diagnostic techniques ( Wu et al, 2023b ; Fan and Xu, 2023 ). Yet, to develop a robust definition of HER2-low, the number of recruited patients in such randomized clinical trials needs to be amplified ( Atallah et al, 2022 ). Recruitment of further diagnostic approaches with a more precise cut-off could facilitate the detection of patients suitable for targeted therapies.…”

“…Moreover, HER2 QCS results had a broad quantitative overlap between IHC and ISH ( Gustavson et al, 2021 ). The use of the artificial neural network (ANN) models that can learn and shape non-linear and complex relationships has been implemented to assist in refining the HER2‐low definition ( Atallah et al, 2022 ). Atallah et al, developed a model by implementing as input the HER2 scoring parameters (i.e., intensity and its distribution, completeness, and percentage of positive cells and cytoplasmic staining) and as an output the HER2 mRNA‐based clusters variable.…”

Evaluation of ERBB2 mRNA Expression in HER2-Equivocal (2+) Immunohistochemistry Cases

“…Due to the recent development of HER2-directed antibody–drug conjugates [ 11 ], the correct classification of these cases is gaining importance, as it may change the clinical management of the patients. In this regard, a recent study by Atallah et al [ 27 ] suggests new refined score patterns to distinguish HER2 0+ and HER2 1+ tumors, which correlates with mRNA expression.…”

The trichotomy of HER2 expression confers new insights into the understanding and managing for breast cancer stratified by HER2 status

“…Interestingly, on the contrary, in a retrospective analysis of 410 patients with lymph node‐negative BC who did not receive adjuvant therapy from 1985 to 2000, scholars found that patients with low HER2 expression had significantly longer DFS and OS, and HER2 status was an independent prognostic factor 34 . In addition, HER2‐low, compared to HER2‐zero, has also been reported as an adverse prognostic factor due to its association with metastases (axillary lymph node metastases, 35 brain metastases 36 ).…”