Current Biological, Pathological and Clinical Landscape of HER2-Low Breast Cancer

Abstract

HER2-low breast cancer (BC) is a newly defined subset of HER2-negative BC that has HER2 immunohistochemical (IHC) score of 1+ or score of 2+/in situ hybridization (ISH) negative phenotype. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating this group of tumors. Trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC was recently approved by the U.S. Food and Drug Administration as the first targeted therapy to treat HER2-low BC. However, HER2-low BC is still not well characterized clinically and pathologically. This review aims to update the current biological, pathological and clinical landscape of HER2-low BC based on the English literature published in the past two years and to propose the future directions on clinical management, pathology practice, and translational research in this subset of BC. We hope it would help better understand the tumor biology of HER2-low BC and the current efforts for identifying and treating this newly recognized targetable group of BC.

Prognostic significance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors

“…Previous studies conducted in large series of primary BCs reported on higher ERα/PgR expression in HER2-low as compared to HER2-0 BCs 12 . The fact that we did not observe such association may derive from the lower number of patients included in our study, or by different methods to evaluate ERα/PgR expression across different studies.…”

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

“…Additionally, the choice of staining methodology, particularly antigen retrieval, and the availability of different antibody clones with varying specificity can also impact the accuracy and reproducibility of results ( Schrohl et al, 2011 ; Zhang et al, 2021 ). The VENTANA PATHWAY anti-HER2/neu (4B5) rabbit monoclonal primary antibody has been approved by the FDA as the first companion diagnostic test to identify HER2-low mBC patients for trastuzumab deruxtecan (T-DXd) targeted therapy ( Zhang and Peng, 2022 ). However, assessing the reliability of other commonly used HER2 IHC testing methods is still pending ( Zhang and Peng, 2022 ).…”

“…The VENTANA PATHWAY anti-HER2/neu (4B5) rabbit monoclonal primary antibody has been approved by the FDA as the first companion diagnostic test to identify HER2-low mBC patients for trastuzumab deruxtecan (T-DXd) targeted therapy ( Zhang and Peng, 2022 ). However, assessing the reliability of other commonly used HER2 IHC testing methods is still pending ( Zhang and Peng, 2022 ). Repeating the test for equivocal results may help to exclude technical problems, however, it does not always lead to a definitive result.…”

“…It should be noted that the HER2 IHC testing was initially designed to distinguish high levels of HER2 expression (i.e., almost 2 million molecules/cell which corresponds to HER2 IHC 3+) from lower levels of HER2 expression (i.e., 20,000 to 500,000 molecules/cell for HER2 IHC 0 to 2+). Therefore, this method has not been developed for detecting HER2-low tumors ( Zhang and Peng, 2022 ). On the other hand, in the post-analytical phase, inter-observer variability can occur due to the lack of consistent epithelial internal positive control for HER2 in non-neoplastic breast tissue ( Sajjadi et al, 2022 ; Zhang et al, 2022 ).…”

Potential Antihuman Epidermal Growth Factor Receptor 2 Target Therapy Beneficiaries: The Role of MRI‐Based Radiomics in Distinguishing Human Epidermal Growth Factor Receptor 2‐Low Status of Breast Cancer

“…With the development of antibody‐drug conjugates (ADCs), HER2‐low expression has been proposed as an emerging subtype based on its potential benefit from anti‐HER2 ADCs 5,8 . Recent clinical studies suggested that HER2‐low expression breast cancers have unique clinicobiological features, different pathological complete rates (pCR) and prognoses compared with HER2‐zero expression 9–11 . In this context, accurate evaluation of HER2 status is critical for the appropriate use of HER2‐targeted therapies, which is not only specific to the distinction of HER2‐positive from HER2‐negative breast cancers but also applicable to the distinction of HER2‐low from HER2‐negative breast cancers.…”