HER2-Low Breast Cancers: New Opportunities and Challenges

Huina Zhang, MD, PhD; Hani Katerji, MD; Bradley M. Turner, MD, MPH, MHA; David G. Hicks, MD


Am J Clin Pathol. 2022;157(3):328-336. 

In This Article

Abstract and Introduction


Objectives: Recent clinical trials have demonstrated significant clinical benefits from novel therapeutic compounds in breast cancer patient with human epidermal growth factor receptor 2 (HER2) immunohistochemical (IHC) score of 1+ or 2+ and negative in situ hybridization (ISH) result. A new concept of "HER2-low" breast cancer has been proposed and applied in the recent and ongoing clinical trials. In this article, we review the literature on the topic of HER2-low breast cancer.

Methods: A literature search in PubMed was performed using key words related to HER2-low breast cancer. Major relevant studies that were presented in international breast cancer conferences were also included.

Results: HER2-low breast cancer is currently defined as breast cancer with HER2 IHC score of 1+ or 2+ and negative ISH result. It likely represents a group of tumors with significant biological heterogeneity. Reports of clinical activity using the next generation of HER2-targeting antibody-drug conjugates in HER2-low breast cancers suggest that some strategies of targeting HER2 might be effective in this patient population while raising considerable concerns over limitations in our current testing methodologies and our ability to accurately identify such patients.

Conclusions: The promising efficacy of novel HER2-targeted therapy in advanced HER2-low breast cancers has raised the possibility for changing the clinical interpretation of HER2 status in breast cancer to include a HER2-low category; however, the definition of HER2-low breast cancer, the corresponding reliable and accurate quantitative HER2 testing methodology, and the biology of HER2-low breast cancer remain poorly defined.


The human epidermal growth factor receptor 2 (HER2), which was discovered in the 1980s, is a 185-kDa transmembrane tyrosine kinase receptor protein encoded by the HER2 (also known as ERBB2) oncogene located on the long arm of chromosome 17.[1,2] Normal breast epithelial cells have one copy of the HER2 gene on each chromosome 17 and express approximately 20,000 HER2 receptor molecules per cell. When HER2 gene is overexpressed/amplified, the HER2 receptor molecules at the tumor cell surface are significantly increased (>2,000,000 per cell).[3] The overexpressed HER2 will stimulate its intrinsic kinase activity upon dimerization, resulting in activation of intracellular signal cascades that ultimately involves cellular proliferation, survival, angiogenesis, invasion, and metastasis; all of which directly contribute to an aggressive tumor biology.[4,5] HER2-positive breast cancers represent ~15% of all invasive breast cancers and usually have an aggressive clinical course and a poor prognosis.[3,6] With the development of HER2-targeted agents, beginning with the monoclonal antibody trastuzumab, followed by the different humanized monoclonal antibody pertuzumab, the tyrosine kinase inhibitors (TKIs; eg, lapatinib, neratinib, and tucatinib), and the antibody-drug conjugates (ADCs; eg, T-emtansine), the natural history and prognosis of HER2-positive breast cancers have been changed dramatically.

Given the results from numerous clinical trials, which showed that only HER2-positive breast cancers benefit from the addition of trastuzumab to chemotherapy,[7–10] the evaluation of HER2 status has been focused on separating HER2-positive cancers, defined as HER2 (3+) by immunohistochemistry (IHC) or HER2 (2+) with gene amplification from HER2-negative breast cancers, defined as HER2 (0+/1+) on IHC or HER2 (2+) without gene amplification.[11]

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-47 phase III randomized trial, patients with high-risk HER2-negative breast cancers gained no benefit from adjuvant trastuzumab added to standard adjuvant chemotherapy in early stage disease.[10] The results of this study and others confirmed the limited clinical value of HER2 pathway blockade by trastuzumab in HER2-negative breast cancers and have reinforced the dichotomous evaluation of HER2 (positive vs negative) as a biomarker in breast cancer for the purpose of treatment planning. In contrast, recent studies have demonstrated significant clinical benefits from novel therapeutic compounds, especially the HER2-targeting ADCs in a subset of patients with advanced breast cancers and negative HER2 by IHC and in situ hybridization (ISH) but had low levels of HER2 IHC expression.[12,13] To meet the need for identifying those HER2-negative patients who may potentially benefit from the newly developed HER2-targeted agents, a new concept of "HER2-low" breast cancer (breast cancers with HER2 1+/2+ on IHC and with a negative result on ISH) has been proposed and applied in the recent and ongoing clinical trials.[10,12–20] This definition of HER2-low breast cancer is largely based on the current HER2 testing methods and scoring system.[11] The clinical development of novel HER2-targeting agents for HER2-low breast cancers has the potential to provide new therapeutic options for patients who are not currently considered candidates for HER2-directed therapy. In this article, we review the literature on the topic of HER2-low breast cancer, including evolving concepts from emerging clinical trial data, the definition and biology, and the challenges and unanswered questions that remain for HER2-low breast cancer.