Clinical and molecular characteristics of human epidermal growth factor receptor 2-positive and human epidermal growth factor receptor 2-negative breast cancer

Background
Breast cancer is the most commonly diagnosed cancer in women worldwide, contributing about 11.7% of the total number of new cases diagnosed in 2020. Because of its high incidence, the clinical treatment of breast cancer is always an area of active investigation. According to the expression of human epidermal growth factor receptor 2 (HER2), breast cancer can be separated into HER2-positive and HER2-negative breast cancer. In particular, about 15-20% of all invasive breast cancers are HER2-positive. HER2-positive is defined as a tumor with HER2 overexpression as measured by ImmunoHistoChemistry (IHC) or in situ hybridization assay (ISH). IHC is a staining process performed on breast cancer tissue removed during biopsy and is used to show whether or not the cancer cells have HER2 receptors and/or hormone receptors on their surface. ISH is a technique used to identify specific genes within the tissue by a process called gene amplification. The overexpressed HER2 results in a more aggressive cancer with a worse prognosis and higher recurrence rate in the absence of therapy in breast cancer patients.

As the development of HER2 targeted agents, including antibody-drug, vaccine and small molecule drugs, the prognosis of the HER2-positive breast cancer has been improved to some extent. However, HER-2 positive patients with an IHC score of 3+ or 2+ and a positive ISH assay have responded to conventional anti-HER2 drugs, but the efficacy of conventional anti-HER2 drugs was not satisfactory. Furthermore, no HER-2-targeted therapy is recommended for clinical treatment for the majority of breast cancer patients either with an IHC score of 0 or 1+, or with an IHC score of 2+ with a negative ISH assay. It is very important to investigate clinical and molecular characteristics of HER2-positive and HER2-negative breast cancer to guide the clinical treatment in breast cancer patients. Hormone receptors (HR) and HER2 are both important markers in breast-cancer, and they have an effect on whether the cancer responds to treatment. Previous studies have found that most HER2-negative tumors are HR-positive, and low expression of HER2 was more common in HR-positive tumors versus tumors that are negative for HER2, HR and to ISH, both in primary and recurrent tumors. Therefore, there is a potential relationship between HR status and the efficacy of anti-HER2 treatment. The subgroup analysis of previous clinical trials demonstrated contradictory results on whether the efficacy of anti-HER2 treatment is independent of HR status, and no study has so far directly compared the outcome of anti-HER2 treatment between HR-positive and HR-negative breast cancer patients. It is imperative to address this important knowledge gap, which will help provide the evidence for the treatment guidance for breast cancer.

Clinical implications
It remains controversial whether HER2-positive and HER2-negative breast cancer patients with distinct HR expression patterns benefit differently from anti-HER2 agents. This study will provide more data to address this question and may guide treatment choices and trial design for these patients.