DOI: 10.25934/pr00008856
title: The impact of human epidermal growth factor receptor 2-low (HER2-low) Expression on the Efficacy of endocrine therapy in Hormone Receptor-positive/HER2-Negative (HR+/HER2-) Breast Cancer

description: Breast cancer is the most common malignancy among women, with over 2,260,000 newly diagnosed cases and nearly 685,000 deaths worldwide annually. Based on the presence of certain proteins in the cancer cells, called human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR), breast cancer can be classified into four subtypes which are used to determine the correct treatment and which predict the patients expected outcomes. 

A test called the ImmunoHistoChemistry (IHC) is used to determine a patient's HER2 status. If the test is 0 to 1, it’s considered HER2-negative. If the score is 1+ to 2+, it's considered low. A score of 3+ is considered HER2-positive. Patients with low levels (IHC test 1+ to 2+) of the HER2 protein in their cancer cells are classified as having HER2-low breast cancer, which accounts for 45-55% of breast cancer patients, and is less likely to benefit from conventional HER2-targeting drugs. Recently, a new generation of drugs which target HER2, called antibody-drug conjugates (ADC), which can specifically target and kill cancer cells, have been shown to be effective in HER2-low breast cancer.

HER2-low breast cancers are more diverse in nature than HER2+ cancers, and are often Hormone Receptor-positive (HR+) tumors. This means that they have receptors on the cancer cells for the hormones estrogen (ER), or progesterone (PR). These cancers may be treated with hormone therapy, but signals exchanged between the HER2 and hormone receptor proteins are thought to contribute to HR+ tumours not responding as well to hormone therapy as HER2-zero tumours.

A previous analysis of four clinical trials of 2,310 HER2-negative breast cancer patients found that HER2-low breast cancers have shown significantly longer survival compared with HER2-0 (those with an IHC test of 0). However, some studies revealed no statistically significant prognostic differences between the two subgroups. 

Currently, it still remains unclear whether HER2-low breast cancer should be considered as a distinct biological subtype compared to HER2-0. In terms of treatment, the therapeutic strategies for HER2-low metastatic breast cancer (MBC, cancer which has spread to other sites in the body) is mainly determined by HR status. In the HER2-low cancers, there is less HER2 per cell than in HER2+ cancers, and hence there may be less cross-talk between the hormone receptors and HER2, and they may therefore respond better to hormone therapy.

To date the clinical impact of the HER2-low expression on the response to hormone therapy in patients with breast cancer remains controversial. This study aims to evaluate the relationship between HER2-low expression and clinical outcomes in HR+/HER2- breast cancer patients who received hormone therapy, and will hopefully help clinicians select personalized treatment strategies for HR-positive HER2-low breast cancer patients. 

We will analyze existing clinical trial data from multiple studies to investigate the impact of HER2-low expression on the efficacy of hormone therapy in HR+/HER2- breast cancer patients. This design enables us to efficiently evaluate a large sample size and obtain meaningful insights from diverse populations. Additionally, we will also conduct subgroup analyses to explore potential differences in treatment efficacy based on other relevant factors, such as age, race, and menopausal status. 

We believe that our design and methods will provide effective data support for our research objectives and make valuable contributions to the clinical management and treatment strategies of breast cancer.