Abstract:

The incidence of breast cancer currently ranks first among malignant tumors in women. Breast cancer exhibits high heterogeneity and can be classified into four molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) overexpression and triple-negative. However, previous molecular subtype classifications have limited treatment options for patients with HER2 low expression. In recent years, with the rapid development of antibody-drug conjugates (ADCs), new treatment options have emerged for breast cancer patients with HER2 low expression. This has also led to updates in the criteria for determining HER2 expression status in both domestic and international guidelines, based on immunohistochemistry (IHC) and in situ hybridization (ISH) testing, categorizing HER2 expression as HER2-positive (IHC 3+ or IHC 2+/ISH+), HER2 low expression (IHC 1+ or IHC 2+/ISH-),and HER2-negative (IHC 0). ADCs are immunotherapeutics composed of a linker that conjugates a monoclonal antibody with a cytotoxic payload. In the field of breast cancer, several large clinical trials have demonstrated clinical benefits of ADCs targeting HER2, such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan targeting trophoblast cell surface antigen 2 (TROP2), in various molecular subtypes of breast cancer. With the phase Ⅲ DESTINY-Breast03 trial and others, T-DXd has been found to have superior efficacy compared to T-DM1 in advanced HER2-positive breast cancer patients (approximately two times higher complete response rate, and four times longer median progression-free survival). T-DXd has now replaced T-DM1 as the recommended second-line therapy for HER2-positive breast cancer and as a second-line treatment option after local treatment for brain metastasis. The phase Ⅲ DESTINY-Breast04 trial confirmed that breast cancer patients with HER2 low expression can also benefit from T-DXd, further reshaping the treatment landscape for advanced breast cancer and supporting the need to redefine molecular subtypes of HER2-negative breast cancer. The phase Ⅲ ASCENT trial demonstrated that sacituzumab govitecan significantly improved survival and quality of life in triple-negative breast cancer (TNBC) patients, and the phase Ⅱ NeoSTAR study suggested its potential as neoadjuvant therapy in TNBC. Based on evidence, T-DM1, T-DXd and sacituzumab govitecan have been approved for marketing in both foreign and Chinese markets. Other ADC drugs, such as HER3-DXd, Dato-DXd and China-developed RC48, are also undergoing extensive clinical trials in the field of breast cancer and other tumors. Furthermore, there are several other ADCs targeting different molecular targets in active development. This article aimed to review the new advances related to ADCs therapy for breast cancer patients with different molecular subtypes and discuss the clinical application value of ADCs in breast cancer.

Key words: Breast cancer, Molecular typing, Human epidermal growth factor receptor 2, Antibody-drug conjugate