Antibody-Drug Conjugates in Breast Cancer: Current Status and Future Directions

Abstract

Antibody drug conjugates (ADCs) are novel medications that combine monoclonal antibodies with cytotoxic payloads, enabling the selective delivery of potent drugs to cancer cells expressing specific surface antigens. This targeted strategy seeks to optimize treatment effectiveness while reducing the risk of systemic toxicity, distinguishing ADCs from conventional chemotherapy. The rapid growth in ADC research has led to numerous developments and approvals for cancer treatment, with significant impacts on the management of breast cancer. ADCs like T-DXd for HER2-low disease and sacituzumab govitecan for triple negative breast cancer (TNBC) have provided valuable options for challenging subtypes of breast cancer. However, essential questions still need to be addressed, including the optimal order of ADCs amidst the growing number of newly developed ones and strategies to overcome resistance mechanisms. Preclinical studies have shed light on potential resistance mechanisms, emphasizing the potential benefit of combinational approaches with other agents such as immune checkpoint inhibitors (ICIs) and targeted tyrosine kinase inhibitors (TKIs) to enhance treatment effectiveness. Additionally, personalized approaches based on molecular profiling hold promise in tailoring ADC treatments to individual tumors, identifying unique molecular markers for each patient to optimize treatment efficacy while minimizing side effects.

Keywords: antibody–drug conjugates; breast cancer; drug resistance.

Figure 1

Graphic depicting the multifactorial mechanism of action of ADCs. ADCs are composed of three distinctive parts: the antibody, linker, and cytotoxic drug. Binding of the antibody to the antigen triggers intracellular cascades that can lead to internalization and release of the cytotoxic drug. ADCs can also have an effect on nearby cells in a process called the bystander effect. During this process, there is extracellular release of the cytotoxic drug leading to apoptosis of nearby cells.