Navigating antibody‒drug conjugates (ADCs): from metastatic to early breast cancer treatment strategies

Abstract

We are currently living in the era of precision medicine, and antibody‒drug conjugates (ADCs) represent promising advancements in targeted cancer therapy. While several ADCs have been investigated over the years, only three have gained FDA approval for breast cancer (BC): ado-trastuzumab emtansine (T-DM1/Kadcyla), trastuzumab deruxtecan (T-DXd/Enhertu), and sacituzumab govitecan (SG/Trodelvy). This review focuses on the three approved ADCs for BC, reviewing the trials that led to their approval and detailing the ongoing trials testing their clinical efficacy and safety profiles. We examine ongoing trials targeting both metastatic and early-stage patients. Notably, we explore trials incorporating investigational ADCs into early management strategies, addressing the unique challenges of biomarker identification, target toxicity, and cost-effectiveness. By summarizing the current landscape of FDA-approved and investigational ADCs, this study highlights the evolving nature of BC treatment. Preliminary findings from ongoing trials suggest that early integration of ADCs can lead to significant improvements in disease-free survival, reinforcing their role in personalized medicine. As research advances, ADCs are likely to become a cornerstone of breast cancer treatment, providing new hope for better patient outcomes.

Keywords: ADCs; Antibody‒drug conjugates; Early breast cancer; Metastatic breast cancer; Trials.

Fig. 1

Research process chart

Fig. 2

Comparison of components in antibody‒drug conjugates: T-DM1, T-DXd, and sacituzumab govitecan

Fig. 3

Mechanism of action of T-DXd, an overview. (1) HER2 targeting and binding: the trastuzumab antibody component binds to HER2 receptors on the surface of HER2- overexpressing tumor cells. (2) Internalization via endocytosis: the HER2-antibody complex undergoes receptor-mediated endocytosis, entering the cell inside a vesicle. (3) Payload release: inside the cell, the linker is cleaved by lysosomal enzymes, releasing the drug deruxtecan a potent topoisomerase I inhibitor, into the cytoplasm. (4) Cytotoxic action and bystander effects: the released deruxtecan can induce DNA damage, leading to the apoptosis of tumor cells. The cytotoxic payload also diffuses to nearby HER2-negative or HER2-low-expressing cells, known as the bystander effect

Fig. 4

Mechanism of action of the SG; an overview. (1) Targeting and binding: the antibody component binds to Trop2 on the surface of tumor cells. (2) Internalization via endocytosis: the antibody-Trop2 complex is internalized into the cell via receptor-mediated endocytosis. (3) Payload release: the linker in SG is a hydrophilic cleavable linker that is hydrolyzed intracellularly by enzymes, releasing SN- 38 and causing DNA damage by inhibiting topoisomerase I, leading to apoptosis in the cell

Fig. 5

Mechanism of action of T-DM1; an overview. (1) HER2 targeting and binding: the trastuzumab antibody component of T-DM1 binds to HER2 receptors on the surface of HER2-overexpressing tumor cells. (2) Internalization via endocytosis: the HER2-antibody complex is internalized through receptor-mediated endocytosis and entrapped in an intracellular vesicle. (3) Payload release: inside the cell, the MCC linker is cleaved, and emtansine, a potent microtubule inhibitor, is released into the cytoplasm. (4) Cytotoxic action: DM1 binds to microtubules, disrupting their assembly and causing cell cycle arrest and apoptosis. Unlike T-DXd, T-DM1 has limited bystander effects

Fig. 6

The sequence of therapy including ADCs in mBC