Antibody-drug conjugates in breast cancer treatment: resistance mechanisms and the role of therapeutic sequencing

Abstract

Antibody-drug conjugates (ADCs) are a transformative approach in breast cancer therapy, offering targeted treatment with reduced toxicity by selectively delivering cytotoxic agents to cancer cells. While ADCs like trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan have shown significant efficacy, resistance mechanisms such as antigen loss, impaired internalization, and efflux of cytotoxic payloads challenge their effectiveness. This review discusses these resistance mechanisms and explores advanced strategies to overcome them, including innovations in linker chemistry, multi-antigen targeting, and biomarker-driven personalization. Additionally, therapeutic sequencing - determining the optimal order of ADCs with other treatments such as chemotherapy, endocrine therapy, and immunotherapy - is examined as a crucial approach to maximize ADC efficacy and manage resistance. Evidence-based sequencing strategies, particularly for human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC), are supported by clinical trials demonstrating the benefits of ADCs in both early-stage and metastatic settings. The potential of combination therapies, such as ADCs with immune checkpoint inhibitors (ICIs), further highlights the evolving landscape of breast cancer treatment. As ADC technology advances, personalized approaches integrating biomarkers and optimized sequencing protocols offer promising avenues to enhance treatment outcomes and combat resistance in breast cancer.

Keywords: Antibody-drug conjugates; breast cancer; combination therapy; resistance mechanisms; targeted treatment; therapeutic sequencing.

Figure 1

Mechanism of action of ADCs. ADCs bind to target antigens on cancer cells, forming an ADC-antigen complex, which is internalized via endocytosis^[5]. Within endosomes, cleavable linkers release the cytotoxic payload upon fusion with lysosomes, triggering mechanisms like DNA intercalation and microtubule disruption that lead to apoptosis. Additionally, the bystander effect allows the cytotoxic payload to impact neighboring tumor cells, enhancing therapeutic efficacy. Created in BioRender. Larose, E. (2024) https://BioRender.com/f12z842. ADCs: Antibody-drug conjugates.

Figure 2

Mechanisms of resistance to ADCs. Resistance mechanisms include antigen loss or (1) decreased antigen binding, (2) impaired internalization, (3) inadequate intracellular trafficking leading to reduced payload release and (4) recycling of the ADC-antigen complex. Additional resistance pathways involve (5) upregulation of drug efflux transporters (e.g., MDR, Pgp), (6) lysosomal degradation defects, and (7) mutations in the payload target, all of which diminish ADC therapeutic efficacy. Created in BioRender. Larose, E. (2024) https://BioRender.com/f12z842. ADCs: Antibody-drug conjugates; MDR: multidrug resistance; Pgp: P-glycoprotein.

Figure 3

Strategies for overcoming resistance in ADC therapy. The illustration highlights three key approaches: redesigning ADCs with next-generation linkers and payloads, identifying biomarkers for personalized treatment, and implementing combination therapies with endocrine therapy, immunotherapy, chemotherapy, and radiotherapy. These strategies aim to optimize therapeutic outcomes and address resistance mechanisms. Created in BioRender. Larose, E. (2024) https://BioRender.com/f12z842. ADC: Antibody-drug conjugate.