Antibody-drug conjugates in breast cancer: redefining targeted therapy
Chenxu Guo, Leif W. Ellisen
Chenxu Guo, Leif W. Ellisen
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Antibody-drug conjugates in breast cancer: redefining targeted therapy

Abstract

Antibody-drug conjugates (ADCs) have transformed the treatment landscape of breast cancer and redefined the conceptual distinction between targeted therapy and conventional chemotherapy. Originally conceived as “magic bullets” that selectively deliver cytotoxic warheads to antigen-expressing tumor cells, clinical and mechanistic evidence indicates that ADC activity depends on a broader interplay of target-dependent and target-independent mechanisms, including extracellular payload release, bystander killing, off-tumor uptake, and immune modulation. Here, we examine ADCs in breast cancer as a distinct therapeutic paradigm. We discuss how antigen biology, linker chemistry, payload features, and drug-to-antibody ratio collectively determine efficacy, toxicity, and therapeutic index. We then compare currently approved and emerging HER2- and TROP2-directed ADCs, highlighting how differences in linker stability, payload pharmacology, and bystander capacity can affect clinical outcomes in ADCs sharing the same target. We further discuss the biological basis and translational challenges of de novo and acquired resistance related to targets, payloads, and tumor microenvironmental constraints, as well as the implications of these mechanisms for biomarker development, sequencing rationales, and combination strategies with immune checkpoint inhibitors and DNA repair–targeting therapies. Finally, we outline future directions of ADC development, including expansion of the target space, novel payload modalities, and next-generation antibody and conjugation engineering.

Authors

Chenxu Guo, Leif W. Ellisen

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Figure 2

Target- and payload-mediated determinants of ADC response and resistance in breast cancer.

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Target- and payload-mediated determinants of ADC response and resistance...
ADC activity is governed by coordinated target-directed and payload-related mechanisms that influence response, de novo resistance, and acquired resistance. (A) Target-directed mechanisms include antigen surface abundance, intratumoral heterogeneity with spatially variable antigen expression, binding site mutations that alter epitopes and reduce antibody binding, target downregulation resulting in loss of antigen expression, and altered target trafficking that reduces surface localization and limits ADC accessibility. (B) Payload-related mechanisms include altered lysosomal function leading to defective ADC processing and payload release, tumor cell–intrinsic features such as growth capacity and apoptosis escape (e.g., via signal transducer and activator of transcription 3 [STAT3] and polo-like kinase 1 [PLK1]), mutations in payload targets (e.g., TOP1) that impair drug engagement, and active payload clearance mediated by efflux transporters. These processes collectively determine intracellular payload delivery and cytotoxic effects, informing biomarker development, treatment sequencing, and rational combination strategies.