Antibody-drug conjugates in breast cancer: Progress and future directions

Sep 23, 2026

Uploaded by Cart

Antibody-drug conjugates (ADCs) have reshaped breast cancer therapy by delivering potent cytotoxic payloads directly to antigen-expressing tumor cells, showing efficacy across subtypes including chemotherapy-refractory disease and brain metastases with manageable side effects. Despite progress, key obstacles remain, especially predictive biomarkers for response and mechanistic understanding of resistance. The review highlights ADC platform versatility—antigen targeting, linker chemistries for controlled payload release, payload classes, and adjustable drug-to-antibody ratios—while outlining next-generation concepts such as bispecific targeting, immune-stimulating conjugates, and novel payloads.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Summary

Introduction

Structure and Mechanisms of ADCs

ll OPEN ACCESS Review Antibody-drug conjugates in breast cancer: Progress and future directions Alexandra Bili Newman,1 Senthil Damodaran,2,3 and Funda Meric-Bernstam3,4,* 1Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA *Correspondence: [fmeric@mdanderson.org](fmeric@mdanderson.org) [https://doi.org/10.1016/j.xcrm.2026.102742](https://doi.org/10.1016/j.xcrm.2026.102742) SUMMARY Antibody-drug conjugates (ADCs) have transformed the treatment landscape of breast cancer, enabling targeted delivery of potent cytotoxic payloads to antigen-expressing tumor cells. These agents have demonstrated efficacy across breast cancer subtypes, including chemotherapy-refractory disease and brain metastases, with manageable side-effect profiles. However, despite significant advances, identifying predictive biomarkers for response and understanding resistance mechanisms remain critical challenges that must be addressed to guide rational sequencing strategies and optimize combination approaches. The ADC platform offers remarkable versatility through diverse antigen targeting, variable linker chemistries enabling controlled payload release, multiple cytotoxic payload classes, and adjustable drug-to-antibody ratios. Next-generation platforms including bispecific targeting constructs, immune-stimulating antibody conjugates, and novel payloads such as PROTACs and RNA polymerase II inhibitors are being developed to further expand therapeutic applications. Realizing the full potential of these agents will require integrated biomarker development, a deeper understanding of resistance mechanisms, and optimized sequencing and combination strategies. INTRODUCTION The concept of a ‘‘magic bullet’’ for targeted therapeutic delivery to cancer cells while sparing healthy tissue was first pioneered by German Nobel Laureate Paul Ehrlich in the early 20th century. Over the subsequent decades, his idea evolved to incorporate monoclonal antibodies as delivery vehicles to preferentially target tumor cells. In 2000, gemtuzumab ozogamicin became the first modern antibody-drug conjugate (ADC) to receive Food and Drug Administration (FDA) approval for use in acute myeloid leukemia. This paved the way for 14 approved ADCs across the field of oncology over the past 25 years.1 These agents merge the targeting precision of monoclonal antibodies with the potency of chemotherapy, thereby addressing the long-standing challenge in oncology of maximizing therapeutic efficacy while reducing systemic toxicity.2 ,3 The breast cancer treatment landscape has been fundamentally reshaped by ADCs, beginning with the approval of trastuzumab emtansine (T-DM1) in 2013 followed by trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd), firmly establishing ADCs as part of standard of care across all breast cancer subtypes (Figure 1) .3–5 Interestingly, meaningful clinical responses have emerged even in tumors with low target antigen expression, a finding that has substantially expanded treatment options for patients with advanced disease.6–8 ADCs are now being integrated throughout the treatment continuum, from neoadjuvant and adjuvant approaches through management of metastatic disease (Table S1) .9 , 10 This rapid adoption has necessitated the development of toxicity mitigation strategies and predictive biomarkers that guide patient selection and raises important questions regarding optimal ADC sequencing, combination strategies, and cost-effectiveness and accessibility.4 , 11–13 With next-generation ADCs now

FAQs

How do antibody-drug conjugates (ADCs) work in breast cancer treatment?

ADCs combine an antibody that targets tumor-associated antigens with a cytotoxic payload connected through a chemical linker. After binding, the complex is internalized and processed so the linker can release the payload inside tumor cells.

What major challenges remain despite advances in ADCs?

The review emphasizes the need for predictive biomarkers to identify responders and a deeper understanding of resistance mechanisms. These are essential for rational treatment sequencing and for optimizing combination strategies.

What design features make the ADC platform versatile?

ADC versatility comes from multiple antigen targeting options, variable linker chemistries that enable controlled payload release, different cytotoxic payload classes, and adjustable drug-to-antibody ratios (DAR).

Sep 23, 2026

Uploaded by Cart