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Review
. 2024 Feb 16;16(4):800.
doi: 10.3390/cancers16040800.

Next-Generation HER2-Targeted Antibody-Drug Conjugates in Breast Cancer

Brittney S Zimmerman  1   2 , Francisco J Esteva  1   2
Affiliations
Review

Next-Generation HER2-Targeted Antibody-Drug Conjugates in Breast Cancer

Brittney S Zimmerman et al. Cancers (Basel). .

Abstract

Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic payload, which is attached by a linker, forming the basic structure of an ADC. Novel combinations and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd. Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal dosing regimens, understanding resistance mechanisms, and identifying patient populations that would derive the most benefit from these treatments. These novel ADCs are at the forefront of a new era in targeted cancer therapy, holding the potential to improve outcomes for patients with HER2-positive and HER2-Low breast cancer.

Keywords: HER2; antibody–drug conjugates; breast neoplasms; drug resistance; targeted therapy; trastuzumab deruxtecan; trastuzumab-DM1.

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Conflict of interest statement

F.J.E. has served as a consultant for AstraZeneca, Genentech, and Novartis for activities unrelated to this manuscript. B.S.Z. has no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
ADC components. Abbreviations: DAR: drug-to-antibody ratio; DM1: derivative of maytansine 1; DM4: derivative of maytansine 4; MMAF: monomethyl auristatin F; MMAE: monomethyl auristatin E.
Figure 2
Figure 2
Mechanism of action of ADCs.
Figure 3
Figure 3
ADC internalization and targeting specificity. IV refers to Domain IV of the extracellular domain of the HER2 protein.
See this image and copyright information in PMC

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This research received no external funding.