Focusing on toxicity management: Challenges and strategies for HER2-targeted antibody-drug conjugates in breast cancer

Sep 23, 2026

Uploaded by Rowan

Antibody–drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER2) have transformed treatment for HER2-positive breast cancer, improving survival, yet clinical expansion has exposed serious adverse events (AEs) that can reduce quality of life, lower adherence, and occasionally cause life-threatening outcomes or early discontinuation. This review summarizes toxicity profiles and mechanisms for key agents including T-DM1 and T-DXd, detailing thrombocytopenia, interstitial lung disease, cardiotoxicity, and hepatotoxicity, with monitoring and intervention evidence. It emphasizes early identification and standardized management and discusses emerging safety improvements via antibody engineering, linker design, and payload selection.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Introduction

Advances in ADC for HER2-positive breast cancer

Clinical advances of T-DM1 in HER2-Positive breast cancer

The Breast 86 (2026) 104741 Contents lists available at ScienceDirect The Breast journal [homepage:](homepage: www.journals.elsevier.com/the-breast)[ www.journals.elsevier.com/the-breast](homepage: www.journals.elsevier.com/the-breast) | Focusing on toxicity management: Challenges and strategies for HER2-targeted antibody–drug conjugates in breast cancer | | | | --- | --- | --- | | Xiaoyu Liu a,1, Saige Yin b,1, Xiyin Li a,*, Jianyun Nie a,**
a Department of Breast Cancer, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, the Third Affiliated Hospital, Kunming Medical University, 519 Kunzhou Road, Kunming, Yunnan, 650118, China
b Department of Anatomy and Histology and Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, Yunnan Province, 650500, China | | | | A R T I C L E I N F O
Keywords:
Antibody-drug conjugate
Human epidermal growth factor receptor 2 Breast cancer
Targeted therapy
Adverse events | A B S T R A C T
Antibody–drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER2) have revolutionized the treatment landscape of HER2-positive breast cancer, significantly improving patient survival. However, their growing clinical application has revealed a spectrum of serious adverse events (AEs) that can compromise quality of life, reduce treatment compliance, and, in some cases, lead to life-threatening outcomes or premature therapy discontinuation. This review provides a comprehensive overview of the toxicity profiles and underlying mechanisms of HER2-targeted ADCs, with a focus on representative agents such as trastuzumabemtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). We examine the pathogenesis of common toxicities, including thrombocytopenia, interstitial lung disease, cardiotoxicity, and hepatotoxicity, and summarize clinical evidence for monitoring and intervention strategies. Emphasis is placed on the importance of early identification and standardized management to mitigate risk. Furthermore, we discuss emerging approaches to improve ADC safety through structural optimization, including advances in antibody engineering, linker design, and payload selection. This review aims to guide clinicians and researchers in improving the safety and clinical utility of HER2-targeted ADCs in breast cancer treatment. | | 1. Introduction In recent years, antibody-drug conjugates (ADCs), as a nextgeneration targeted therapeutic strategy, have demonstrated significant breakthroughs in oncology. Human epidermal growth factor receptor 2 (HER2)-targeted ADCs such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) have demonstrated remarkable therapeutic potential in breast cancer, benefiting not only patients with HER2 overexpression but also those with HER2-low tumors [1,2]. However, the complex molecular structure of ADCs, while enabling their targeted efficacy, is also associated with a range of potentially severe adverse events, including thrombocytopenia, interstitial lung disease (ILD), gastrointestinal toxicity, cardiotoxicity, and ocular injury—some of which may reach grade ≥3 severity and threaten treatment continuity or patient safety [3,4]. These toxicities not only compromise treatment adherence and patient quality of life but may also limit the broader clinical application of ADCs. Thus, elucidating the molecular basis of these toxicities and developing early warning systems, intervention strategies, and optimized dosing regimens has become a critical research priority. This review focuses on the toxicity challenges of HER2-targeted ADCs in breast cancer therapy, providing a systematic overview of their mechanistic underpinnings, representative adverse events, and mitigation strategies. The goal is to inform future ADC development toward safer and more effective therapeutic applications. 2. Advances in ADC for HER2-positive breast cancer ADCs are a novel class of targeted therapeutics compo

FAQs

Why do HER2-targeted antibody–drug conjugates cause serious adverse events in breast cancer treatment?

Their complex structure enables targeted efficacy but also drives a spectrum of severe toxicities, including thrombocytopenia, interstitial lung disease, gastrointestinal toxicity, cardiotoxicity, and ocular injury. Some events can reach grade ≥3 and threaten continuity or patient safety.

Which HER2-targeted ADCs are highlighted as representative agents in the review?

The review focuses on trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). It also notes other anti-HER2 ADCs under clinical investigation.

How does the review propose to mitigate toxicity risk from HER2-targeted ADCs?

It emphasizes early identification and standardized management, supported by monitoring and intervention strategies. It also discusses emerging approaches to improve safety through structural optimization, including antibody engineering, linker design, and payload selection.

Sep 23, 2026

Uploaded by Rowan