HER2-Targeted Antibody-Drug Conjugates in Advanced HER2-Low Breast Cancer: Mechanisms, Clinical Efficacy, and Resistance Strategies

Abstract

Abstract Globally, breast cancer is the most frequently diagnosed malignancy in women, with the HER2-low subtype (IHC 1+ or IHC 2+/ISH−) accounting for approximately 45%–55% of all invasive breast cancer cases. Conventional HER2-targeted therapies are ineffective for this subtype, and treatment has long relied on endocrine therapy or chemotherapy, with a median overall survival of less than 18 months after resistance development. This narrative review synthesizes evidence from clinical trials identified through systematic searches of the PubMed, ASCO, and ESMO databases until December 2025. Antibody-drug conjugates (ADCs) combine targeted delivery with potent cytotoxicity. The next-generation ADC trastuzumab deruxtecan (T-DXd) has achieved a breakthrough in the treatment of HER2-low breast cancer, attributed to its high drug-to-antibody ratio (DAR = 8), robust bystander effect, and non-classical killing mechanisms mediated by the tumor microenvironment. The landmark DESTINY-Breast04 trial provided the first definitive evidence that T-DXd significantly prolongs progression-free survival (PFS) and overall survival (OS). The DESTINY-Breast06 study further expanded the population that may benefit to include patients with HER2-ultralow expression and moved treatment to an earlier line, after endocrine therapy failure and before chemotherapy initiation. Chinese ADCs, such as disitamab vedotin (objective response rate [ORR], 33.3%), SHR-A1811, and MRG002, have also shown promising efficacy. However, resistance mechanisms, including target loss, impaired endocytosis, payload efflux, abnormalities in DNA repair, and suppression of the immune microenvironment, are emerging. Combination strategies involving endocrine therapy, immune checkpoint inhibitors, and HER2 tyrosine kinase inhibitors are expected to overcome resistance and enhance the efficacy of treatment. This review provides a comprehensive overview of ADC development in advanced HER2-low breast cancer, summarizes key clinical data, resistance mechanisms, and combination strategies, and discusses future directions, including biomarker development and optimal treatment sequencing, to guide clinical practice and future research in this area.