Recent advances in trastuzumab and its antibody-drug conjugates-related liver injury

INTRODUCTION: Trastuzumab and its antibody-drug conjugates (ADCs) are pivotal in treating human epidermal growth factor receptor 2(HER2)-positive cancers. With the growing scope of clinical use, an increasing body of evidence from studies and case reports suggests that these agents can induce hepatotoxicity of varying severity. AREAS COVERED: This review synthesizes evidence from published clinical trials, preclinical studies, pharmacovigilance data, drug labeling information, meta-analyses and clinical guidelines to comprehensively evaluate the potential mechanisms, risk factors, potential predictive methods, and preventive strategies associated with liver injury induced by trastuzumab and its ADCs. EXPERT OPINION: Trastuzumab-related liver injury is uncommon but occurs more frequently with its antibody-drug conjugates, particularly trastuzumab emtansine (T-DM1), which can cause hepatopulmonary syndrome (HPS), nodular regenerative hyperplasia (NRH), and sinusoidal obstruction syndrome (SOS). Risk factors include dosage, treatment duration, and drug interactions. T-DM1 shows dose-dependent hepatotoxicity, while cytochrome P450 3A4 (CYP3A4) inhibitors may increase hepatic accumulation of trastuzumab deruxtecan (T-DXd). Trastuzumab mainly induces hepatocellular and cholestatic injury, whereas T-DM1 involves both HER2-dependent and independent pathways. Diagnosis relies on causality assessment, and most cases are reversible with liver function monitoring and timely dose adjustment.