Systematic analysis and mechanistic investigation of cardiac adverse events associated with antibody-drug conjugates using FAERS database

Background: Antibody-drug conjugate (ADC), combining monoclonal antibodies with cytotoxic payloads through covalent linkers, is leading a new era of targeted cancer therapy. Despite its therapeutic success, cardiotoxicity has been a recognized concern in early approved ADCs such as trastuzumab, yet the cardiac safety profiles and mechanisms of recently approved ADCs remain poorly characterized. Assessing the nature of their cardiac events using the FDA Adverse Event Reporting System (FAERS) database is vital for risk assessment in surgical oncology. This study aimed to analyze cardiac adverse events related to ADCs in the FAERS database to detect cardiac risk signals, characterize clinical patterns, and investigate mechanistic pathways, ultimately informing risk mitigation strategies in clinical practice. Materials and methods: This systematic study analyzed FAERS data (Jan 2019-Sep 2023) for ADC-related adverse events. Adverse events were standardized using MedDRA terminology. Disproportionality analysis using the Reporting Odds Ratio (ROR) method was performed to identify ADC-related cardiac adverse events (cAEs). Potential risk factors were evaluated through logistic regression analyses. To understand the molecular basis, TCGA transcriptome data were analyzed to explore mechanisms of ADC-related cAEs. Results: Cardiac adverse events comprised 11.77% (range: 8.63%–23.50%) of all ADC-related reports from 2019 to 2023. 49 cAE categories were identified. The mean age of reports with ADC-related cAEs was 60 (±13) with 8.67% of reports having a fatal outcome. Breast cancer indications dominated. Combining ADCs with dexamethasone significantly reduced the risk of cardiac failure (ROR decreased from 3.18 to 0.85). ADC-related cAEs correlated with dysregulated HSP70 binding (R = 0.82, p = 4.66e-4) and heat shock protein pathways. Conclusions: This study underscores the importance of recognizing and managing the cardiac adverse events associated with ADC therapy. Our findings provide a nuanced understanding of the burden, risk factors, and potential biological mechanisms of ADC-related cAEs, which can inform clinical decision-making and guide the development of safer and more effective ADC therapies.