Real-world cardiotoxicity with HER2 antibody–drug conjugates and survival after treatment continuation.

1057 Background: HER2 antibody–drug conjugates (ADCs) are central to HER2-positive breast cancer (BC) treatment, yet cardiotoxicity remains a clinically relevant complication that may prompt treatment interruption. While HER2-related cardiac dysfunction is frequently reversible, uncertainty persists regarding the safety and survival impact of treatment continuation, particularly with newer ADCs. We assessed real-world cardiotoxicity and the association between treatment continuation and overall survival (OS), focusing on trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1). Methods: Using the TriNetX Research Network (2010–2025), adults with BC treated with HER2-targeted therapy and no prior diagnosis of heart failure or cardiomyopathy were identified. Incident cardiotoxicity (heart failure or cardiomyopathy) within one year of therapy initiation was captured. OS from cardiotoxicity diagnosis was compared between patients (Pts) who resumed versus discontinued HER2-targeted therapy. Kaplan–Meier methods were used to estimate survival, and Cox proportional hazards models generated hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Among 31,656 HER2-treated Pts, 4,593 (14.5%) developed cardiotoxicity within one year; 629 (11.1%) occurred with HER2 ADCs. Incidence was lower with ADCs than non-ADC therapy (T-DM1 11.6%, T-DXd 9.9%). After cardiotoxicity, 3,374 Pts (73.5%) resumed HER2 therapy, including 48.5% with T-DM1 and 47.7% with T-DXd. 5-year OS was significantly higher with HER2-targeted treatment resumption versus discontinuation (79.5% vs 66.9%; absolute difference 12.6%; p<0.0001), with a 55% mortality risk reduction (HR 0.45, 95% CI 0.39–0.51). ADC-specific analyses showed benefit, greatest for T-DXd (HR 0.25, 95% CI 0.14–0.43; absolute 5-year OS difference 19.3%) and T-DM1 (HR 0.34, 95% CI 0.23–0.50; absolute difference 21.0%). Pts who resumed therapy were younger than those who discontinued (58.0±13.1 vs 61.8±13.5 years). After multivariable adjustment, treatment resumption remained independently associated with improved OS (adjusted HR 0.45, 95% CI 0.39–0.51), though residual confounding cannot be excluded. Conclusions: In this large real-world cohort, continuation of HER2 ADCs after cardiotoxicity was associated with substantially improved OS. These findings support a multidisciplinary cardio-oncology approach and suggest that, when feasible, resuming HER2 ADCs—particularly T-DXd and T-DM1—may confer meaningful survival benefit. Cardiotoxicity and survival outcomes with HER2/ADCs. Agent Total Treated (N) Cardiotoxicity (%) Therapy Resumed (%) 5-year OS % (Resumed vs Not) Absolute OS Difference HR (95% CI) All HER2 31,656 14.5 73.5 79.5 vs 66.9 +12.6% 0.44(0.39-0.51) T-DM1 4,085 11.6 48.5 74.9 vs 53.9 +21.0% 0.34(0.23-0.50) T-DXd 1,558 9.9 47.7 48.0 vs 28.7 +19.3% 0.25(0.14–0.43)