Safety of withdrawal of pharmacological treatment after recovery from HER2 therapy-related cardiac dysfunction: the HER-SAFE trial

BACKGROUND: Heart failure therapy (HFT) is routinely continued in breast cancer survivors after recovery from anti‐HER2 cancer therapy‐related cardiac dysfunction (CTRCD), despite limited evidence. HER‐SAFE is the first randomised trial to assess HFT withdrawal in this population. METHODS: In this open‐label, multicentre, randomised controlled trial, breast cancer survivors with recovered anti‐HER2 CTRCD (asymptomatic, left ventricular ejection fraction [LVEF] ≥50%, normalised biomarkers) were randomised to HFT withdrawal or continuation. Antecedent CTRCD was mild (relative global longitudinal strain [GLS] decline >15%, LVEF ≥50%), moderate (LVEF fall >10% to <50%), or severe (LVEF <40%). The primary endpoint was a moderate or severe CTRCD event over 12 months analysed by intention to treat; secondary endpoints included serial cardiac function, biomarkers, and quality of life. RESULTS: Between July 2023 and June 2025, 90 patients were randomised (all female; median age 50 years [IQR 43‐59]; median 17.3 months [IQR 7.7‐33.2] since CTRCD recovery; HFT predominantly renin‐angiotensin system inhibitors [98%] and beta‐blockers [88%]) ‐ 46 randomised to HFT withdrawal (1 lost to follow‐up) and 44 to continuation. The primary endpoint occurred in 1 of 45 with withdrawal (moderate asymptomatic CTRCD) versus 0 of 44 with continuation (between‐group difference 2.2pp; 90% CI upper limit 9.4pp). No cardiovascular deaths, heart failure hospitalisations or symptomatic CTRCD occurred. Cardiac magnetic resonance‐derived LVEF remained stable in both arms at 12 months (between‐group difference ‐0.8% [‐2.0 to +0.4], p=0.21). CONCLUSIONS: Among breast cancer survivors with recovered anti‐HER2 CTRCD, HFT withdrawal was not associated with symptomatic events or significant between‐group difference in LVEF at 12‐months.