Interception of molecular relapse in breast cancer: The SURVIVE HERoes study (NCT06643585).

TPS646 Background: Current research on circulating tumor DNA (ctDNA) in the adjuvant setting of early breast cancer (eBC) demonstrates its strong prognostic significance. Patients who are ctDNA-positive in the absence of radiological evidence of disease recurrence (i.e., molecular relapse) have significantly reduced disease-free and overall survival. Secondary adjuvant intervention trials employing highly potent therapeutic agents represent an innovative and promising strategy to intercept disease recurrence at the molecular stage. Methods: SURVIVE HERoes is a phase III, randomized clinical trial comparing the antibody–drug conjugate trastuzumab deruxtecan (T-DXd) with standard of care (SoC) in patients with molecular residual or recurrent disease. Eligible patients must have a positive circulating tumor DNA (ctDNA) result detected using a tumor-informed assay (RaDaR), while staging examinations show no evidence of residual or recurrent disease. Participants must have HER2-positive, HER2-low, or—following an approved study amendment—HER2-ultralow early breast cancer (eBC), irrespective of hormone receptor (HR) status, and must have completed primary therapy, including surgery with R0 resection, with or without chemotherapy and/or radiotherapy. 180 participants are randomized in a 2:1 ratio to receive T-DXd (+ endocrine therapy for HR positive patients) or standard of care for 48 weeks, followed by a 48-week follow-up phase. Stratification factors include hormonal receptor status (positive versus negative) and HER2-status (positive versus low versus ultralow). Staging examinations and ctDNA assessments will be performed every 12 weeks during the 2-year study phase per patient. The study is accompanied by a comprehensive translational research program. The primary endpoint is the ctDNA clearance rate after 48 weeks, comparing participants in the experimental arm (receiving T-DXd) with those in the control arm (receiving standard of care), irrespective of ctDNA test results at other time points. Secondary endpoints include invasive disease-free survival, overall survival, ctDNA clearance at other time points, safety, and quality of life (QoL), as assessed by EORTC QLQ-C30 and PA-F12. Recruitment: Recruitment began in Q2/2025 and is anticipated to continue until 2030. Fifty sites across Germany are planned for participation. Discussion: Treating ctDNA-positive patients without radiographic evidence of recurrence is a novel therapeutic strategy. If SURVIVE HERoes and similar studies targeting molecular relapse yield positive results, they could pave the way for a new molecularly driven personalized surveillance and treatment approach. Clinical trial information: NCT06643585 .