Abstract Background: Current research on circulating tumor DNA (ctDNA) in the adjuvant setting of early breast cancer (eBC) highlights its strong prognostic significance. Patients who are ctDNA-positive but show no radiological signs of relapse (i.e., molecular relapse) exhibit reduced disease-free and overall survival. Secondary adjuvant intervention studies with potent therapeutics represent an innovative and promising approach to intercept molecular relapase. Study Design: The SURVIVE HERoes study is a phase III randomized clinical trial comparing the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) to standard of care (SoC) in patients with molecular residual or recurrent disease. Patients tested positive for ctDNA in a tumor-informed approach (RaDaR®) are eligible, if staging examinations do not show any residual or recurrent cancer. Participants must have HER2-positive or HER2-low eBC (hormone receptor (HR) positive or negative) and have completed primary therapy (operation (R0) ± chemotherapy ± radiation). A total of 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). 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. Endpoints: 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, and as of July 2025, two sites are actively recruiting. 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. Funding: AstraZeneca, NeoGenomics Inc., Menarini Silicon Biosystems, Tosoh Bioscience Citation Format: K. Pfister, T. W. Friedl, S. T. Huesmann, S. Heublein, H. Schäffler, F. Mergel, F. Mehmeti, A. Fink, T. Braun, T. N. Fehm, V. Müller, L. Wiesmüller, K. Pantel, B. Rack, A. D. Hartkopf, C. Pipinikas, A. Chevalier, P. A. Fasching, W. Janni. The SURVIVE HERoes study NCT06643585: Targeting molecular relapse in breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-28.
Pfister et al. (Tue,) studied this question.