Background As part of the COGNITION diagnostic registry program, residual tumor material after neoadjuvant therapy (NAT) of patients with early breast cancer (eBC), who are still at high-risk for relapse after NAT, is analyzed by next generation sequencing to identify biomarkers and actionable alterations. This strategy aims to stratify patients for subsequent genomics-guided therapies to reduce the significant risk of metastatic dissemination and hence to improve disease-free survival. Patients and Methods COGNITION-GUIDE is a multicenter umbrella phase-II-trial to translate molecular biomarker profiles generated in the COGNITION platform into six molecular-guided post-neoadjuvant therapeutic options in addition to standard-of-care treatment. Patients can be allocated to immune checkpoint inhibition (PD-L1-antibody), PI3K inhibition, AKT inhibition, PARP inhibition, anti-Trop-2 antibody-drug-conjugate, HER2 inhibition or, in case of missing biomarkers, to observation for 12 months. The primary endpoint is invasive disease-free survival (IDFS) four years after surgery. Secondary endpoints include IDFS in each study arm separately, distant disease-free survival, overall survival and safety. 240 patients will be enrolled within four years. Conclusions The COGNITION-GUIDE trial, which was activated in June 2023 and will recruit in different centers in Germany, empowers a risk-adapted, biomarker-guided therapy escalation algorithm in eBC patients who are still at high risk of metastasis.