COGNITION: Genomics-Guided Precision Oncology in Early High-Risk Breast Cancer

* Patient registration and enrolment: pts with histologically confirmed early breast cancer and indication for neoadjuvant chemotherapy (NACT, any subtype) who give their consent for the integrative genomic profiling study as pre-requisite for molecular stratification in the coupled phase II COGNITION-GUIDE (NCT05332561) therapy trial. * Collection of biomaterial: Fresh-frozen tumor tissue from primary breast tumors is collected during routine procedures at study entry (T1: baseline-treatment naive) and from residual bulk tumors (T2: w/o pCR after NACT). To account for germline alterations (genomic control) and to fuel companion programs, consecutive blood samples are taken at baseline (V1) and after NACT (V2). * Processing and analyses of patient samples: Biomaterials are centrally processed (standard histology/IHC and pathology review for tumor content; analyte extraction, QC according to standardized, quality-controlled, accredited workflows. Molecular profiling \& clinical bioinformatics: Genomic profiling encompasses Whole-Genome on fresh-frozen tissue biopsies or Whole-Exome on FFPE surgical specimens (if fresh-frozen tissue has insufficient tumor cell content \>20%). Both options are complemented by RNA-Seq facilitating an unbiased integrated view on the expression of multiple biomarkers. * Clinical curation and data interpretation: Based on the curative intent, a rigorous, pre-defined biomarker algorithm (strong and soft biomarkers) is applied. This strategy allows assessment whether the tumor profile qualifies for one of the molecular-guided treatment arms. * Molecular Tumor Board (MTB): Molecular data are interpreted by clinicians, bioinformaticians, molecular biologists, human geneticists and pathologists in a weekly interdisciplinary MTB established at NCT. Treatment-relevant biomarkers and actionable drug targets are validated independently. Disease-relevant germline alterations will lead to genetic counselling. * Treatment recommendations and therapy implementation: Conclusive biomarker profiles from clinical, histopathological and genomic data drive assignment to one treatment arm. Therapeutic options are prioritized within a molecular report. * Patient Monitoring / Follow-Up: Comprehensive documentation will be conducted at study entry and every 6 mths for 10 years. * Pre-Clinical Companion Programs: The valuable pre- and post neoadjuvant biomaterial will be exploited to fuel collaborative studies around therapy failure, biomarker development and tracking of residual cancer burden in liquid biopsies (ctDNA).