Circulating tumor DNA (ctDNA) is an emerging biomarker for the treatment of early breast cancer (EBC). We sought to evaluate a highly sensitive tumor-informed ctDNA assay in a real-world cohort of patients receiving neoadjuvant therapy (NAT) to assess clinical validity and explore prognostic outcomes. ctDNA is detected in 77.2% (88/114) of participants at baseline, with 18/88 (20.5%) having a baseline estimated variant allele frequency (eVAF) of <
0.01%. Persistent detection of ctDNA, measured midway through NAT (mid-NAT), is associated with disease recurrence in all participants, reaching statistical significance in those with HER2-negative disease. Stratified analyses demonstrate that ctDNA detected mid-NAT enhances the prognostic accuracy of the residual cancer burden (RCB) score for disease recurrence. Postoperative or follow-up detection of ctDNA demonstrates a 100% positive predictive value for disease recurrence, with a median lead time of 374 days (range: 13-1010 days). These data suggest that assays with high analytical sensitivity may improve baseline ctDNA detection in patients with EBC. The ability to replicate the prognostic association of ctDNA dynamics in a real-world cohort supports further investigation. Prospective trials incorporating ctDNA testing are warranted to assess and develop the clinical utility of ctDNA-guided treatment strategies.