Personalized whole-genome–based ctDNA dynamics during neoadjuvant therapy across breast cancer subtypes: results from MONITOR-Breast

Purpose Pathological complete response (pCR) after neoadjuvant therapy (NAT) strongly associates with reduced breast cancer relapse risk. Circulating tumor DNA (ctDNA) shows promise as a therapy-response biomarker, but prior studies had limited sampling and assay sensitivity. MONITOR-Breast characterized ctDNA dynamics across NAT at high temporal resolution using an ultrasensitive molecular residual disease (MRD) assay.Experimental design In this prospective observational study, 154 enrolled patients with breast cancer (all subtypes, Stages I-III) were tested at baseline, throughout NAT, and post-surgery using a whole genome sequencing-based MRD assay tracking up to 1,000 variants per patient.Results Baseline ctDNA was detected in 93% of patients, with 20% detected in the ultrasensitive range (<100 parts per million). Post-NAT ctDNA positivity strongly associated with residual disease (RD) (odds ratio (OR)>20, p = 1 × 10−7) and post-operative positivity (OR =47, p = 1 × 10−6). All 56 patients with pCR and an evaluable sample had undetectable post-NAT ctDNA. Frequent testing revealed distinct patterns: 78% achieved rapid and/or sustained ctDNA clearance, while 22% exhibited persistent or intermittent positivity, and had significantly higher RD (OR =52, p = 3 × 10−9), and post-operative positivity (OR =25, p = 1 × 10−5).Conclusions Frequent, ultrasensitive ctDNA assessment provided comprehensive characterization of treatment response, revealing opportunities for de-escalation in early responders and escalation in those with persistent ctDNA.