Abstract Purpose: Detection of circulating tumor DNA (ctDNA) in patients who have completed treatment for early-stage breast cancer is associated with a high risk of relapse, yet the optimal assay for ctDNA detection is unknown. Experimental design: The cTRAK-TN clinical trial prospectively used tumor informed digital PCR (dPCR) assays for ctDNA molecular residual disease (MRD) detection in early-stage triple negative breast cancer. We compared tumor informed dPCR assays with tumor informed personalized multi-mutation sequencing assays in 141 patients from cTRAK-TN. Results: MRD was first detected by personalized sequencing in 47.9% of patients, 0% first detected by dPCR, and 52.1% with both assays simultaneously (p<0.001, Fisher’s exact test). The median lead time from ctDNA detection to relapse was 6.1 months with personalized sequencing and 3.9 months with dPCR (p=0.004, mixed effects Cox model). Detection of MRD at the first timepoint was associated with a shorter time to relapse compared with detection at subsequent timepoints (median lead time 4.2 vs 7.1 months, p=0.02). Conclusions: Personalized multi-mutation sequencing assays have potential clinically important improvements in clinical outcome in the early detection of MRD.