Abstract Background: Detection of MRD after curative intent treatment may identify patients at high risk for recurrence. Most ctDNA-based MRD assays require a priori knowledge of genomic alterations from tumor tissue to achieve acceptable sensitivity and specificity. However, tissue availability may be limited in some patients with breast cancer, particularly following neoadjuvant therapy. Here we report results of a pilot study evaluating a plasma-only multiomic ctDNA MRD assay and its association with breast cancer recurrence. Methods: 47 plasma samples from 38 patients with early-stage breast cancer were collected through the BRandO BiO Registry at 12- or 36-months post-diagnosis and/or at the time of clinical recurrence. BRandO BiO is a multi-center regional registry with longitudinal biobanking from patients with newly diagnosed breast cancer at 20 affiliated network hospitals in Germany. The presence of ctDNA was evaluated using the Guardant Reveal multi-cancer assay, a next generation sequencing panel covering ~500 genes and ~4Mb of epigenomic regions that undergo differential methylation in multiple solid tumor types. The presence/absence of ctDNA is determined by a custom bioinformatics classifier that identifies tumor-derived somatic variants and methylation profiles specific to individual cancer types without the need for tumor tissue or peripheral blood mononuclear cell analysis. Samples were analyzed blinded to recurrence status.Results: 20 patients were confirmed to have clinical recurrence (7 local, 13 distant). ctDNA was detected at or prior to distant recurrence in 11/13 (85%) patients and in 1/7 (14%) patients with local recurrence. Five patients with distant recurrence had a sample available that was collected prior to distant recurrence; ctDNA was detected in 4/5 with a 3.8-18.6 month lead time. Among 15 ctDNA+ samples, 5 were positive for both methylation and somatic variant calls, 1 by somatic variants only, and 9 by methylation only. Somatic mutations were identified in AKT, RB1, KRAS, PIK3CA, ERBB2, MAP3K1, GATA3, and ESR1. The ESR1 mutation occurred in a patient with endocrine therapy resistance, confirming the ability of the assay to identify acquired treatment resistance mutations. ctDNA was not detected in samples from the 14 patients who had no confirmed clinical recurrence (100% specificity). Conclusions: This is the first study to demonstrate the feasibility of MRD detection in breast cancer using a plasma-only multiomic ctDNA-based approach. The Guardant Reveal assay demonstrated high sensitivity and specificity to detect distant breast cancer recurrence. Larger studies in this population are ongoing to further validate the clinical performance of the assay and demonstrate its applications in the management of early-stage breast cancer. Citation Format: Wolfgang Janni, Jens Huober, Tatjana Braun, Volkmar Müller, Angelina Fink, Amelie de Gregorio, Brigitte Rack, Thomas W. Friedl, Lisa Wiesmüller, Klaus Pantel, Thereasa Rich, Princy Parsana, Elena Zotenko, Shile Zhang, Sophia Huesmann. Multiomic, plasma-only circulating tumor DNA (ctDNA) assay identifies breast cancer patients with minimal residual disease (MRD) and predicts distant recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3403.