Abstract Background: Breast cancer constitutes approximately 30% of cancers in women, with a mortality-to-incidence ratio of 15%. While early and middle-stage breast cancer patients can undergo radical surgical resection, postoperative recurrence remains a significant challenge for clinicians. Molecular residual disease (MRD) is the main cause of postoperative recurrence of breast cancer. However, the baseline tumor genomic characteristics and therapeutic implications of breast cancer patients with detectable MRD are still unknown. Methods: In this study, we enrolled 80 patients with breast cancer who underwent next-generation sequencing (NGS)-based genetic testing of 1,021 cancer-related genes performed on baseline tumor and postoperative plasma from Army Specialty Medical Center between June 2017 and January 2023. The criteria for the patient’s enrollment were: (1) pathological diagnosis as breast cancer, (2) no distal metastasis, (3) radical surgery and R0 resection, (4) 1021 cancer-related gene testing of the tumor, (5) plasma MRD testing performed within 3 months after surgery and before adjuvant therapy. Results: A total of 18 patients in our cohort had detectable MRD. Baseline clinical characteristics found that patients with higher clinical stages were more likely to have detectable MRD. Analysis of single nucleotide variations and small insertions/deletions in baseline tumors showed that somatic mutations in MAP3K1, ATM, FLT1, GNAS, POLD1, SPEN, and WWP2 were significantly enriched in patients with postoperative MRD. Oncogenic signaling pathway analysis revealed that alteration of the Cell cycle pathway was more likely to occur in patients with detectable MRD (p=0.0125). Mutational signature analysis showed that defective DNA mismatch repair and activation-induced cytidine deaminase (AID) mediated somatic hypermutation (SHM) were associated with detectable MRD. Somatic copy number variation analysis found that amplification of CDKN2A, HOXB13, PPM1D, MPL, and VHL was significantly enriched in patients with detectable MRD. According to the OncoKB database, 77.8% (14/18) of patients with detectable MRD had U.S. Food and Drug Administration-approved mutational biomarkers and targeted therapy. Conclusion: For the first time, our study reports genomic characteristics of breast cancer patients with detectable MRD. The tumor biology is probably the main driver of detectable MRD. We also found the vast majority of patients with detectable MRD have the opportunity to access targeted therapy. Keywords: Breast cancer, MRD, Genomic character, Cell cycle pathway, Defective DNA mismatch repair, Activation-induced cytidine deaminase Figure 1. Somatic mutational landscape and clinical actionability of breast cancer patients with detectable MRD A. Oncoplot of top 20 genes altered in patients with detectable MRD. B. Forest plot of different mutant genes between patients with detectable and undetectable MRD. OR means odds ratio. Inf means infinity. * means P-value < 0.05. C. The ten cancer-related signaling pathways were affected by somatic mutations both in patients with detectable and undetectable MRD. * means P-value < 0.05. D&E. The fraction and etiology of each signature in patients with detectable (D) or undetectable (E) MRD. F. The number of patients with detectable MRD in different actionable alterations. gBRCA1 means germline BRCA1 mutation. sBRCA1 means somatic BRCA1 mutation. sBRCA2 means somatic BRCA2 mutation. TMB-H means TMB-High. Citation Format: Xu Yan, Shu Zhang, Lu zhou, Yan Jiang, Jing Xu, Gang Zhang, Lu Shen. Genomic characteristics and its therapeutic implications in breast cancer patients with detectable molecular residual disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-13-05.