Abstract 6815: Biologic processes enriched in the primary tumors of invasive breast cancer patients with disseminated tumor cells

Abstract Background: Disseminated tumor cells (DTCs) can persist despite systemic therapy and drive distant recurrence, a major cause of breast cancer-related mortality. Objective: To identify biologic processes enriched in the primary tumors of invasive breast cancer patients with DTCs detected at the time of their breast cancer diagnosis. Methods: We performed tumor-normal whole-genome sequencing and bulk RNA sequencing on matched tumor and blood specimens from 65 patients with newly diagnosed invasive breast cancer who underwent bone marrow biopsy at diagnosis to assess DTC status. Mutational signatures were identified using SigProfilerExtractor. Differential expression and gene set enrichment analyses were conducted with DESeq2. Pathways were defined using MSigDB hallmark gene sets. Genes with Bonferroni-adjusted p < 0.05 and |log2 fold change| > 1 were considered significantly differentially expressed. Analyses were adjusted for tumor purity, tissue source, stage, age, and neoadjuvant therapy. Results: Among 41 DTC-positive and 24 DTC-negative patients, DTC-positive tumors were more likely to harbor intronic somatic mutations in MARCHF1 (78.7% vs 56%, p = 0.001) and MARCHF4 (31.9% vs 4%, p = 0.007). Mutations in genes within the WNT and RTK-RAS signaling pathways were more frequent in DTC-positive tumors (WNT: 43.5% vs 27.1%, p = 0.037; RTK-RAS: 43.5% vs 27.1%, p = 0.011). Gene set enrichment revealed upregulation of E2F targets and G2M checkpoint pathways in DTC-positive tumors (normalized enrichment score = 2.12, p = 0.01; 2.04, p = 0.01, respectively). Individual genes enriched in DTC-positive patients included HAVCR1, TRIM55, MUC13, and KCNJ12. Recurrent somatic mutations in canonical breast cancer genes (PIK3CA, TP53, GATA3, CHD1, MAP3K1) and mutational signatures associated with APOBEC activity and homologous recombination deficiency occurred similarly across DTC-positive and DTC-negative patients. Conclusion: Primary tumors of patients with bone marrow DTCs at diagnosis exhibit upregulation of proliferative programs and increased mutation burden in WNT and RTK-RAS signaling genes. These findings highlight candidate biological pathways in the primary tumor that may facilitate early dissemination and persistence of DTCs. Citation Format: Katherine Anne Lawson-Michod, Taleb Ahsan, Keara Malone, Bailey Harmon, Megan Stackouse, Paul Seth, Michael C. Haffner, Matthew Fitzgibbon, Alexander Zevin, Arun Paul Wiita, Jayanta Debnath, Katherine E. Varley, Alana L. Welm, Stanley Riddell, Cyrus M. Ghajar, Christopher I. Li. Biologic processes enriched in the primary tumors of invasive breast cancer patients with disseminated tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6815.