Abstract PS2-10-23: Circulating Tumor DNA Dynamics in Patients with Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer Assessed Using an Ultrasensitive Tumor-Informed Assay

Abstract PURPOSE Circulating tumor DNA (ctDNA) in early-stage breast cancer (EBC) is a prognostic biomarker for disease recurrence. ctDNA dynamics in the low shedding EBC subtype, hormone receptor-positive (HR+) human epidermal receptor 2-negative (HER2-) EBC are challenging to track, motivating the use of ultrasensitive ctDNA assays. In this study we used an ultrasensitive tumor-informed ctDNA assay to detect molecular residual disease (MRD) and its association with disease recurrence among patients with HR+/HER2-EBC who were receiving oncological treatment. METHODS Using a whole-genome sequencing tumor-informed assay that tracks up to 1800 mutations we assessed for MRD and ctDNA dynamics among patients with stage II-III HR+/HER2- EBC who provided serial plasma samples at varying intervals while receiving oncological therapy. MRD was defined as a plasma sample that tested positive for ctDNA with this assay. We then examined the association of ctDNA dynamics with disease recurrence. We defined lead time as the time interval between the first plasma sample that tested positive for ctDNA and the clinical detection of disease recurrence. RESULTS Of 28 patients who provided two or more serial plasma samples, 26 (93%) had tumor tissue suitable for DNA sequencing. The median follow-up time was 5.0 years from surgery (range, 2.3-10.8 years). Patient-specific ctDNA assays were designed to test 118 plasma samples (2-9 samples per patient). Eleven patients (42%) had MRD detected at one or more time points, with 58% of detections in the ultrasensitive range (100 parts per million). Six patients (23%) eventually experienced distant disease recurrence, all of whom had MRD detected prior to standard clinical detection of disease recurrence, with a median lead time of 1.5 years (range, 1.0-2.5 years). All 15 patients who remained persistently ctDNA-negative and 5 patients who experienced ctDNA clearance (from ctDNA-positive to ctDNA-negative) while receiving oncological treatment remained clinically recurrence-free throughout the follow-up of the study. CONCLUSION Using an ultrasensitive tumor-informed ctDNA assay, we found that all patients with HR+/HER2-EBC who eventually experienced distant disease recurrence had MRD detected prior to standard clinical detection, with a median lead time of 1.5 years, and ctDNA dynamics showed a strong correlation with oncological outcomes with 100% of patients that persistently or eventually cleared ctDNA remaining disease free, and 100% of patients that persistently or became ctDNA positive experiencing recurrence, with 100% sensitivity and specificity of this assay for disease recurrence. This assay appears to have the high sensitivity needed for this application and is being tested in large prospective trials. Citation Format: C. H. Barcenas, A. Contreras, A. Alexander, H. Lopez, R. Yu, S. Shete, Y. Chen, C. Abbott, K. Keough, S. M. Boyle, R. O. Chen, D. Tripathy, V. Valero. Circulating Tumor DNA Dynamics in Patients with Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer Assessed Using an Ultrasensitive Tumor-Informed Assay abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-10-23.