Abstract PS2-10-19: Circulating tumor DNA (ctDNA) as a strong prognostic biomarker of minimal residual disease (MRD) using a tissue-free, epigenomic assay in early-stage breast cancer

Abstract Background: ctDNA may serve as an early biomarker of recurrence and could facilitate identification of patients with asymptomatic distant metastasis who might benefit from early treatment intervention. Here, we utilized a tissue-free, epigenomic assay for the detection of ctDNA in patients with early-stage breast cancer. Patients and Methods: Plasma samples were analyzed in 359 patients with stage I-III breast cancer who were enrolled in the SUCCESS-A phase 3 clinical trial (NCT02181101). All plasma samples were collected approximately two years after completion of adjuvant chemotherapy from patients without evidence of prior disease recurrence. In this updated analysis of a previously presented study, samples were re-analyzed using the Guardant Reveal assay featuring an updated bioinformatics algorithm for ctDNA detection. This algorithm was independently trained and validated in breast cancer samples. The primary objective of the ctDNA analysis was to predict distant metastatic recurrence from a single post-treatment time point in patients with early-stage breast cancer. Results: Out of 359 samples tested, 313 (87.2%) were evaluable; 46 samples failed quality control (QC) due to low plasma cfDNA levels and low ctDNA enrichment. The ctDNA positivity rate was 5.8% (18/313), and ctDNA positivity was strongly associated with worse outcomes, including a significantly shorter distant recurrence-free interval (HR 33.3, 95% CI 4.12-268, p0.0001) and poorer overall survival (HR 27.3, 95% CI 1.15-647, p0.0001). The sensitivity for distant recurrence in patients who had a sample collected within one year of recurrence was 73% (11/15). Of all ctDNA-positive samples, 94% (17/18) were from patients who subsequently developed a distant recurrence, with ctDNA detected at a median interval of 7.9 months prior to recurrence. The negative predictive value for distant recurrence was 93% (274/295), and the specificity was 99.6% (267/268). Conclusion: Detection of ctDNA approximately two years after adjuvant chemotherapy was highly prognostic in this early-stage breast cancer cohort. These data support the conduct of treatment intervention trials for patients with molecular relapse and negative staging for distant metastases to demonstrate clinical utility. Citation Format: W. Janni, B. Rack, P. A. Fasching, A. Hartkopf, H. Tesch, R. Lorenz, G. Heinrich, J. Blohmer, T. Fehm, V. Müller, A. Schneeweiss, M. W. Beckmann, M. Rübner, N. Harbeck, K. Pantel, D. Dustin, M. Cai, T. W. Friedl. Circulating tumor DNA (ctDNA) as a strong prognostic biomarker of minimal residual disease (MRD) using a tissue-free, epigenomic assay in early-stage breast cancer 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 PS2-10-19.