Tissue-free minimal residual disease evaluation and clinical utility in early breast cancer: A real-world study.

3052 Background: Minimal residual disease (MRD) detected using circulating tumor DNA (ctDNA) is associated with increased breast cancer (BC) relapse risk in patients (pts) with early BC after curative-intent surgery. However, the clinical utility of ctDNA-based MRD testing for post-surgical surveillance and risk stratification remains incompletely defined. We used real-world data to evaluate the performance of Guardant Reveal, a tissue-free epigenomic assay for MRD detection, and the clinical significance of a positive MRD test (+MRD) in pts with resected early BC. Methods: Data of pts with resected stage I-IIIA BC in the Guardant InfinityAI Data Library who underwent Guardant Reveal testing between February 2023 and September 2025 was analyzed. Pts with ≥1 post-surgical MRD were included if they had either no distant metastatic BC recurrence with ≥1 year of follow up after the last MRD test or a documented distant metastatic BC postoperatively; pts with a new non-breast primary malignancy were excluded. Sensitivity was assessed by site of distant metastasis and interval from MRD test to recurrence; nodal recurrences were excluded due to claims data limitations. Specificity was assessed using all tests from pts without recurrence and ≥1 year of follow up after the last post-treatment MRD test. Claims data were used to infer treatment changes following +MRD. Results: A total of 822 pts was analyzed. 114 pts with real-world clinico-genomics data were evaluable for sensitivity and 708 for specificity. One-year sensitivity for distant metastatic recurrence was 71%, and was highest for bone-only (97%, 35/36 cases) or lung (89%, 8/9 cases) recurrences and lowest for brain-only recurrences (33%, 1/4 cases). Sensitivity within 12 months of recurrence was higher in hormone receptor-positive (HR+)/HER2-negative BC (79%) and stage IIIA BC (81%) and for multiple-organ versus single-organ metastasis (83% versus 69%). Sample-level specificity was 94%. Following +MRD, 41 pts did not initiate or switch systemic therapy; 29 had distant BC recurrence, including 24 within 90 days after +MRD. Twenty pts switched therapy within 90 days of +MRD; 19 recurred, including 17 within 90 days after +MRD. Among 10 pts with post-recurrence MRD testing, only 3 had +MRD. Conclusions: In a real-world cohort of pts with resected early-stage BC, a tissue-free epigenomic ctDNA MRD assay demonstrated high specificity and clinically meaningful sensitivity for distant metastatic recurrence, particularly for bone-only and lung metastases and in pts with HR+ BC. These findings support ctDNA-based MRD testing as a noninvasive tool for postsurgical surveillance and risk stratification in early BC.