Abstract PS2-08-21: Circulating tumor DNA (ctDNA) Dynamics in Early-stage Breast Cancer Patients (pts) with Brain Metastases

Abstract Introduction: Brain metastases in breast cancer (BC) present significant clinical challenges. The utility of circulating tumor DNA (ctDNA) in detecting intracranial progression is not well established. This study investigated ctDNA kinetics before and after brain relapse from early-stage BC in pts undergoing routine surveillance with a tumor-informed ctDNA assay. Methods: To identify pts with brain metastases from early-stage breast cancer and relevant ctDNA timepoints, we utilized Natera’s proprietary real-world database, which is linked to Komodo's Healthcare Map® claims database and available results of tumor-informed ctDNA testing (SignateraTM, Natera, Inc.) from 2019 to 2024. Hormone receptor and HER2 status and date of relapse were inferred from ICD-10 claims codes associated with interventions and secondary neoplasms. We evaluated ctDNA kinetics before and after brain relapse, including relative timing of ctDNA positivity, ctDNA levels (mean tumor molecules (MTM)/mL), and ctDNA clearance after initiation of therapy. Results: We identified 77 pts with early-stage breast cancer who developed subsequent brain relapse, including 28 pts with brain-only metastasis (BOM) and 49 pts with brain and extracranial metastases (BM+ECM) at the time of initial metastatic diagnosis. Among 28 pts with BOM, TNBC was the most represented subtype (40%; 11/28), followed by HER2+ (32%; 9/28) and ER+/HER2- (28%; 8/28). BOM were diagnosed at a median of 21.2 months (range: 1.8 - 87.0) and BM+ECM at a median of 19.2 months (range: 1.21 - 90.4) after surgery. The overall ctDNA detection rate prior to relapse was 54% (15/28) for pts with BOM and 92% (45/49) for pts with BM+ECM. Median time from ctDNA detection to BOM was 3.21 months (range: 0.2 to 14.5 months) and to BM+ECM was 2.66 (range: 0.03 to 39.2 months), acknowledging that the timing of ctDNA assessments was not controlled in this real-world dataset. Median ctDNA level prior to BOM was 1.27 MTM/mL (range: 0.04 - 227) compared to a median of 47.7 MTM/mL (range: 0.09 - 3854) in pts with BM+ECM. Among pts with BOM with matching pre- and post-relapse timepoints (n=17), 9 pts were ctDNA positive prior to BOM; of these, ctDNA clearance was observed in 44.4% (4/9) following post-relapse treatment, while the remaining pts were persistently ctDNA-positive 55.5% (5/9). Eight pts were ctDNA negative at BOM, and 25% (2/8) converted to positive after the diagnosis of isolated brain relapse. Among 34 pts with BM+ECM and matching pre- and post-relapse ctDNA timepoints, 30 pts were ctDNA positive prior to BM+ECM; of these, 13.3% (4/30) achieved clearance following post-relapse treatment, and 86.6% (26/30) remained positive. Four pts were ctDNA negative at BM+ECM, and 25% (1/4) converted to ctDNA-positive after the diagnosis of BM+ECM. Conclusions: Our RWD study provides evidence that tumor-informed ctDNA test results were positive in 50% of early-stage BC pts with BOM and 90% of early-stage BC pts with BM+ECM prior to the date of metastatic relapse. As expected, median ctDNA levels were generally lower in those with BOM compared to BM+ECM. Our data confirm the utility of ctDNA to identify pts who are at high risk of relapse, and provide evidence that ctDNA can detect CNS-limited recurrences. Given the potential for CNS involvement in pts with BC, pts with ctDNA-positivity and negative extracranial scans should be considered for CNS imaging to exclude BOM. Citation Format: A. J. Xu, B. Dwivedi, E. Kalashnikova, J. Ortiz, J. McKenzie, A. Rodriguez, M. C. Liu, L. A. Huppert, C. K. Anders, N. U. Lin, S. L. Sammons. Circulating tumor DNA (ctDNA) Dynamics in Early-stage Breast Cancer Patients (pts) with Brain Metastases 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 PS2-08-21.