Abstract PS2-09-20: Circulating Tumor DNA Dynamics and Anatomical Patterns of Relapse Following Curative Therapy in Early-Stage Breast Cancer

Abstract Background: Predicting the anatomical patterns of relapse after an initial diagnosis of early-stage breast cancer (BC) and understanding their association with circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection by tumor subtype and treatment history may inform surveillance strategies and enable earlier therapeutic intervention. Methods: This retrospective study explored the association between sites of relapse and ctDNA detection rates and dynamics in a real-world cohort (2019-2024) of patients (pts) with early-stage BC. We utilized Natera’s proprietary real-world database linked to Komodo's Healthcare Map® claims database and results of tumor-informed ctDNA testing (SignateraTM, Natera, Inc.). Hormone receptor (HR), HER2 status, and the date of relapse were inferred from the claims codes associated with interventions and secondary neoplasms (i.e., metastases). Pts with a diagnosis code of secondary neoplasms were categorized by the anatomic site(s) of recurrence. ctDNA detection rate (required time points: ctDNA positivity within 6 months prior to relapse; for ctDNA-negative pts, three or more time points were included), and dynamics were analyzed in relation to subtype and relapse site. Results: Evaluation of Natera's real-world database identified 532 pts with early-stage breast cancer who developed subsequent distant metastatic disease. The distribution of patients by subtype was: HR+/HER2-: 52% (276/532), triple-negative (TNBC): 34% (182/532), and HER2+: 14% (74/532). Among pts with isolated relapses (N=259), the most common sites were bone (HR+HER2-: 59%; 82/138, HER2+: 36%; 14/39 TNBC: 30%; 25/82) and lung (HR+HER2-:16%; 22/138, [HER2+: 31%; 12/39, TNBC: 34%; 28/82), concordant with common sites of metastasis by subtype. Relapses occurred within a median of 1.84 years (yrs) after surgery, varying by subtype (TNBC: 1.33 yrs, HER2+: 1.92 yrs, HR+HER2-: 2.41 yrs). Among pts with required timepoints (77%, 411/532), ctDNA was detectable prior to/at the time of recurrence in 91% (373/411) of cases; 90% (130/145) for TNBC, 90% (187/208) for HR+HER2- and, 97% (56/58) for HER2+ disease. For the subset of patients with an isolated relapse, the rate of ctDNA positivity at the time of recurrence was the highest for liver (100%; 23/23), followed by bone (93%; 95/102) metastases. In terms of ctDNA quantification, median ctDNA levels differed by subtypes, with TNBC showing the highest levels (16.4 MTM/mL, range: 0.03-17053) compared to HR+/HER2- (5.58 MTM/mL, range: 0.018-8343) and HER2+ (5.44 MTM/mL, range: 0.03-2879). ctDNA levels among secondary neoplasms prior to/at the time of recurrence were highest for multi-site relapses (median = 15 MTM/mL, IQR:1.5-143), followed by lung (median: 19.9, IQR: 1.5 - 82), bone (median: 5.6, IQR: 0.9-29), and liver (3.4, IQR: 0.52-76.8) only metastases. Serial ctDNA measurements preceding the date of secondary neoplasms showed rising ctDNA levels over time in 90% of cases, with the most rapid increase observed in TNBC. The cases that exhibited declining ctDNA levels without achieving clearance were predominantly HR+HER2- pts with bone metastases. Conclusions: Our findings highlight the potential utility of serial ctDNA monitoring in clinical practice to identify pts at high risk of relapse across multiple organ sites, including isolated progression in individual organs. These findings could potentially inform future ctDNA-guided intervention strategies, including increased surveillance by imaging for pts with ctDNA positivity. Citation Format: D. Stover, B. Dwivedi, P. Dutta, S. Beyer, H. LeFebvre, E. Kalashnikova, J. McKenzie, A. Rodriguez, M. Liu. Circulating Tumor DNA Dynamics and Anatomical Patterns of Relapse Following Curative Therapy 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 PS2-09-20.