Abstract PS1-13-11: Personalized Whole-Genome-Based ctDNA Dynamics During Neoadjuvant Therapy Across Breast Cancer Subtypes: Early Insights From MONITOR-Breast

Abstract Introduction In patients with breast cancer who receive neoadjuvant treatment, therapy adjustments are primarily guided by predefined imaging and clinical assessments. Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) testing offers a real-time approach to evaluate treatment response and inform escalation or de-escalation strategies. Prior studies have generally examined binary MRD status at sparse timepoints, resulting in limited resolution and a lack of quantitative data on treatment response. The MONITOR-Breast study employs an ultrasensitive, whole-genome sequencing (WGS)-based assay with frequent ctDNA sampling across the neoadjuvant period. Here, we report initial results from an exploratory analysis of this multi-center, prospective study, and provide a quantitative, high-resolution dataset on ctDNA dynamics. Methods: Patients with stage I-III breast cancer of any subtype who were planning to receive neoadjuvant chemotherapy were prospectively enrolled in MONITOR-Breast. WGS of core needle biopsy tissue from the primary tumor was used to design individualized capture panels with up to 1,000 tracking variants (Precise® MRD, Myriad Genetics). Plasma was collected before treatment initiation, prior to each neoadjuvant chemotherapy cycle, after completion of neoadjuvant therapy, up to 7 days before or 3 days after surgery, and approximately 3 weeks after surgery. Subtype and treatment-specific ctDNA trajectories were assessed relative to imaging and pathologic response (complete pathologic response (pCR) vs residual disease (RD)). Results At the time of analysis, 87 patients with available MRD results were enrolled. Subtypes included HR+/HER2- (n=21), HR+/HER2+ (n=22), HR-/HER2+ (n=10), and triple-negative breast cancer (TNBC, n=34). Clinical stage distribution was I (n=24), II (n=48), and III (n=15). Most patients presented with a single primary tumor (n=83); four had multiple primaries. Histological subtypes comprised invasive ductal carcinoma (n=80), invasive lobular carcinoma (n=6), and mucinous carcinoma (n=1). 734 plasma samples were analyzed, ranging from 1 to 15 timepoints per patient (median=10). Neoadjuvant treatments included chemotherapy (n=85), HER2-targeted therapy (n=33), and immunotherapy (n=37). Follow-up time ranged from 4 to 29 months (median=14). 44 patients had undergone surgery with documented pathologic response. Panels were successfully designed for 80 of 87 patients (92%). Baseline ctDNA, prior to any treatment initiation, was detected in 74 of 80 (92.5%) patients, with the following distribution of tumor fractions: >100 parts per million (PPM) (77.0%), 20-100 PPM (16.2%), and <20 PPM (6.8%). ctDNA levels showed a rapid decline across chemotherapy cycles; at cycle 2, fewer than half (45%) remained ctDNA+ (19% at <20 PPM), decreasing to 25% by cycle 4 (56% at <20 PPM). At the time of surgery, 13% were ctDNA+, one at >100 PPM and the rest at <20 PPM. All patients achieving pCR (n=22) were ctDNA- at surgery, while 28.6% (n=4) of patients with RD were ctDNA+ at surgery. Patients achieving pCR typically demonstrated early response with sustained ctDNA clearance, while persistent or re-emergent ctDNA was associated with RD. HER2+ and TNBC tumors demonstrated faster clearance compared to HR+ tumors. Conclusions Ultrasensitive, personalized ctDNA monitoring enables high-resolution tracking of neoadjuvant treatment response. Early ctDNA clearance was strongly associated with pCR, supporting its potential as a biomarker for treatment de-escalation, whereas persistent ctDNA positivity may identify patients at risk of RD. Together, these findings establish the feasibility and clinical relevance of integrating ultrasensitive ctDNA assays into real-time neoadjuvant treatment management. Citation Format: J. Foldi, G. Hogan, M. LaBella, B. Mabey, M. Balic, D. Muzzey, K. Johansen Taber, J. Jasper. Personalized Whole-Genome-Based ctDNA Dynamics During Neoadjuvant Therapy Across Breast Cancer Subtypes: Early Insights From MONITOR-Breast [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 PS1-13-11.