Abstract PS4-02-02: Ultrasensitive ctDNA-based MRD monitoring predicts relapse in postoperative HR+ inflammatory breast cancer

Abstract Background: Inflammatory breast cancer (IBC) is a rare, aggressive subtype characterized by rapid progression and a high risk of relapse despite curative-intent therapy. Outcomes are particularly poor for patients with residual disease following neoadjuvant treatment. Circulating tumor DNA (ctDNA)-based assays offer a noninvasive means of detecting minimal residual disease (MRD) and may enable real-time, risk-adapted decisions regarding adjuvant therapy. However, feasibility and performance data for personalized ctDNA monitoring in IBC remain limited. Methods: We prospectively enrolled adults with hormone receptor (HR)-positive (≥10% ER or PR) stage III IBC who did not achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy to a single-arm phase II trial (NCT02971748). Eligible patients had no prior immunotherapy or active autoimmune disease and received pembrolizumab 200 mg IV every three weeks plus physician-chosen endocrine therapy for up to 24 months, starting during or after radiation. The primary endpoint was 2-year event-free survival (EFS); secondary endpoints included safety, toxicity, and overall survival (OS). As an exploratory analysis, the Myriad Precise ultrasensitive MRD assay was used to perform whole-genome sequencing of paired tumor/normal DNA and to subsequently design 1,000-variant capture panels. Plasma was collected postoperatively, serially during therapy, and at end-of-treatment (EOT) for ctDNA analysis. Quantitative tumor fraction (TF) and quality control (QC) metrics were tracked longitudinally. Results: Of 23 enrolled patients, 19 (83%) provided sufficient tumor or normal tissue for personalized panel design. A total of 153 out of 154 plasma samples (99%) passed all quality control (QC) metrics. ctDNA was detected in 42 of 154 samples (27%), with 23 (96%) ctDNA-positive calls below 0.01% tumor fraction (TF), underscoring the need for ultrasensitive detection. One patient who cleared ctDNA detection early remains recurrence-free (early molecular clearance). Two patients who were negative at baseline became MRD positive 10 and 15 months prior to clinical progression. For all patients with disease progression <24 months, we observed persistent and rising ctDNA levels ahead of radiographic relapse with lead times up to 18 months. In contrast, all patients who were MRD negative at the post-operative baseline and throughout treatment remained progression-free at 24 months. Correlative analyses of baseline MRD status and end-of-treatment (EOT) conversion patterns with EFS and overall survival (OS) are ongoing and will be presented. Conclusions: Personalized ctDNA MRD testing is feasible and highly sensitive in the postoperative HR-positive IBC setting, with >99% QC pass rate and detection capability below 0.001% TF. Preliminary data show that ctDNA kinetics correlate with clinical outcomes and ctDNA detection often precedes radiographic relapse by months. These findings support incorporating MRD monitoring into adjuvant trials for real-time therapeutic adaptation in high-risk breast cancer. Citation Format: R. Upadhyay, A. Alexander, Q. Ye, K. Chen, C. Yam, G. J. Hogan, S. Zhang, M. L. LaBella, S. Ratzel, The MDACC Inflammatory Breast Cancer Team, A. Lucci, W. A. Woodward, B. Lim. Ultrasensitive ctDNA-based MRD monitoring predicts relapse in postoperative HR+ inflammatory 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 PS4-02-02. Acknowledgments: The participants included in the current project were recruited through a Merck supported investigator-initiated trial (NCT02971748). The WGS and ctDNA analyses were performed by the Myriad and MDACC teams through a Myriad and MDACC strategic alliance. The Morgan Welch IBC Research and Clinic Program is funded by Texas State.