Abstract Background: Despite advances in early detection and adjuvant therapy, metastatic recurrences of ER-positive/HER2-negative (ER+/HER2-) breast cancer account for over sixty percent of breast cancer-specific deaths. Circulating tumor DNA (ctDNA) has emerged as a highly sensitive and specific biomarker for identifying individuals at specific risk of metastatic recurrence. ctDNA detection (molecular residual disease, MRD) using a tumor-informed structural variant assay can anticipate clinical relapse with a high positive predictive value and long lead time. Capecitabine has clinical activity in ER+/HER2- disease and, when administered metronomically, exerts anti-angiogenic and immunomodulatory effects with a favorable safety profile. This trial will evaluate whether secondary adjuvant metronomic capecitabine can eradicate ctDNA in early-stage ER+/HER2- breast cancer as a surrogate for recurrence prevention. Eligibility Criteria: Adult patients (≥18 years) with resected stage I-III ER+/HER2- breast cancer with ctDNA+ MRD (Pathlight, SAGA Dx) identified through the in Circulating Liquid biomarkers for Assessment and Identification of Recurrence in Early breast cancer (CLAIRE) study (NCT05196087), ECOG PS 0-1, completion of ≥24 months of endocrine therapy (and ≥12 months of CDK4/6 inhibitor, if indicated), adequate organ function and no clinical or radiographic evidence of recurrence will be enrolled in this single arm interventional trial. Methods: This is an open-label, non-randomized Simon two-stage Phase II study enrolling up to 13 evaluable MRD+ patients (up to 15 enrolled to account for dropouts). The primary endpoint is ctDNA clearance at week 16 (ctDNAwk16=0) as measured by the Pathlight assay. In stage I, eight participants receive metronomic capecitabine 500 mg orally TID for up to 12 months; if ≥2 of 8 have ctDNA clearance at week 16, stage II will enroll five additional patients. Secondary endpoints include distant recurrence-free survival (DRFS), invasive disease-free survival (iDFS), overall survival (OS), and toxicity per CTCAE v5.0. Serial plasma for ctDNA and biobanking will occur with each cycle. Radiographic imaging will be performed every 4 months in year 1 and every 6 months thereafter. Follow-up for survival and ctDNA continues for up to 5 years. The Simon design tests P0 = 0.10 versus P1 = 0.40 with α = 0.05 and 80% power; interim analysis follows the first eight patients, with continuous accrual between stages. Aims: The primary aim is to evaluate the rate of ctDNA clearance 16 weeks following treatment initiation. Secondary aims are to describe clinical outcomes (DRFS, iDFS, and OS) and to assess the safety and tolerability of metronomic capecitabine in this setting. Exploratory aims include evaluation of ctDNA dynamics and analysis of tissue and plasma genomic features associated with ctDNA persistence or clearance. Conclusion: This proof-of-concept trial will determine whether ctDNA-guided secondary adjuvant therapy with metronomic capecitabine can result in ctDNA clearance in patients with ER+/HER2- breast cancer MRD, potentially preventing metastatic relapse. Findings will inform larger MRD-directed intervention studies aimed at transforming postoperative management, developing secondary adjuvant therapy strategies, and improving long-term outcomes. Clinical Trial Information: NCT05196087 Citation Format: M. J. Elliott, E. Amir, M. B. Nadler, M. Li, C. Yu, M. Audoin, G. Putcha, W. Levin, S. Birkeäl, K. Howarth, P. Bedard, L. L. Siu, H. Berman, C. Townsley, M. Wu, D. W. Cescon. Capecitabine for Targeted Eradication of aRising ctDNA Molecular Residual Disease in ER-positive/HER2-negative 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 PS5-09-28.
Elliott et al. (Tue,) studied this question.