Copper plays a critical role in tumor progression through its interactions with enzymes driving extracellular matrix remodeling and angiogenesis. This study evaluated the impact of long-term copper depletion using tetrathiomolybdate (TM) in 75 high-risk breast cancer patients without evidence of disease following standard therapy. Patients received daily oral TM targeting a ceruloplasmin level ≤17 mg/dL, with serial monitoring of VEGFR2⁺ endothelial progenitor cells, hematologic markers, imaging, and clinical events. Event-free survival was 71.4%, and overall survival 64.7%, with improved survival observed across both triple-negative and other high-risk subgroups. Results support TM-induced copper depletion as a potential strategy for prolonging remission. However, mechanisms underlying improvement remain unclear. Ongoing investigations aim to characterize cytokine modulation, effects on matrix metalloproteinases, and biomarkers of collagen turnover to elucidate TM’s role within the tumor microenvironment.