Abstract PS5-07-23: Novel Targeting of the Microenvironment to Decrease Metastatic Recurrence of High-Risk TNBC: A Randomized Phase 2 Study of Tetrathiomolybdate (TM), an oral copper depletion agent plus capecitabine +/- pembrolizumab in patients wit

Abstract Triple-negative breast cancer (TNBC) accounts for only 17% of all breast cancer (BC) patients (pts), but 50% of metastasis-related deaths. Pts who complete neoadjuvant therapy and have significant residual disease at surgery are at highest risk with >60% relapse at 5 years (yrs) due to resistant disease. We and others have demonstrated that copper (Cu), an essential trace element, plays key roles in supporting TNBC resistance pathways [Ramchandani et al. Nat Comm 2021; Shanbhag et al PNAS 2019]. We completed a pilot phase 2 clinical trial of Cu-depletion with TM in 75 BC pts at a high-risk of relapse. We found that TM was safe, well tolerated and event-free survival (EFS) for TNBC pts is 88% for high-risk adjuvants (stage 3 BC) and 59.3% for stage 4 NED TNBC at a median follow-up of 10.4 yrs. We found that 3 components of the tumor microenvironment were significantly affected specifically VEFGR2+ endothelial progenitor cells (EPCs) and Cu-dependent LOXL-2 were significantly reduced, and the collagen microenvironment was normalized in Cu-depleted pts [Chan et al Clin Cancer Res 2017, Liu NPJ Breast 2021], recapitulating our observations in pre-clinical models. These findings have led to the hypothesis that Cu contributes to 3 key aspects of metastasis: (1) cancer cell intrinsic mitochondrial bioenergetics that mediates invasion/metastasis/chemoresistance; (2) the “pre-metastatic niche” that supports colonization, and outgrowth of disseminated metastatic tumor cells, and (3) stromal remodeling that promotes immune evasion and immunotherapy resistance. We expect that complementing standard chemo-immunotherapy with a Cu depletion strategy will overcome resistance and improve outcome. We will test this through a randomized phase 2 trial and seek mechanistic insights through comprehensive correlative studies. Our study design is a randomized phase 2 trial of TM with capecitabine vs capecitabine alone +/- pembrolizumab, in TNBC pts with significant residual invasive disease after completion of standard neoadjuvant therapy and surgery (RCB 2,3). The primary endpoint is distant relapse free survival and secondary endpoints are (i) safety, (ii) invasive disease-free survival (iDFS), and OS for the entire cohort and (iii) those who complete 6 months of TM therapy, (iv) Pt reported outcomes and (v) effect of therapy on biomarkers. Preceding this randomized phase 2 study will be a phase Ib clinical trial in 6 to 18 pts to establish the safety of the combination of adjuvant TM, capecitabine and pembrolizumab. There is a robust scientific correlative and exploratory component including evaluating the effect of Cu depletion on serial blood-based biomarkers including: (i) VEGFR2+ EPC (by flow cytometry), (ii) LOXL 2 (by ELISA), (iii) ctDNA (by PhasED-Seq, Foresight Diagnostics), (iv) immune monitoring. We plan to enroll 186 pts in this study across 8 sites. The study is open and actively accruing since November 2024. Citation Format: N. Kornhauser, N. Chan, B. Park, K. Miller, K. Kalinsky, N. Vidula, M. Robson, C. Seymour, V. Mittal, L. Vahdat. Novel Targeting of the Microenvironment to Decrease Metastatic Recurrence of High-Risk TNBC: A Randomized Phase 2 Study of Tetrathiomolybdate (TM), an oral copper depletion agent plus capecitabine +/- pembrolizumab in patients with breast cancer at high risk of recurrence (NCT06134375) [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 PS5-07-23.