Abstract CT072: Novel targeting of the microenvironment to decrease metastatic recurrence of high-risk TNBC: A randomized phase II study of tetrathiomolybdate (TM) plus capecitabine in patients with breast cancer at high risk of recurrence

Abstract Through a randomized phase 2 trial, we aim to overcome resistance and improve outcomes for triple-negative breast cancer (TNBC) patients (pts) with significant residual disease at surgery. We and others have demonstrated that copper (Cu) 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 and well tolerated. 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. Three components of the tumor microenvironment were significantly affected: VEFGR2+ endothelial progenitor cells (EPCs) and Cu-dependent LOXL-2 were significantly reduced, whereas 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 aspects of metastasis: (1) cancer cell intrinsic mitochondrial bioenergetics that mediate 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 of TM with capecitabine (C) vs C alone +/- pembrolizumab (P), in TNBC pts with RCB 2, 3 residual disease after completion of neoadjuvant therapy and surgery. The primary endpoint is distant relapse free survival. Secondary endpoints are (i) safety, (ii) invasive disease-free survival (iDFS), and OS for both the entire cohort and those who complete 6 months of TM therapy, (iii) Pt-reported outcomes and (iv) effect of therapy on biomarkers. Prior to the randomized phase 2 study, a phase Ib clinical trial in 6 to 18 pts will be done to establish the safety of the combination of adjuvant TM, capecitabine and pembrolizumab. Robust scientific correlative and exploratory work will evaluate the effect of Cu depletion on serial blood-based biomarkers. We plan to enroll 186 pts in this study across 10 sites. The study has 8 pts accrued to the phase 1b portion at dose levels 1 and -1. TM appears safe and well tolerated in combination with C and P. Citation Format: Linda T. Vahdat, Nancy Chan, Ben H. Park, Jessica M. Sharpe, Kathy D. Miller, Bryan P. Schneider, Kevin M. Kalinsky, Neelima Vidula, Mark E. Robson, Peter A. Kauffman, Rebecca A. Shatsky, Joyce A. O'Shaughnessy, Sujata Patil, Eileen H. Shinn, James Talton, Raven M. Lavoie, Naomi T. Kornhauser, Christina A. Seymour, Rebecca E. Dabrowski, Vivek Mittal. Novel targeting of the microenvironment to decrease metastatic recurrence of high-risk TNBC: A randomized phase II study of tetrathiomolybdate (TM) plus capecitabine in patients with breast cancer at high risk of recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT072.