The effect of tetrathiomolybdate on endothelial progenitor cells in patients at high risk for breast cancer recurrence.

Abstract

1054 Background: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. Tetrathiomolybdate (TM), an oral copper-depleting compound, inhibits angiogenesis and maintains tumor dormancy. This study explores the effect of TM on EPCs in patients (pts) at high risk for breast cancer recurrence. Methods: This phase II study enrolled pts with stage III, stage IV without evidence of disease (NED) breast cancer, and stage II if triple negative (TN). Only concomitant hormone therapy was allowed. Pts received induction TM 180 mg daily followed by 100 mg daily to maintain ceruloplasmin (Cp) level < 17 mg/dL (target for copper depletion). TM was continued for 24 months (mo), or until relapse or toxicity, with an extension study for additional 24 mo in selected pts. We monitored EPCs (CD45dim/CD133+), Cp, CEA and CA15-3 at baseline (BL) and monthly. EPCs were quantitated from peripheral blood mononuclear cells by flow cytometry. Median BL EPCs was compared to subsequent time points by Wilcoxon signed-rank. Results: 41 pts (29 adjuvant, 12 stage 4 NED, 11 TN) were enrolled and 802 cycles of TM were administered. Median age was 51 years (29-64). Median tumor size was 3.6 cm (1.2-7) and number of positive lymph nodes was 9 (0-42). Median BL Cp level was 29 mg/dL (20-47). 61% pts were adequately copper depleted, by a median time of 1 mo. Four pts discontinued treatment before reaching target. Median BL EPCs/mL was 712 (0-3332). EPCs significantly decreased from BL in copper depleted pts, p=0.03 at 12 mo. Only grade 3/4 toxicity was hematologic: neutropenia in 18 cycles (2.2%), febrile neutropenia in 1 cycle, anemia in 1 cycle. All resolved in 5-13 days with TM held and resumed at a lower dose. Sixteen pts discontinued therapy because of toxicity (3), patient preference (4), inability to copper deplete (2) and disease progression (7). In pts with recurrence, a marked rise in EPCs preceded overt relapse and a tumor marker rise by at least 2 mo. Conclusions: TM is a well-tolerated copper chelator that may contribute to maintaining EPCs below baseline in copper-depleted pts. Further, the rise in EPCs prior to overt relapse in pts with recurrent disease may signify a potential surrogate marker for early relapse.