A Phase II Trial Tetrathiomolybdate (TM), a Copper Depleting Compound, and Its Effect on Circulating Endothelial Progenitor Cells (EPCs) in Patients with Breast Cancer (BC) at High Risk of Recurrence.
Authors: Vahdat L. , Ward M. , Chuang E. , Cigler T. , Moore A. , Donovan D. , Cobham M. , Schpero J. , Wiener N. , Blinder V. , Christos P. , Rafii S. , Lane M. 
Published: December 2010

Abstract
Background: EPCs are critical to tumor angiogenesis, are increased in BC patients (pts) and are probably an early marker for paclitaxel response. Copper is required for angiogenesis, and pre-clinical data suggest that TM, a copper-depleting compound, inhibits angiogenesis and maintains tumor dormancy. We sought to measure the effect of TM on circulating endothelial progenitor cells (EPCs) in pts at high risk of BC recurrence and to evaluate the effect of copper depletion on EPCs. Methods: This analysis is part of an ongoing phase II study of TM in BC pts at high risk of recurrence defined as any node positive triple negative (TN) BC, Stage III or IV with no evidence of disease (NED). All therapy other than hormonal was completed at least 6 weeks prior to study. Treatment: TM 180 mg daily to achieve a target ceruloplasmin (Cp) level of 5-15 mg/dL (copper depletion), and then 100 mg daily. We monitored levels of EPCs (CD45dim, CD133+, VEGFR2+), CEA, CA15-3, and Cp at baseline and monthly. Imaging studies are done every 6 months (mos). Results: 28 pts are enrolled and 304 cycles of TM have been administered. Adjuvant: 20 pts, Stage 4 NED: 8 pts, Triple negative: 8 pts (5 stage IV NED, 3 Adjuvant) The median age is 51 years (range: 29-64), median number of positive lymph nodes among Stage III patients is 7 (4-42). The median baseline Cp level was 28 mg/dL (21-43). Among 21 patients who have reached target Cp, the median time to target is 6 weeks (2-16 weeks). Two pts discontinued treatment before reaching target. The median baseline EPCs is 17.38 cells/ml (0.0-286.1) Although there was a trend toward increased EPCs at month 1, this was not statistically significant (p=0.8964) and the majority of pts EPCs were maintained below baseline over time when Cp levels were below target (ie. copper depleted). Toxicity: Grade 3/4 neutropenia occurred in 3 patients (0.02%) with 1 pt with febrile neutropenia. All resolved 5-13 days later with TM held and resumed at a lower dose in 2 patients. No other grade 3/4 toxicity was observed. Three patients were diagnosed with recurrent breast cancer at 1, 9 and 10 mos. An EPC rise preceded an abnormal marker or overt relapse by 3-5 months in 2 of 3 pts. Conclusions: TM is well tolerated in breast cancer patients. TM might contribute to maintaining EPCs below baseline in pts who are copper depleted. We postulate that the increased EPCs noted in both patients with recurrent disease 2-4 months prior to overt relapse could represent the turning on of an angiogenic switch, resulting in an outpouring of CEPCs to the new site of metastasis. Other studies geared toward understanding the mechanism for metastases are underway. The trial continues to accrue.Supported by the Susan B Komen for the Cure, NY Community Trust, Breast Cancer Alliance of Greenwich and the Madeline and Stephen Anbinder Foundation.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6090.