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

Abstract

Abstract Abstract #1036 Background: Endothelial progenitor cells are critical to tumor angiogenesis and are increased in breast cancer patients. Copper is required for angiogenesis, and pre-clinical data suggest that tetrathiomolybdate (TM), a copper-depleting compound, inhibits angiogenesis and maintains tumor dormancy. We sought to measure circulating endothelial progenitor cells (CEPCs) in patients at high risk of breast cancer recurrence and to evaluate the effect of copper depletion on CEPCs.
 Methods: This analysis is part of an ongoing phase II study of TM in breast cancer patients at high risk of recurrence defined as Stage III or IV with no evidence of disease. 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 CEPCs (CD45dim, CD133+, VEGFR2+), CEA, CA15-3, and Cp at baseline and monthly. CEPCs were also measured in 6 healthy controls.
 Results: To date we have enrolled 16 patients with a median age of 51 years (range: 29-64). 14 had a history of Stage III disease, while 2 were considered to be Stage IV with no evidence of disease. The median number of positive lymph nodes among Stage III patients was 7 (1-42), with 2 patients having received neoadjuvant therapy. The median baseline Cp level was 28 mg/dL (21-41). Among 12 patients who have reached target Cp, the median time to target was 1 month (1-3 months). The median follow-up of the 4 patients who have not yet achieved target is 2.5 months. 1 of these discontinued treatment before reaching target. The median baseline CEPCs was lower in patients than healthy controls: 0.022 cells/μL (0.000-0.286) vs. 0.123 cells/μL (0.058-0.418); p=0.03. There was no statistically significant change in CEPCs from baseline over time.
 One patient was diagnosed with recurrent breast cancer at month 10. A rise in her CEPCs preceded a rise in a CEA and overt relapse by 1 and 5 months, respectively.
 Toxicity: Grade 3/4 neutropenia occurred in 3 patients. TM was held, and this resolved 5-13 days later, after which TM was resumed. No other grade 3/4 toxicity was observed. One patient discontinued TM due to diarrhea attributed to the lactose used in the compounding of TM.
 Conclusions: TM is well tolerated in breast cancer patients. We postulate that the increased CEPCs noted in one patient at month 4, 6 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. The trial is ongoing, and with additional follow-up other trends might emerge.
 Supported by Komen for the Cure Foundation, Anbinder Foundation, NY Community Trust and Breast Cancer Alliance of Greenwich. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1036.