The Effect Of Tetrathiomolybdate (Tm) On Circulating Endothelial Progenitor Cells In Women At Moderate To High Risk Of Bc Recurrence

Background: Bone marrow (BM) derived endothelial progenitor cells (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 copperdepleting compound, inhibits angiogenesis and maintains tumor dormancy through unknown mechanisms. We sought to measure the effect of TM on BM derived EPCs in pts at high risk of BC recurrence and to evaluate the effect of copper depletion on their absolute number. 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). Initial study duration is 24 mos. Extension study for an additional 24 mos in selected pts. Results: 40 pts are enrolled and 566 cycles of TM have been administered. Adjuvant: 28 pts, Stage 4 NED: 12 pts, Triple negative: 11 pts (4 stage 4 NED, 7 Adjuvant). Median age is 51 yrs (range: 29-64). Median number of positive lymph nodes among Stage 2/3 pts is 7 (4-42). Median baseline Cp level is 29 mg/dL (21-47). Among 36 pts who have reached target Cp, the median time to target is 4 wks (2-20 wks). Four pts discontinued treatment before reaching target. The median baseline EPCs is 0.01 cells/ml (0.0-0.286), and the majority of pts’ EPCs were maintained below baseline when Cp levels remained below target (i.e. copper depleted). Toxicity: Grade 3/4 neutropenia occurred in 15 cycles (2.6%) with 1 pt with febrile neutropenia. One cycle was complicated by Grade 3 anemia. All resolved 5-13 days later with TM held and resumed at a lower dose. No other grade 3/4 toxicity was observed. Six pts were diagnosed with recurrent breast cancer at 1, 2, 2, 9, 10 and 10 mos. An EPC rise preceded an abnormal marker or overt relapse by 3-5 months in 4 of 6 pts (2 pts too early to tell). 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 4 pts with recurrent disease 2-4 months prior to overt relapse could represent the turning on of an angiogenic switch, resulting in an outpouring of BM derived EPCs to the new site of metastasis. Other studies geared toward understanding the mechanism for metastases are underway. The trial continues to accrue. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-14.