Annals of Oncology
Background: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. Patients and methods: This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs. Results: Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%–96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%). Conclusions: TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.
Jain, S.; Cohen, J.; Ward, M. M.; Kornhauser, N.; Chuang, E.; Cigler, T.; Moore, A.; Donovan, D.; Lam, C.; Cobham, M. V.; Schneider, S.; Hurtado Rua, Sandra M.; Benkert, S.; Greenwood, C. Mathijsen; Zelkowitz, R.; Warren, J. D.; Lane, M. E.; Mittal, V.; Rafii, S.; and Vahdat, L. T., "Tetrathiomolybdate-Associated Copper Depletion Decreases Circulating Endothelial Progenitor Cells in Women with Breast Cancer at High Risk of Relapse" (2013). Mathematics Faculty Publications. 234.
This is a pre-copyedited, author-produced PDF of an article accepted for publication in Annals of Oncologyfollowing peer review. The version of record Jain, S. et al. "Tetrathiomolybdate-Associated Copper Depletion Decreases Circulating Endothelial Progenitor Cells in Women with Breast Cancer at High Risk of Relapse." Annals of Oncology, vol. 24, no. 6, 2013, pp. 1491-1498, doi:10.1093/annonc/mds654. is available online at: https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mds654