Abstract 2699: Phase II study evaluating the effect of tetrathiomolybdate on circulating endothelial progenitor cells in patients with high risk for breast cancer recurrence
Authors: Jain Sarika , Rua Sandra Hurtado , Cohen Jules , Ward Maureen M. , Boeck Marissa , Wiener Naomi , Chuang Ellen , Cigler Tessa , Moore Anne , Donovan Diana , Lam Christina , Cobham Marta , Schneider Sarah , Baergen Rebecca , Lane Maureen E. , Mittal Vivek , Rafii Shahin , Vahdat Linda T. 
Published: August 2012

Abstract
Background: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. Tetrathiomolybdate (TM), a 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 (BC) recurrence. Methods: This phase II study enrolled Stage 3, 4 without evidence of disease (NED), and any node-positive triple negative (TN) BC pts. Only concomitant hormonal therapy was allowed. Pts received induction TM 180 mg daily at baseline (with exception of one pt) followed by an equal or lower daily dose (median 100mg, range 0-140) to maintain ceruloplasmin (Cp) level &lt; 17 mg/dl (target for copper depletion). We monitored EPCs (CD45dim/CD133+/VEGFR2+), Cp, CEA and CA15-3 at baseline and monthly. To assess the association between Cp and EPCs over time, 3 independent mixed effects linear models with subject as a random effect were used to account for the correlation between observations on the same subject. All p-values were two-sided with statistical significance evaluated at the 0.10 alpha level. Results: 40 pts (28 adjuvant, 12 Stage 4 NED, 11 TN) were enrolled and 426 cycles of TM (average 10.65 per pt) were administered in the first 12 months on study. Median age was 50 yrs (29-66). Median number of tumor size and positive lymph nodes among adjuvant pts were 3.5 cm (1.2-7) and 9 (0-42), respectively. Of the patients receiving hormone therapy, 10 patients were on tamoxifen and 15 patients were on an aromatase inhibitor. 20% of patients were receiving a proton pump inhibitor (PPI). Median baseline Cp level was 28 mg/dL (20-47). 75% pts adequately copper depleted at month 1. 91% of TN patients copper depleted compared to hormone receptor positive subtypes (38-43%) and HER2/neu positive subtypes (40-67%). EPCs/ml decreased from baseline to last dose by 12 in pts that were copper-depleted (p=0.10) and by −52 in pts that did not achieve the copper depletion target (p=0.95). Multivariable modeling revealed an association of EPCs with Cp over time (p=0.005), with type of hormone therapy administered (p=0.007), and with co-administration of a PPI (p=0.0008). Six pts relapsed while on study in which a 200-fold increase in EPCs preceded an objective clinical relapse and a tumor marker rise by median of 1 month. Only grade 3/4 toxicity was hematologic, occurred in 20 cycles (4.7%) and resolved in 5-13 days with TM held and resumed at lower dose. Conclusions: TM is a well-tolerated oral copper chelator that may contribute to maintaining EPCs below baseline in copper-depleted pts. PPI may facilitate TM absorption. Molecular subtype and hormone therapy may impact on the ability to copper deplete. EPCs may have potential as a surrogate marker for early relapse and as a therapeutic target for interrupting the metastatic progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2699. doi:1538-7445.AM2012-2699