Abstract P3-02-12: Effect of Platelet Function Inhibition on Circulating Tumor Cells in Patients with Metastatic Breast Cancer: A Randomized Phase II Trial
Authors: Roop R , Naughton M , Schneider J , Lammers P , Pluard T , Johnson F , Eby C , Weilbaecher K. 
Published: April 2011

Abstract
Background: Tumor-recruited platelets have been implicated in tumor cell survival in the circulation, and in tumor cell arrest and adhesion at distant metastatic sites. Tumor cells activate platelets through a variety of mechanisms including the generation of thrombin and ADP. Blockade of platelet activation and aggregation can inhibit metastasis in animal models. Clopidogrel (Plavix) inhibits ADP mediated platelet activation through blockade of the P2Y12 receptor. Aspirin blocks thromboxane production and can partially disrupt thrombin and ADP mediated activation of platelets. We hypothesized that disruption of platelet function and aggregation will result in a decrease in circulating tumor cells (CTC) number. We evaluated the impact of platelet inhibitors clopidogrel and aspirin on CTC in women with metastatic breast cancer.
Methods: Eligible patients had a diagnosis of metastatic breast cancer, had no contraindications to receive aspirin or clopidogrel, and were on a planned anti-neoplastic treatment break or were on stable endocrine therapy for at least 2 months. Maintenance zoledronic acid and/or trastuzumab was allowed. Patients were randomized to receive either aspirin and clopidogrel or no treatment. CTC was measured at baseline, 2 weeks, 1 month, and monthly thereafter. CTC determinations were made via the CellSearch® assay from Veridex®. Platelet aggregation in whole blood using VerifyNow® P2Y12 and aspirin cartridges was performed on all samples to monitor drug compliance. The primary endpoint was proportion of patients with detectable CTC at 1 month.
Results: 48 patients were enrolled, 22 and 19 remained on study at 1 month for the no treatment and treatment arms. Patient characteristics: the median age was 56, 58% of patients were ER positive, 35% were Her2 positive, the median number of organs involved with metastasis was 2, and the median time since diagnosis of metastasis was approximately 22 months. Baseline CTC was ≥1 in 65% of patients and was ≥5 in 13% of patients. Proportion of patients with CTC ≥1 at time of study completion was compared between groups using Fisher's Exact Test and showed no difference between groups. Mean CTC was compared using non-parametric testing and was not different at any time point; however, the no treatment group's mean CTC increased more rapidly over time compared to the treatment group. Medication compliance as monitored by platelet function testing was outstanding. Clopidogrel and aspirin were well tolerated with no patients developing an SAE related to bleeding. Discussion: There was no statistically significant difference between patients who received anti-platelet therapy and those who did not with respect to the primary endpoint, proportion of detectable CTC at one month. In this population of patients with treated metastatic breast cancer, the CTC numbers were lower than expected, which likely decreased our ability to detect a difference in CTC number with anti-platelet therapy. Aspirin and clopidogrel were well tolerated in patients with metastatic breast cancer. Future studies addressing the utility of CTC in clinical settings as well as the potential role for anti-platelet therapy in breast cancer are needed.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-12.