Rosuvastatin Lowers Circulating Tissue Factor Antigen-Bearing Microparticles In Metastatic Breast Cancer: A Phase II, Multi-Dose, Randomized Trial (MicroSTAT Trial)

Background Elevated numbers of circulating bloodborne tissue factor antigen-bearing microparticles represent a significant risk factor for the development of venous thromboembolic events in cancer patients. We recently demonstrated the efficacy of low molecular weight heparin to prevent thrombosis in cancer patients with high levels of circulating tissue factor bearing microparticles. Enthusiasm for prophylactic anticoagulation in cancer cohorts is tempered by the requirement for daily self-injection and potential risk for hemorrhage. Statins significantly reduce the incidence of venous thromboembolic events in healthy individuals by an uncertain mechanism. Statins reduce the generation of tissue factor bearing microparticles in vitro and in animal models. Whether statins affect tissue factor bearing microparticles in cancer patients has not been previously assessed. We performed a randomized phase II study to evaluate whether rosuvastatin reduces the number of circulating tissue factor bearing microparticles in women with metastatic breast cancer. Methods Eligibility requirements included women with metastatic breast cancer on stable endocrine therapy (no changes within previous 6 weeks) with preserved bone marrow function. Patients were excluded if actively receiving chemotherapy (within prior 5 weeks) or currently taking statins. Baseline laboratory testing was performed at days 0 and 28 following enrollment. Study subjects were randomized to rosuvastatin 20 mg or 40 mg to be initiated from days 28 to 56. Repeat laboratory testing was performed on days 42 and 56 to assess for a reduction of tissue factor bearing microparticles and D-dimer. The number of circulating tissue factor bearing microparticles was measured by impedance-based flow cytometry and tissue factor activity was measured by a chromogenic Xa assay. Two-sided Wilcoxon signed rank test was used to compare the median levels at baseline and post treatment of laboratory endpoints within group, and Fisher exact test and Wilcoxon rank sum test to compare baseline characteristics between groups. Results A total of 19 women have been enrolled. Nine women were randomized to rosuvastatin 20 mg and ten were randomized to 40 mg. There were no significant differences between the two groups in baseline characteristics (e.g. age, body mass index, performance status, blood counts, renal function or number of tissue factor bearing microparticles). For the group randomized to rosuvastatin 20 mg, we observed no change in the number of tissue factor bearing microparticles (1576/μl vs 1888/μl , P= 0.55), microparticle-associated tissue factor activity, D-dimer or C-reactive protein (CRP), (P>0.05). In the group of women who received 40 mg rosuvastatin, the median decrease in the number of circulating tissue factor bearing microparticles per patient was -28%, with a median baseline value of 1763/μl versus a post-treatment value of 1216/μl (P=0.047). The group receiving 40mg rosuvastatin also demonstrated a non-significant median change in D-dimer of -21% (P=0.44), microparticle-associated tissue factor activity of -2% (P=0.84), and CRP of -10% (P= 0.81). Conclusions In a randomized phase II study in women with metastatic breast cancer, we observed a statistically significant 28% decrease in circulating tissue factor bearing microparticles following initiation of rosuvastatin 40 mg. Furthermore, these results emphasize that assay of tissue factor antigen-bearing microparticles does not correlate with assay of tissue factor activity. Based on the association between tissue factor-antigen bearing microparticles and cancer-associated thrombosis, these data provide additional support for a large scale clinical trial to assess the efficacy of statins to prevent thrombosis in cancer patients. Disclosures: Off Label Use: rosuvastatin to lower tissue factor bearing microparticles.