A comparative study of circulating endothelial cells (CECs) and circulating progenitor cells (CPCs) kinetics in four multidisciplinary phase II studies of antiangiogenic agents

Abstract

3544 Background: CECs and CPCs are being evaluated as generic biomarkers of antiangiogenic therapy in cancer patients (pts). We hypothesized that: 1. CEC and CPC kinetics depend on the antiangiogenic agent used; and 2. CECs and CPCs have differential biomarker value. Methods: Using a standard flow cytometry protocol, we measured the fraction of cells with CEC and CPC phenotype among blood mononuclear cells at multiple time-points during treatment in 4 phase 2 studies of anti-VEGF agents: 1. sunitinib in hepatocellular carcinoma (HCC); 2. cediranib in glioblastoma (GBM); 3. bevacizumab (BV) with chemoradiation in rectal cancer (RC); and 4. BV with chemotherapy in ovarian cancer (OC). The changes posttreatment were evaluated using the Wilcoxon test. Correlations between CECs and CPCs with measures of tumor response (imaging, histology, RECIST) were analyzed with a Spearman’s correlation test in a mixed effects model or using the Wald test in a proportional hazards model. Results: Sunitinib induced a sustained decrease in CPCs (p<0.05), but not CECs in HCC pts. Cediranib did not significantly change the CECs or CPCs over time in GBM pts. BV decreased the CECs and CPCs on day 3 (p<0.05) but not on day 12 when given alone, and not when combined with chemoradiation in RC pts. BV with chemotherapy induced a sustained increase in CPCs (p<0.01), but not CECs in OC pts. The number of CECs correlated with RC response to BV/chemoradiation when evaluated at pre- surgery (p<0.05) and tended to correlate with GBM radiographic relapse on cediranib (p=0.06). In contrast to results from preclinical studies, best tumor responses to BV/chemotherapy in OC correlated with higher pretreatment CPCs (p<0.05). In HCC pts, the time-dependent CPC changes positively correlated with mortality risk on sunitinib (p<0.05). Conclusions: CEC and CPC kinetics depend on the type of antiangiogenic agent. Similarly, their biomarker value is differential. Further characterization of the CECs and CPCs in an agent-specific manner might provide ways to use them to optimize antiangiogenic therapies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Bayer, Dyax, Eli Lilly and Company, Genentech, GlaxoSmithKline, Pfizer, Takeda Pharmaceuticals Genentech AstraZeneca, Bayer HealthCare Pharmaceuticals, CuraGen Corporation, DARA Biosciences, Genentech, Inc., MGI Pharma, Inc.