Predictive Potential of Angiogenic Growth Factors and Circulating Endothelial Cells in Breast Cancer Patients Receiving Metronomic Chemotherapy Plus Bevacizumab

Abstract

Purpose: The association of chemotherapy and antiangiogenic drugs has shown efficacy in clinical oncology. However, there is a need for biomarkers that allow selection of patients who are likely to benefit from such treatment and are useful for indicating best drug combination and schedule. Experimental Design: We investigated the predictive potential of six angiogenic molecules/transcripts and nine subpopulations of circulating endothelial cells (CEC) and progenitors (CEP) in 46 patients with advanced breast cancer treated with metronomic cyclophosphamide and capecitabine plus bevacizumab. Results: Median time to progression was 281 days. Baseline CECs higher than the first quartile were associated with an increased time to progression (P = 0.021). At progression, CECs were markedly reduced (P = 0.0002). In the cohort of 15 long-term responders, who progressed later than 1 year after beginning of therapy, circulating vascular endothelial growth factor (VEGF)-A levels measured after 2 months of therapy were significantly reduced, and there were significant trends toward lower levels of PDGF-BB, CEPs, and CECs. At the time of progression, angiogenic growth factors VEGF-A and basic fibroblast growth factor were significantly increased. Conclusions: Baseline CECs (likely reflecting an active vascular turnover) predicted a prolonged clinical benefit. At the time of relapse, a pattern of decreased CECs and increased angiogenic growth factors suggested a switch toward a different type of cancer vascularization. VEGF-A and basic fibroblast growth factor levels after 2 months of therapy were also useful to identify patients whose disease was likely to progress. These biomarkers are likely to be useful for treatment selection and might be incorporated in design of future studies. (Clin Cancer Res 2009;15(24):7652-7)

Phase I Dose-Escalation Study and Biomarker Analysis of E7080 in Patients with Advanced Solid Tumors

“…Higher baseline CEC was correlated with delayed disease progression in patients with non-small cell lung and breast cancer (29,30). We did not find a correlation between baseline CEC numbers and therapeutic effect, however significant correlations between baseline levels of SDF1, c-kit(þ) CEP number and c-kit(þ) ratio in CEC were shown with E7080 treatment duration.…”

A phase 2 trial of standard-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab plus bevacizumab for patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: SWOG 0515

“…The utility of plasma or serum VEGF levels as a prognostic or predictive biomarker in oncology has been inconsistent in the literature. [21][22][23] This is probably secondary to the difficulties in accurately measuring tumor released or associated VEGF as recent data suggest that plasma or serum measurements of VEGF are highly dependent on platelet count and phlebotomy technique. 19,20 Thus, our results with urine VEGF and plasma VCAM may be more relevant clinically, precisely because we have chosen to study a more robust, and therefore predictive, marker of in vivo VEGF effects.…”

Circulating perivascular progenitors: A target of PDGFR inhibition

“…However, the lack of surrogate biomarkers able to define their optimal biological dosage (OBD), and/or to predict the clinical benefit in a given patient, and/or to predict patient's escape from the therapy is hampering their clinical development. 18 We and others [19][20][21][22][23][24][25][26][27][28][29] have recently reported that the measurement of CECs and CEPs in cancer patients receiving antiangiogenic drugs is a surrogate biomarker that has clinical predictive potential for patients' selection and follow-up. Using a flow cytometry approach similar to what we have developed and validated for CEC and CEP count, 13 we report here a protocol for PPC enumeration in the preclinical and clinical settings.…”