VEGF/sVEGFR-2 and VEGF/TSP-1 ratios as probable predictors of response to metronomic chemotherapy with cyclophosphamide and celecoxib in advanced breast cancer patients.

HERMAN A. PERROUD, CARLOS M. ALASINO, MARÍA J. RICO, FRANCISCO QUERALT, STELLA M. PEZZOTTO, VIVIANA R. ROZADOS, O. GRACIELA SCHAROVSKY

Washington DC

Congreso; 104th Annual Meeting de la American Association for Cancer Research; 2013

The efficacy and low toxicity of antiangiogenic metronomic chemotherapy (MCT) with cyclophosphamide (Cy) and celecoxib (Cel) in advanced breast cancer patients (ABCP) was demonstrated in our studies but no reliable biomarkers or predictors of response have been found yet. The aim of this study was to analyze several pro- and anti-angiogenic parameters and evaluate their potential role as predictor of response duration in ABCP treated with MCT with daily Cy and Cel. Treatment plan: Patients received Cy 50 mg p.o./day + Cel 200 mg p.o. bid. This clinical trial was authorized by the School of Medicine Bioethics Committee and by A.N.M.A.T. (Argentine Regulatory Authority). .Angiogenesis parameters: Serum levels of vascular endothelial growth factor (VEGF), VEGF-C, soluble VEGF Receptors 2 and 3 (sVEGFR-2, sVEGFR-3) and Thrombospondin 1 (TSP-1) were determined by ELISA. Blood samples were collected before and during treatment and parametric tests were used to analyze data. Fifteen patients were enrolled, A partial response (PR) was observed in 1 patient (6.7%), which lasted 6 weeks. Prolonged Stable disease (pSD ≥24 weeks) was observed in 6/15 patients (40%). Median TTP among patients with pSD was 37.5 weeks (range: 26.43-81.57). The OCB obtained was 46.7% (PR=1/15 + SD=6/15). The median TTP (PR+pSD) was 33 weeks (range: 10.43-81.57). Treatment toxicity was very low and no grade 3 or 4 adverse events were registered. Biomarkers were determinated in 13 patients. Serum VEGF concentration decreased as a function of time (P=0.004); sVEGFR-2 increased during response (P= 0.0268) while non-significant variations were detected in VEGF-C, sVEGFR-3 and TSP-1. The baseline values of VEGF, and VEGF/sVEGFR-2 and VEGF/TSP-1 ratios were significantly correlated with response duration (P=0.029, P=0.015, P=0.014, respectively). To assess which of the three variables measured at the beginning of the treatment could be used to predict response duration, linear regression analyses were done. VEGF/sVEGFR-2 and VEGF/TSP-1 ratios were good predictors (P=0.028, P=0.029, respectively), meanwhile VEGF was not (P=0.059). When considering VEGF, VEGF/VEGFR-2 and VEGF/TSP-1 in a multiple regression analysis, the goodness of prediction was not improved with respect to that obtained with each putative predictor. We conclude that the antiangiogenic nature of MCT with Cy plus Cel is confirmed through the decrease of VEGF and the increase of sVEGFR-2; the absence of variation in VEGF-C and sVEGFR-3 would indicate the lack of effect on lymphangiogenesis; if confirmed in a higher number of patients, VEGF/sVEGFR-2 and VEGF/TSP-1 ratios could be useful as early predictors of treatment response.