Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer.

F Loupakis, C Cremolini, A Fioravanti, P Orlandi, L Salvatore, G Masi, T Di Desidero, B Canu, M Schirripa, P Frumento, A Di Paolo, R Danesi, A Falcone, G Bocci

Journal: British journal of cancer 2011;104(8):1262-9

PMID: 21407216

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Abstract

BACKGROUND

The identification of molecular and genetic markers to predict or monitor the efficacy of bevacizumab (BV) represents a key issue in the treatment of metastatic colorectal cancer (mCRC).

METHODS

Plasma levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble VEGF receptor 2 (sVEGFR-2) and thrombospondin-1 (TSP-1) were assessed by ELISA assay at different time points in a cohort of 25 patients enroled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC. VEGF: -2578A/C, -1498C/T, -1154A/G, -634C/G and 936C/T; and VEGFR-2: -604A/G, +1192C/T and +1719A/T, polymorphisms were assessed in a total of 54 patients.

RESULTS

Treatment with GONO-FOLFOXIRI plus BV determined a prolonged and significant reduction in plasma free, biologically active VEGF concentration. Interestingly, VEGF concentrations remained lower than at baseline also at the time of PD. Conversely, PlGF levels increased during the treatment if compared with baseline, suggesting a possible role in tumour resistance; moreover, sVEGFR-2 increased at the time of PD, as well as TSP-1. No association of assessed polymorphisms with outcome was found.

CONCLUSION

Our study suggested the possible mechanisms of resistance to combined therapy in those patients with a progressive disease to be tested in ongoing phase III randomised studies.

Address: Unit of Medical Oncology, Department of Oncology, Transplants and New Technologies in Medicine, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Via Roma, 67, Pisa, 56126, Italy.

DOI: 10.1038/bjc.2011.85