Open Access Highly Accessed Research article

Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

Fotios Loupakis1*, Annamaria Ruzzo2, Lisa Salvatore1, Chiara Cremolini1, Gianluca Masi1, Paolo Frumento3, Marta Schirripa1, Vincenzo Catalano4, Nadia Galluccio2, Emanuele Canestrari2, Bruno Vincenzi5, Daniele Santini5, Katia Bencardino6, Vincenzo Ricci6, Mariangela Manzoni7, Marco Danova7, Giuseppe Tonini5, Mauro Magnani2, Alfredo Falcone1 and Francesco Graziano4

Author Affiliations

1 U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori and Dipartimento di Oncologia, dei Trapianti e delle Nuove Tecnologie in Medicina, Università di Pisa, Italy

2 Dipartimento di Scienze Biomolecolari, Università degli Studi "Carlo Bo", Urbino, Italy

3 Scuola Superiore di Studi Universitari e Perfezionamento "Sant'Anna", Pisa, Italy

4 U.O. Oncologia Medica, Ospedale di Pesaro, Italy

5 U.O. Oncologia Medica, Università Campus Biomedico, Roma, Italy

6 Unità di Oncologia, Istituto Scientifico San Raffaele, Milano, Italy

7 U.O. Oncologia Medica, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy

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BMC Cancer 2011, 11:247  doi:10.1186/1471-2407-11-247

Published: 14 June 2011

Abstract

Background

Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific VEGF polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.

Methods

Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. VEGF -2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of VEGF polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of VEGF -1498 C/T polymorphism between bevacizumab-and control group.

Results

In the bevacizumab-group median PFS and OS of patients carrying VEGF -1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). VEGF -1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of VEGF -1498 C/T allelic variants and PFS or OS was found. Interaction between VEGF -1498 C/T variants and treatment effect suggested that the relation of VEGF -1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.

Conclusions

These data suggest a possible role for VEGF -1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.