Single nucleotide polymorphisms in the vascular endothelial growth factor A gene predicts response to chemotherapy in patinets with metastatic colorectal cancer

 

Single nucleotide polymorphisms in the vascular endothelial growth factor A gene predicts response to chemotherapy in patients with metastatic colorectal cancer.
Torben Frøstrup Hansen, Karen-Lise Garm Spindler, Rikke Fredslund Andersen, Jan Lindebjerg, Ivan Brandslund and Anders Jakobsen
Danish Colorectal Cancer Group South, University of Southern Denmark, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark.

Background: Besides the cytotoxic effect on cancer cells, chemotherapy may exert a similar effect on the rapidly dividing endothelial cells involved in the tumour associated neoangiogenesis. These immature endothelial cells are known to be dependent on vascular endothelial growth factor A (VEGF-A) as a survival factor. Recent evidence suggests a clinical importance of single nucleotide polymorphisms (SNP's) in the VEGF-A gene, but a possible association between these SNP's and the efficacy of chemotherapy has not been elucidated. The aim of this study was to investigate the predictive and prognostic role of SNP's in the VEGF-A gene in relation to first line treatment with capecitabine and oxaliplatin in patients with metastatic colorectal cancer (mCRC).

Materials and methods: The study prospectively included 72 patients with mCRC. Genomic DNA was isolated from whole blood, and 4 SNP's in the VEGF-A gene were analysed by polymerase chain reaction. Clinical response was assessed by radiologic examination. The response evaluation criteria in solid tumors (RECIST) were used for evaluation, and compared by a chi-square test. Progression free survival (PFS), according to genotypes, was compared using the Kaplan-Meier method and the log rank test, and the Cox regression method was used for multivariate analysis.

Results: Three of the 4 SNP's demonstrated a significant association with response to chemotherapy. Response was observed in approximately 25% of the patients with heterozygous genotypes, compared to 55% in the patients with homozygous genotypes; the +405 G/C SNP, p=0.02; the -460 C/T SNP, p=0.008; and the -2578 C/A SNP, p=0.001. Heterozygosity in two of these 3 SNP's were significantly associated with PFS, but only the +405 GC genotype remained an independent prognostic marker after multivariate analysis, hazard ratio 2.07, 95% confidence interval 1.05-4.10, p=0.04.

Conclusions: The results demonstrated an association between 3 SNP's in the VEGF-A gene and response to first line treatment with capecitabine and oxaliplatin in patients with mCRC, which translated to a significant difference in PFS. The results call for validation in a bigger prospective trial.