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

Abstract

BackgroundMolecular 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.MethodsGenomic 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.ResultsIn 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.ConclusionsThese 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.

Vascular Endothelial Growth Factor Pathway Polymorphisms as Prognostic and Pharmacogenetic Factors in Cancer: A Systematic Review and Meta-analysis

“…In contrast, Schneider and colleagues evaluated 341 breast cancer patients treated with paclitaxel with or without bevacizumab and found 2 variants (VEGF À2578C>A and À1154G>A) associated with improved OS, whereas 2 different variants (VEGF þ405G>C and À460C>T) were significantly associated with hypertension; the VEGF À1154G>A and À460C>T are, in general, highly linked in the Caucasian population (9). Both the A allele of VEGF À1154G>A, and the C allele of VEGF À460C>T, were associated with improved outcome in 2 separate pharmacogenetics studies (11,12). However, these relationships await validation.…”

“…SNP, single-nucleotide polymorphism. comparisons (10,11,15). In 3 other studies by Jain and colleagues (n ¼ 178), Zhang and colleagues (n ¼ 65; using both univariate and multivariate analyses), and Smerdel and colleagues (n ¼ 38), VEGF, KDR, and NRP1 polymorphisms were found to have no association with survival (13,16,17).…”

Predictive Biomarkers of Antiangiogenic Therapy for Advanced Hepatocellular Carcinoma: Where Are We?

“…For patients with colon cancer who received bevacizumab-containing chemotherapy, VEGF-A polymorphisms may also predict the efficacy of bevacizumab [94,95].…”

Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

“…Genetic studies of colorectal cancer did not associate p53, KRAS or BRAF mutations with bevacizumab treatment outcome [71] . Single nucleotide polymorphisms (SNPs) in VEGF, VEGFR2 and VEGFR1 were associated with survival after treatment with bevacizumab based regimens [45,52,72] . In line with the important role of inflammatory cytokines in angiogenesis, a consistent finding appeared to be the association between SNPs in CXCR2 and IL-8 genes and the outcome after anti VEGF therapies [57,73,74] .…”