Abstract
BackgroundBevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of bevacizumab efficacy have not yet been identified. We analyzed vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) polymorphisms in relation to response to bevacizumab.MethodsTwo hundred and thirty-seven patients with mCRC enrolled onto the phase III prospective multicentre randomized “Italian Trial in Advanced Colorectal Cancer (ITACa)” trial were evaluated. One hundred fourteen patients received chemotherapy plus bevacizumab (CT + B) and 123 received chemotherapy (CT) alone. Five single nucleotide polymorphisms (SNPs) (−2578, −1498, −1154, −634 and +936) for VEGF and 2 SNPs (−786, +894) and one variable number tandem repeat in intron 4 for eNOS were analyzed for each patient. The polymorphisms were assessed in relation to progression-free survival (PFS), objective response rate (ORR) and overall survival (OS).ResultsVEGF 936C/T, eNOS +894 G/T and VNTR were significantly correlated with outcome in CT + B patients, but not in CT-only patients. In particular, patients with a specific haplotype combination of the 2 eNOS polymorphisms (defined eNOS Haplo1/Haplo1 and eNOS Haplo 2/Haplo2) showed significantly longer PFS (15.0 vs 9.1 months, P = 0.001) and OS (34.5 vs 20.5 months P = 0.002), and a higher ORR (71 vs 45.9%, P = 0.013) than those with the other genotypes, respectively.ConclusionsSpecific eNOS polymorphisms may be capable of identifying a subset of mCRC patients who are more responsive to bevacizumab-based chemotherapy. If confirmed, these results would permit individually tailored treatment with bevacizumab.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0619-5) contains supplementary material, which is available to authorized users.
Highlights
Bevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer
We previously demonstrated that vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) polymorphism analysis showed concordant results regardless of starting material used (FFPE or blood sample) in all but the VEGF −1154G>A single nucleotide polymorphisms (SNPs) [18]
The observed allele distributions of VEGF −2578, −1498, −1154, −634, +936 polymorphisms and eNOS +894, −786, variable number tandem repeat (VNTR) 4a/b are shown in an Additional file 2; all were in Hardy–Weinberg equilibrium (HWE) (P = 0.95; P = 0.95, P = 0.12, P = 0.30, P = 0.91, P = 0.50, P = 0.85, P = 0.26 respectively)
Summary
Bevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer (mCRC). A prospective study by Koutras and colleagues reported that only the VEGF −1154 G/A variants were associated with response and overall survival (OS) in patients treated with bevacizumab plus FOLFIRI or XELIRI [9]. The same VEGF SNPs were associated with progressionfree survival (PFS) in another study [8] in which VEGF −634 G/C was associated with response These SNPs have been associated with cardiovascular adverse effects induced by bevacizumab, in particular, hypertension [10], and a correlation has been reported between response and bevacizumab-induced hypertension [13]. Another study found that VEGF and endothelial nitric oxide synthase (eNOS) polymorphisms were associated with sunitinib-induced hypertension in patients with metastatic renal cancer, with grade three hypertension identified as an independent predictor of OS [14]
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