Elsevier

The Lancet Oncology

Volume 13, Issue 7, July 2012, Pages 724-733
The Lancet Oncology

Articles
VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials

https://doi.org/10.1016/S1470-2045(12)70231-0Get rights and content

Summary

Background

No biomarkers that could guide patient selection for treatment with the anti-VEGF monoclonal antibody bevacizumab have been identified. We assessed whether genetic variants in the VEGF pathway could act as biomarkers for bevacizumab treatment outcome.

Methods

We investigated DNA from white patients from two phase 3 randomised studies. In AViTA, patients with metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine and erlotinib plus either bevacizumab or placebo. In AVOREN, patients with metastatic renal-cell carcinoma were randomly assigned to receive interferon alfa-2a plus either bevacizumab or placebo. We assessed the correlation of 138 SNPs in the VEGF pathway with progression-free survival and overall survival in a subpopulation of patients from AViTA. Significant findings were confirmed in a subpopulation of patients from AVOREN and functionally studied at the molecular level.

Findings

We investigated DNA of 154 patients from AViTA, of whom 77 received bevacizumab, and 110 patients from AVOREN, of whom 59 received bevacizumab. Only rs9582036, a SNP in VEGF receptor 1 (VEGFR1 or FLT1), was significantly associated with overall survival in the bevacizumab group of AViTA after correction for multiplicity (per-allele hazard ratio [HR] 2·1, 95% CI 1·45–3·06, p=0·00014). This SNP was also associated with progression-free survival (per-allele HR 1·89, 1·31–2·71, p=0·00081) in bevacizumab-treated patients from AViTA. AC and CC carriers of this SNP exhibited HRs for overall survival of 2·0 (1·19–3·36; p=0·0091) and 4·72 (2·08–10·68; p=0·0002) relative to AA carriers. No effects were seen in placebo-treated patients and a significant genotype by treatment interaction (p=0·041) was recorded, indicating that the VEGFR1 locus containing this SNP serves as a predictive marker for bevacizumab treatment outcome in AViTA. Fine-mapping experiments of this locus identified rs7993418, a synonymous SNP affecting tyrosine 1213 in the VEGFR1 tyrosine-kinase domain, as the functional variant underlying the association. This SNP causes a shift in codon usage, leading to increased VEGFR1 expression and downstream VEGFR1 signalling. This VEGFR1 locus correlated significantly with progression-free survival (HR 1·81, 1·08–3·05; p=0·033) but not overall survival (HR 0·91, 0·45–1·82, p=0·78) in the bevacizumab group in AVOREN.

Interpretation

A locus in VEGFR1 correlates with increased VEGFR1 expression and poor outcome of bevacizumab treatment. Prospective assessment is underway to validate the predictive value of this novel biomarker.

Funding

F Hoffmann-La Roche.

Introduction

Bevacizumab, a humanised monoclonal antibody that binds to VEGF, was the first anti-VEGF specific drug to be approved in the clinic. When used together with standard therapies, bevacizumab is effective in several cancers such as metastatic colorectal cancer,1 non-small-cell lung cancer,2 breast cancer,3 renal-cell carcinoma,4 and recurrent glioblastoma.5 Other antiangiogenic drugs are the VEGF receptor tyrosine-kinase inhibitors (TKIs) such as sorafenib, sunitinib, and pazopanib, which have proven efficacy in renal-cell carcinoma,6 hepatocellular carcinoma,7 and gastrointestinal stromal tumours.8

Antiangiogenic drugs have changed clinical practice in several cancers, but various clinical challenges remain. Particularly, although initial responses can be detected, adaptive escape mechanisms lead to subsequent disease progression in most patients.9 Furthermore, remarkable heterogeneity exists in patients, with some relapsing almost immediately and others having prolonged periods of stabilised disease. Compensatory upregulation of alternative proangiogenic factors by the tumour has been proposed as an underlying escape mechanism, although tumour-associated fibroblasts and circulating inflammatory cells have also been involved.9 Various predictive genetic markers have also been proposed.10, 11, 12, 13 Despite these initial insights, no validated biomarkers that identify which patients benefit most from antiangiogenic therapy have been discovered.

The ability of VEGF to stimulate angiogenesis varies between individuals. A quantitative analysis of circulating VEGF in the Framingham study14 revealed, for instance, that heritability accounts for almost 80% of the variation in VEGF levels. Likewise, Rohan and colleagues15 showed large variations between different mouse inbred strains in their ability to trigger a VEGF-mediated angiogenic response in the corneal neovascular assay. This indicates that genetic factors influence inter-individual variability in VEGF responsiveness. Based on these findings, we postulated that genetic variability also influences the response of the tumour vasculature to VEGF inhibition. We therefore investigated whether genetic variants in the VEGF pathway could act as biomarkers for bevacizumab treatment outcome.

Section snippets

Study design and patients

AViTA (BO17706) and AVOREN (BO17705) were multicentre, randomised phase 3 trials, including 607 patients with metastatic pancreatic adenocarcinoma and 649 patients with metastatic renal-cell carcinoma, respectively. Patients in AViTA were randomly assigned to receive gemcitabine and erlotinib plus either bevacizumab (n=306) or placebo (n=301). Patients in AVOREN were randomly assigned to receive interferon alfa-2a plus either bevacizumab (n=327) or placebo (n=322). Details of these studies have

Results

Blood samples from AViTA were available for 160 (26%) of 607 patients. Six patients were Asian and 154 were white. Since SNP frequencies differ between ethnic groups, we analysed only DNA from white patients. The genetic biomarker subgroup was similar to the full patient cohort with respect to age and sex distribution, smoking status, Karnofsky performance status, overall survival, and progression-free survival (table 1). Median overall survival did not significantly differ between the

Discussion

The most important finding of our study is the identification of a genetic locus in the VEGFR1 tyrosine-kinase domain that is associated with progression-free survival and overall survival in pancreatic cancer patients (AViTA) and with progression-free survival in renal-cell carcinoma patients (AVOREN). Importantly, this association was specific for patients receiving bevacizumab since no significant effects were noted in placebo-treated patients. We also validated this locus at the functional

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