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

Abstract

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.

• Authors: Diether Lambrechts, Bart Claes, Paul Delmar, Joke Reumers, Massimiliano Mazzone, Betül T Yesilyurt, Roland Devlieger, Chris Verslype, Sabine Tejpar, Hans Wildiers, Sanne de Haas, Peter Carmeliet, Stefan J Scherer, Eric Van Cutsem
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 13 Issue 7 Pg. 724-33 (Jul 2012) ISSN: 1474-5488 [Electronic] England
• PMID: 22608783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal, Humanized
• Biomarkers
• Vascular Endothelial Growth Factor A
• Bevacizumab
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Adult
• Aged
• Angiogenesis Inhibitors (therapeutic use)
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Base Sequence
• Bevacizumab
• Biomarkers
• Carcinoma, Renal Cell (drug therapy)
• Clinical Trials, Phase III as Topic
• Female
• Humans
• Kidney Neoplasms (drug therapy)
• Male
• Middle Aged
• Molecular Sequence Data
• Pancreatic Neoplasms (drug therapy)
• Polymorphism, Single Nucleotide
• Proportional Hazards Models
• Randomized Controlled Trials as Topic
• Treatment Outcome
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, physiology)
• Vascular Endothelial Growth Factor Receptor-1 (genetics)