No biomarkers are available to guide patient selection for treatment with the anti-VEGF monoclonal antibody bevacizumab (Avastin). Lambrechts and colleagues from VIB and KULeuven and University Hospital Gasthuisberg, Belgium, and F. Hoffmann-La Roche in Basel, Switzerland, have identified a locus in the VEGF receptor 1 gene (VEGFR1) that appears to be associated with poorer outcome of bevacizumab treatment.
The investigators first assessed the association of 138 single nucleotide polymorphisms (SNPs) with outcome in 154 white patients, including 77 bevacizumab recipients, from the phase III AViTA trial of gemcitabine/erlotinib (Tarceva) plus bevacizumab or placebo in metastatic pancreatic adenocarcinoma. Only rs9582036, a single nucleotide polymorphism in VEGFR1, was significantly associated with overall survival in bevacizumab recipients after correction for multiple comparisons, with a per-allele hazard ratio of 2.1 (P = .00014); this SNP was also significantly associated with progression-free survival (per-allele HR = 1.89, P = .00081). Compared with the AA genotype, AC (HR = 2.0, P = .0091) and CC (HR = 4.72, P = .0002) variants were associated with significantly worse overall survival among bevacizumab recipients. No such effects were observed among placebo patients, and the genotype by treatment interaction was significant (P = .041).
Fine-mapping studies of the locus showed that the single nucleotide polymorphism rs7993418 was the functional variant associated with these predictive effects. This SNP affects tyrosine 1213 in the VEGFR1 tyrosine kinase domain, causing a shift in codon usage and resulting in increased VEGFR1 expression and downstream signaling.
Analysis of outcomes among a subgroup of white patients in the AVOREN trial, which assessed interferon alfa-2a (Roferon A) plus either bevacizumab or placebo in metastatic renal cell carcinoma, showed a significant association of this VEGFR1 locus with progression-free survival (HR = 1.81, P = .033) but not overall survival (HR = 0.91, P = .78) among bevacizumab recipients. According to the investigators, prospective evaluation is underway to validate the predictive value of this potential biomarker.
Funding for the study was provided by F. Hoffman-La Roche. ■
Lambrechts D, et al: Lancet Oncol 13:724-733, 2012.