Association between VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with bevacizumab

David O. Bates*, Paul J. Catalano, Kirsty E. Symonds, Alex H.R. Varey, Pramila Ramani, Peter J. O'Dwyer, Bruce J. Giantonio, Neal J. Meropol, Al Bowen Benson, Steven J. Harper

*Corresponding author for this work

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52 Scopus citations

Abstract

Purpose: Bevacizumab improves survival for patients with metastatic colorectal cancer with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF165b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF 165b levels treated with bevacizumab. Experimental Design: Blinded tumor samples from the phase III trial of FOLFOX4 ± bevacizumab were assessed for VEGF165b and VEGFtotal by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF165b:VEGFtotal for 44 samples from patients treated with FOLFOX + bevacizumab (arm A) and 53 samples from patients treated with FOLFOX4 (arm B), and PFS, and overall survival (OS) analyzed on the basis of PI relative to median ratio. Results: Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF165b:VEGFtotal ratio scores below median treated with FOLFOX4 + bevacizumab compared with FOLFOX4 alone (median, 8.0 vs. 5.2 months; P < 0.02), but no effect of bevacizumab on PFS in patients with VEGF165b:VEGFtotal ratio >median (5.9 vs. 6.3 months). These findings held after adjustment for other clinical and demographic features. OS was increased in arm A (median, 13.6 months) compared with arm B (10.6 months) in the low VEGF165b group, but this did not reach statistical significance. There was no difference in the high VEGF 165b:VEGFtotal group between FOLFOX + bevacizumab (10.8 months) and FOLFOX alone (11.3months). Conclusion: Low VEGF165b: VEGFtotal ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit.

Original languageEnglish (US)
Pages (from-to)6384-6391
Number of pages8
JournalClinical Cancer Research
Volume18
Issue number22
DOIs
StatePublished - Nov 15 2012

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bates, D. O., Catalano, P. J., Symonds, K. E., Varey, A. H. R., Ramani, P., O'Dwyer, P. J., Giantonio, B. J., Meropol, N. J., Benson, A. B., & Harper, S. J. (2012). Association between VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with bevacizumab. Clinical Cancer Research, 18(22), 6384-6391. https://doi.org/10.1158/1078-0432.CCR-12-2223