Pharmacogenetic angiogenesis profiling for first-line Bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer

Armin Gerger, Anthony El-Khoueiry, Wu Zhang, Dongyun Yang, Harpreet Singh, Pierre Bohanes, Yan Ning, Thomas Winder, Melissa J Labonte, Peter M Wilson, Leonor Benhaim, David Paez, Rita El-Khoueiry, Gudrun Absenger, Heinz-Josef Lenz, Melissa LaBonte Wilson

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

Abstract

PURPOSE: There is substantial germline genetic variability within angiogenesis pathway genes, thereby causing interindividual differences in angiogenic capacity and resistance to antiangiogenesis therapy. We investigated germline polymorphisms in genes involved in VEGF-dependent and -independent angiogenesis pathways to predict clinical outcome and tumor response in metastatic colorectal cancer (mCRC) patients treated with bevacizumab and oxaliplatin-based chemotherapy.

EXPERIMENTAL DESIGN: A total of 132 patients treated with first-line bevacizumab and FOLFOX or XELOX were included in this study. Genomic DNA was isolated from whole-blood samples by PCR-RFLP or direct DNA sequencing. The endpoints of the study were progression-free survival (PFS), overall survival (OS), and response rate (RR).

RESULTS: The minor alleles of EGF rs444903 A>G and IGF-1 rs6220 A>G were associated with increased OS and remained significant in multivariate Cox regression analysis (HR: 0.52; 95% CI: 0.31-0.87; adjusted P = 0.012 and HR: 0.60; 95% CI: 0.36-0.99; adjusted P = 0.046, respectively). The minor allele of HIF1α rs11549465 C>T was significantly associated with increased PFS but lost its significance in multivariate analysis. CXCR1 rs2234671 G>C, CXCR2 rs2230054 T>C, EGFR rs2227983 G>A, and VEGFR-2 rs2305948 C>T predicted tumor response, with CXCR1 rs2234671 G>C remaining significant in multiple testing (P(act) = 0.003).

CONCLUSION: In this study, we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line bevacizumab and oxaliplatin-based chemotherapy.

Original languageEnglish
Pages (from-to)5783-92
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number17
DOIs
Publication statusPublished - 01 Sep 2011

Bibliographical note

©2011 AACR.

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols
  • Chemokines
  • Colorectal Neoplasms
  • Cytokines
  • Deoxycytidine
  • Disease-Free Survival
  • Female
  • Fluorouracil
  • Genetic Variation
  • Genotype
  • Humans
  • Leucovorin
  • Male
  • Middle Aged
  • Neovascularization, Pathologic
  • Organoplatinum Compounds
  • Pharmacogenetics
  • Polymorphism, Restriction Fragment Length
  • Polymorphism, Single Nucleotide
  • Vascular Endothelial Growth Factor A

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