Epidermal growth factor receptor R521K polymorphism shows favorable outcomes in KRAS wild-type colorectal cancer patients treated with cetuximab-based chemotherapy

Yao Yu Hsieh, Cheng Hwai Tzeng, Ming Huang Chen, Po Min Chen, Wei Shu Wang

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The R521K polymorphism of epidermal growth factor receptor has attenuated affinity in ligand binding and proto-oncogene induction, which may affect the efficacy of cetuximab. We analyzed the effect of this polymorphism on the outcome of 112 patients with KRAS wild-type metastatic colorectal carcinoma treated with first-line cetuximab plus FOLFOX-4. The associations of this polymorphism with vascular endothelial growth factor (VEGF) expression and clinicopathologic characteristics were also examined. The results showed that the frequencies of the G/G, G/A, and A/A genotypes were 32.1% (n = 36), 42.9% (n = 48), and 25.0% (n = 28), respectively. A marked decrease in VEGF expression levels (66.7% vs 28.9%, P <0.01) was observed in patients with 521A allele variants (Arg/Lys or Lys/Lys), which were associated with a decreased tumor size (55.6% vs 31.6%, P = 0.02), good histological differentiation (63.9% vs 85.5%, P = 0.01), decreased lymphovascular invasion (69.4% vs 39.5%, P <0.01), and a higher response rate to cetuximab plus FOLFOX treatment (55.6% vs 78.9%, P = 0.01). In addition, this polymorphism was associated with a longer progression-free period (P = 0.001) and overall survival (P = 0.001). By multivariate analysis, this polymorphism was also identified as an independent prognostic factor. These data suggest that the R521K polymorphism of epidermal growth factor receptor, by reducing its activation and a consequential downregulation of its target genes, including VEGF, could be a key determinant of an increased response to cetuximab-based chemotherapy and a longer survival for KRAS wild-type colorectal carcinoma patients.

Original languageEnglish
Pages (from-to)791-796
Number of pages6
JournalCancer Science
Volume103
Issue number4
DOIs
Publication statusPublished - Apr 2012
Externally publishedYes

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Epidermal Growth Factor Receptor
Colorectal Neoplasms
Vascular Endothelial Growth Factor A
Drug Therapy
Survival
Proto-Oncogenes
Down-Regulation
Multivariate Analysis
Alleles
Genotype
Ligands
Cetuximab
Genes
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Epidermal growth factor receptor R521K polymorphism shows favorable outcomes in KRAS wild-type colorectal cancer patients treated with cetuximab-based chemotherapy. / Hsieh, Yao Yu; Tzeng, Cheng Hwai; Chen, Ming Huang; Chen, Po Min; Wang, Wei Shu.

In: Cancer Science, Vol. 103, No. 4, 04.2012, p. 791-796.

Research output: Contribution to journalArticle

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abstract = "The R521K polymorphism of epidermal growth factor receptor has attenuated affinity in ligand binding and proto-oncogene induction, which may affect the efficacy of cetuximab. We analyzed the effect of this polymorphism on the outcome of 112 patients with KRAS wild-type metastatic colorectal carcinoma treated with first-line cetuximab plus FOLFOX-4. The associations of this polymorphism with vascular endothelial growth factor (VEGF) expression and clinicopathologic characteristics were also examined. The results showed that the frequencies of the G/G, G/A, and A/A genotypes were 32.1{\%} (n = 36), 42.9{\%} (n = 48), and 25.0{\%} (n = 28), respectively. A marked decrease in VEGF expression levels (66.7{\%} vs 28.9{\%}, P <0.01) was observed in patients with 521A allele variants (Arg/Lys or Lys/Lys), which were associated with a decreased tumor size (55.6{\%} vs 31.6{\%}, P = 0.02), good histological differentiation (63.9{\%} vs 85.5{\%}, P = 0.01), decreased lymphovascular invasion (69.4{\%} vs 39.5{\%}, P <0.01), and a higher response rate to cetuximab plus FOLFOX treatment (55.6{\%} vs 78.9{\%}, P = 0.01). In addition, this polymorphism was associated with a longer progression-free period (P = 0.001) and overall survival (P = 0.001). By multivariate analysis, this polymorphism was also identified as an independent prognostic factor. These data suggest that the R521K polymorphism of epidermal growth factor receptor, by reducing its activation and a consequential downregulation of its target genes, including VEGF, could be a key determinant of an increased response to cetuximab-based chemotherapy and a longer survival for KRAS wild-type colorectal carcinoma patients.",
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