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

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.

Figure 1

Representative patterns of different KRAS exon 1 genotypes. The PCR products containing codons 12 and 13 of KRAS were amplified with PCR. After amplification, the PCR products were sequenced directly. wt, wild type.

Figure 2

Representative PCR‐RFLP patterns of different EGFR 521 genotypes. Genomic DNA obtained from patients' WBCs was subjected to PCR amplification. After being digested by Sty I, the PCR products were separated by agarose gel electrophoresis. Lanes 1, 4, 5, 6, and 8 represent G/A; lanes 2 and 7 represent A/A; lane 3 represents G/G. M, marker; UC, PCR product that has not been digested.

Figure 3

Representative immunohistochemical staining patterns of vascular endothelial growth factor (VEGF). The staining results for VEGF were divided into two groups, <10% and more than 10% positive cells, according to the percentage of carcinoma cells showing specific immune‐reactivity.

Figure 4

Epidermal growth factor receptor (EGFR) codon 521 G/A or A/A genotypes in KRAS wild‐type metastatic colorectal carcinoma patients are associated with longer progression‐free as well as overall survival. (A) Progression‐free survival curves of 112 metastatic colorectal carcinoma patients with different EGFR codon 521 genotypes were plotted by the Kaplan–Meier method (P = 0.001; log–rank test). (B) A similar method was used to plot overall survival curves (P = 0.001; log–rank test).