EGFR polymorphisms as predictors of clinical outcome in patients with advanced colorectal cancer (ACRC) treated with cetuximab and panitumumab

Abstract

4124 Background: To evaluate EGFR polymorphisms as predictors of clinical outcome in patients (pts) with ACRC treated with cetuximab or panitumumab. Methods: 84 pts with ACRC who received cetuximab or panitumumab in second and third line therapy were included. We analyze three polyphormisms: a single nucleotide polymorphism (SNP) in codon 216 (216 G/T), a SNP in codon 497 (497 G/A), and a dinucleotide repeat polymorphism in intron 1. DNA was extracted from paraffin-embedded tissue using the QiaAmp DNA Mini kit. The sAVH3, - 216G>T and R497K polymorphisms were genotyped in each pts. In order to differentiate genotypes, a specific PCR amplification was followed by an electrophoresis on an Applied Biosystems ABI310 genetic analyzer to detect a FAM-labeled PCR product (sAVH3), a restriction endonuclease enzyme digestion and a 4% agarose electrophoresis (-216G>T), or a detection on a Applied Biosystems 7300 RT-PCR System using the TaqMan technology (R497K). The number of the CA repeats (sAVH3) and genotype assignment (-216G>T and R497K) were confirmed by direct sequencing. Results: Polymorphisms analysis could be performed in 65 of 84 pts (77%). Overall response rate (ORR) was 21.7%, median progression-free survival (PFS) 3.7 months (m) (2.8–4.5) and median overall survival (OS) 7.1 m (5.6–8.6). Polymorphism in intron 1 (>18 vs <18) and promoter SNP -216G>T were not associated to ORR, PFS and OS. SNP R497K (GA/AA vs GG) was significantly associated with a lower ORR (33.3% vs 66.7% p=0.08), and a shorter PFS (1.6 vs 4.27 m p= 0.0052) and OS (5.25 vs 10.28 m p=0.0068). By multivariate analysis CEA (1.003 IC95% 1.001–1.004 p=0.0001), LDH (1.001 IC95% 1–1.002 p=0.001) and polymorphism R497K (3.295 IC95% 1.7–6.2 p=0.0001), were identified as an independent prognostic factors for PFS and OS. Conclusions: SNP in codon 497 of EGFR, by reducing EGFR activity, could be a determinant of resistance in ACRC, treated with anti- EGFR monoclonal antibodies. No significant financial relationships to disclose.