Association of a polymorphism in amphiregulin with worse prognosis in metastatic colorectal cancer patients treated with cetuximab.

Abstract

e14543 Background: Accumulating data suggests that Amphiregulin (AREG) and Epiregulin (EREG), ligands of the EGFR pathway, are potential prognostic and predictive markers in metastatic colorectal cancer (mCRC). Elevated AREG and EREG gene expression levels are predictive of improved response rates in mCRC patients treated with cetuximab and longer overall survival (OS) in patients with mCRC who did not receive cetuximab. Since polymorphisms in AREG and EREG may affect their expression or function, we tested whether AREG and EREG polymorphisms were associated with clinical outcome in mCRC patients treated with cetuximab. Methods: Seventy-three patients (n=73) with histopathologically-confirmed mCRC with Kras/Braf wild type were enrolled in Italy. These patients were treated with cetuximab monotherapy or irinotecan plus cetuximab as second or third line treatment. Genomic DNA was extracted from blood and 4 SNPs in AREG and 5 SNPs in EREG were analyzed by direct DNA-sequencing. Results: The median follow-up period was 13.3 months in this cohort. The median progression-free survival (PFS) and OS were 5.2 and 12.9 months respectively. The results indicate that the intronic AREG polymorphism rs28364983 A/C was associated with shorter PFS and OS. Patients with homozygous C/C (n=2) showed a median PFS of 2.3 months vs. 5.3 months for patients harboring at least one-A allele (n=71) (HR: 4.26 [95%CI: 0.98-18.5], p=0.05). Patients with homozygous C/C showed a median OS of 3.0 months vs. 13.1 months for patients harboring at least one-A allele (HR: 3.98 [95%CI: 0.93-16.9], p=0.062). An independent cohort of thirty-three patients was used to validate these initial findings and showed that patients with homozygous C/C (n=3) had a median PFS of 2.3 months vs. 3.8 months for patients harboring at least one-A allele (n=103) (HR: 3.79 [95%CI: 1.16-12.3], p=0.027) and a median OS of 3.0 months vs. 8.4 months (HR: 3.01 [95%CI: 0.93-9.71], p=0.065), respectively. Conclusions: AREG rs28364983 predicted worse outcome in mCRC patients treated with cetuximab; however, further analyses are necessary to understand the mechanism and further validate the prognostic and/or predictive role of this polymorphism.