KRAS, BRAF mutations, and HER2 expression in patients operated for pancreatic adenocarcinomas.

Abstract

4043 Background: The results of cytostatic treatment in pancreatic ductal adenocarcinomas (PDAC) are still disappointing. Standard treatment is still gemcitabine, monotherapy or in combinations. Studies have shown an association between high hENT1 expression and response to Gemcitabine. New biological treatments have been tried with disappointing results. Activation of the KRAS oncogene is a key genetic step in the development and growth of PDAC. Most of these mutations occur in codon 12. Concomitant mutations in codons 13 and 61 are described. In colo-rectal cancer KRAS (codon 12,13) and BRAF (exon15, V600E) mutational status predict the response to treatment with monoclonal antibodies directed against the EGFR. In breast and gastric adenocarcinomas patients with HER3+ and 2+/FISH+ tumors benefits from Trastuzumab treatment. Aim:To describe the frequency of KRAS and BRAF mutations and the expression of HER2 in a population of patients operated for pancreatic (PDAC) and ampullary (AMPC) adenocarcinomas. Methods: Tumor specimens from 277 patients operated at Herlev Hospital were screened for KRAS and BRAF mutations using PCR and LightScanner (Idaho Technology). Samples suspected for mutations were selected for gene sequencing. DNA from KRAS wildtype (WT) samples was analysed again using TheraScreen KRAS mutation kit (DXS diagnostics). HER2 expression was analyzed by IHC, DAKO Hercep Test. Results: In PDAC 20% were WT and 72% had mutations in codon 12 and 13, 8% had other mutations. In AMPC 33% were WT and 55% had mutations in codon 12 and 13, 12% other mutations. Multivariate analysis showed that KRAS mutation was associated with short overall survival (OS) (HR = 1.48, 95% CI: 1.07-2.05, p = 0.02). Patients with codon 12 Asp or Val mutations had a shorter OS compared to WT and other KRAS mutations (HR = 1.79, 1.35-2.37, p = 0.0001). 22% of PDAC and 40% of ampullary cancers were both KRAS (codon12,13) and BRAF (exon15) WT. 7% PDAC and 13% AMPC were HER2 3+/2+. No association between BRAF or HER2 status and OS was found. Conclusions: We suggest that future studies should evaluate the effect of targeting EGFR in the subgroups of patients with PDAC or ampullary cancer with KRAS (codon 12,13) BRAF WT and HER2 in the HER2 3+, 2+/FISH+ subgroups. No significant financial relationships to disclose.