Molecular markers of the EGFR pathway in erlotinib-treated patients with advanced pancreatic cancer (APC): Translational analyses of a randomized, cross-over AIO phase III trial.

Abstract

4047 Background: Within a cross-over phase III trial, we compared gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in patients with treatment-naive APC (Boeck S et al, ASCO 2010, LBA4011). Valid translational data are still lacking from APC phase III trials. Methods: 281 patients (pts) were randomized; archival formalin fixed paraffin embedded (FFPE) tumor tissue was available from 208 pts. We centrally analysed KRAS exon 2 mutation status (PCR), EGFR expression (immunohistochemistry, IHC and fluorescence in-situ hybridization, FISH), PTEN expression (IHC), as well as the EGFR intron 1 polymorphism [PM] (PCR) and the EGFR exon 13 R497K PM (PCR). Translational biomarker data were correlated (either as dichotomous or continuous variables, respectively) with overall survival (OS) by using Kaplan-Meier estimates and the log rank test. Results: KRAS mutations (all in codon 12) were found in 121/173 pts (70%), EGFR expression was detected in 174/181 pts (96%) by IHC, and 77/166 pts (46%) had an EGFR gene amplification by FISH; 30/171 pts (18%) had a loss of PTEN expression. Median number of CAn repeats in the intron 1 PM (allele 1+2, n=186) was 34 (range 28-41) and 112/194 pts (58%) had the GG wildtype sequence for the exon 13 R497K PM of the EGFR gene. EGFR intron 1 PM showed no correlation with EGFR expression either by IHC (p=0.264) or FISH (p=0.311). Median OS for all 208 pts was estimated with 6.2 months. In univariate biomarker analyses KRAS mutation status was significantly associated with OS (HR 1.68, 95% CI 1.17-2.41, p=0.005); no significant correlation was found for EGFR-IHC (HR 1.01, p=0.985), EGFR-FISH (HR 1.22, p=0.252), PTEN-IHC (HR 0.77, p=0.216), EGFR intron 1 PM (HR 1.02, p=0.540) or EGFR exon 13 R497K PM (HR 0.83, p=0.231). None of the 6 molecular biomarkers analysed correlated with the occurrence of skin rash. Conclusions: Translational research with archival FFPE tissue is feasible in APC phase III trials. Molecular markers of the EGFR pathway may be associated with treatment outcome in erlotinib-treated pts with APC.