Coordinated over-expression of genes in the EGFR pathway predicts sensitivity to EGFR inhibition in pancreatic cancer

B108 Background: The EGFR inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal. Known predictive factors for EGFR inhibitor efficacy are not prevalent in pancreatic cancer. We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy in pancreatic cancer. Methods: Tumors originated as fresh xenografts directly from pancreatic cancer specimens obtained at surgery were treated with EGFR inhibitors. A series of biological studies including global gene expression analysis, mutation and amplification assessment were performed and results linked to drug activity. Results: Two of ten tumors were sensitive to the EGFR inhibitors erlotinib and cetuximab. A ceiling of activity was seen, as combined EGFR targeting did not have enhanced antitumor effect in those, or prompt sensitivity in any other. By global gene expression profiling with gene set enrichment and pathway analysis the EGFR pathway was coordinately and highly expressed in sensitive compared with resistant tumors. The core gene components that drove EGFR pathway over-expression were pathway ligands and positive effectors. In a prospective validation set, the signature correctly predicted anti-EGFR treatment response in eight additional tumors, for an overall accuracy of 18/18 (P