The relationship of K-ras mutations and EGFR gene copy number to outcome in patients treated with Erlotinib on National Cancer Institute of Canada Clinical Trials Group trial study PA.3

4521 Background: The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) PA.3 study compared treatment with the EGFR tyrosine kinase inhibitor erlotinib to placebo in patients with advanced stage pancreatic carcinoma who were receiving gemcitabine. This study demonstrated a significant advantage in survival [HR=0.82; P<0.04] and in progression free survival [HR=0.77; P<0.004] for patients who received erlotinib [Moore MJ et al, J Clin Oncol 2007]. While high-level expression of EGFR is common in pancreatic cancer, EGFR protein expression level as evaluated by immunohistochemistry did not predict which patients might benefit from erlotinib. In non- small cell lung cancer (NSCLC) where erlotinib has shown a survival benefit; the use of EGFR copy number measured by FISH is a better predictive factor for benefit, and patients whose tumor had a K-ras mutation do not respond nor benefit. Methods: The NCIC-CTG PA.3 trial had a sample size of 569 and NCIC.CTG has collected 280 archival formalin-fixed and paraffin embedded tumor biopsy or primary resection specimens from patients randomized on study. Many were fine needle aspirates and a total of 181 had sufficient tissue to allow molecular analysis. We performed a K-ras mutation analysis by PCR of exon 2 followed by sequencing, with negative results being validated by DHPLC. EGFR gene copy number was analysed by fluorescent in situ hybridization. Both methods were performed on all tumor samples adequate for analysis. Results: Overall 146 cases were suitable for K-ras mutation analysis and preliminary results have identified K-ras mutation in 90 patients [76%] and wild type KRAS in 29 patients; the remainder are pending. A total of 118 cases are suitable for EGFR FISH analysis, results have been obtained in 73 patients, and the remaining cases are pending. The correlations between K-ras mutational status and EGFR copy number, and outcomes [survival and disease control] in patients randomized to both erlotinib and placebo will be presented. [Table: see text]