| The predictive capacity of epidermal growth factor receptor (EGFR) activating mutations for patients treated with EGFR tyrosine kinase inhibitors erlotinib and gefitinib has long been recognized; however, their implementation into clinical practice is limited to just a few institutions. Similarly, KRAS mutations are strongly associated with a lack of response to these agents as well as to the EGFR-targeted monoclonal antibody cetuximab. In non-surgical NSCLC patients, impediments to routine biomarker analysis include limited availability of archival tumor specimens, minimal tumor material on those specimens that are obtainable (often from small needle biopsies or aspirates), artifacts produced from the formalin-fixation process, and tumor heterogeneity. In contrast to archival material, plasma specimens are readily acquired and almost universally available from all patients. Plasma specimens are stored frozen in aliquots and are thus not subject to misleading formalin-induced DNA alterations. Most NSCLC patients have detectable levels of shed tumor DNA in peripheral circulation. We have established an allele-specific, real-time PCR approach with Scorpion primers using the Amplification Refractory Mutation System (Scorpion-ARMS) that is sensitive enough to detect tumor-specific KRAS and EGFR mutations in patient plasma. In our initial testing in a phase I/II clinical trial of 49 NSCLC patients at UC Davis, we found that this assay could identify patients both sensitive and resistant to an erlotinib-containing regimen (ASCO 2008, accepted for presentation). We propose to determine the frequency of mutations in KRAS (codon 12 and 13) and EGFR (exons 19, 20 and 21) detectable in baseline plasma specimens from patients enrolled on SWOG trials S0342 (chemotherapy plus cetuximab) and S0023 (randomized maintenance gefitinib vs. placebo). This analysis will provide the proof-of-principle required to propose a prospective clinical trial using the Scorpion-ARMS approach for patient screening.
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