Use Of A Prognostic Pathway Signature For Colorectal Cancer Comprised Of Egfr/Cox2 And Imatinib Drug Target Activation To Predict Occult Metastasis In M0 Crc

4042 Background: Development of distant metastasis is the main cause of death among CRC patients. Approximately 30% of CRC patients initially staged M0-N0 die from tumor recurrence. Previously, we determined that members of EGFR/PDGFR/cAbl/cKit pathways were hyperactivated in hepatic synchronous CRC metastasis compared to primary tumor. In order to determine if this signature was a distinguished repertoire of the early stage primary tumor, we analyzed 58 CRC M0 at the moment of the diagnosis that upon 5 yr follow-up had differing disease progressions. Methods: All tissues were immediately snap frozen after surgery. Reverse phase protein microarray (RPMA) was performed using microdissected material to generate multiplexed pathway profiling. For each sample 75 different endpoints were analyzed. Results: Statistical comparison of the 75 endpoints in 8 M0 patients who progressed to M1 and 50 patients who remained M0 regardless of initial staging, revealed a number of signaling proteins whose activation/phosphorylation were elevated and subsumed in a linked pathway. Specifically COX2 and c-Kit/PDGFR/Notch were highly activated in the 8 patients with occult metastasis. A prognostic pathway signature comprised of 13 interlinked molecules was developed. Univariate, ROC and Kaplan-Meier analysis of this signature revealed a statistically significant prognostic signature with an AUC of 0.87 and a 95% confidence interval. Conclusions: A signaling portrait of 13 interlinked proteins provided a strong prognostic indicator for metastasis regardless of stage. This signature was comprised of the phosphorylation/activation of growth factor receptors, including the entire suite of Gleevec targets. A large number of these prognostic signature components were previously found activated in the metastatic lesions themselves which indicates a potential functional role of this linked protein network in metastatic progression and maintenance. If validated in larger study sets, clinical trials to test Gleevec therapy combined with Cox2 /EGFR inhibitors to prevent/delay development of distant metastasis in patients with M0 should be considered. [Table: see text]