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Background  Recognizing EGFR as key orchestrator of the metastatic process in colorectal cancer, but also the substantial heterogeneity of responses to anti-EGFR therapy, we examined the pattern of composite tumor kinase activities governed by EGFR-mediated signaling that might be implicated in development of metastatic disease.    Patients and Methods  Point mutations in  KRAS ,  BRAF , and  PIK3CA  and  ERBB2  amplification were determined in primary tumors from 63 patients with locally advanced rectal cancer scheduled for radical treatment. Using peptide arrays with tyrosine kinase substrates,  ex vivo  phosphopeptide profiles were generated from the same baseline tumor samples and correlated to metastasis-free survival.    Results  Unsupervised clustering analysis of the resulting phosphorylation of 102 array substrates defined two tumor classes, both consisting of cases with and without  KRAS/BRAF  mutations. The smaller cluster group of patients, with tumors generating high  ex vivo  phosphorylation of phosphatidylinositol-3-kinase-related substrates, had a particularly aggressive disease course, with almost a half of patients developing metastatic disease within one year of follow-up.    Conclusion  High phosphatidylinositol-3-kinase-mediated signaling activity of the primary tumor, rather than  KRAS/BRAF  mutation status, was identified as a hallmark of poor metastasis-free survival in patients with locally advanced rectal cancer undergoing radical treatment of the pelvic cavity.

Tumor Phosphatidylinositol-3-Kinase Signaling and Development of Metastatic Disease in Locally Advanced Rectal Cancer