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PETACC-3 study and correlation of molecular markers with stage-specific prognosis

Posted May 06 2009 12:00am

The Pan-European Trials in Alimentary Tract Cancers (PETACC-3) is a large phase III randomized trial that yielded pathologic samples evaluable for IHC and molecular testing from 1404 patients with stage II/III cancer in a substudy to correlate various markers with stage-specific prognosis.  The markers evaluated included p53, SMAD4, thymidylate synthase, telomerase, MSI, 18q LOH, KRAS mutation, and BRAF mutation.

The study compared 420 stage II patients and 984 stage III patients.  The most interesting finding from this substudy is strikingly different changes in marker expression between the two groups.  This suggests that stage II and stage III CRC develop through distinctly different molecular pathways and, thus, may represent different biological and clinico-pathologic entities, instead of the conventional idea that stage III cancers progress sequentially from stage II cancers.

MSI, p53 overexpression, and loss of SMAD4 expression are predictive of outcome but the predictive value is different between stage II and stage III.  MSI had prognostic significance in stage II but not stage III, while p53 overexpression and SMAD4 loss had prognostic significance in stage III but not stage II.  Studies such as these have implications for not only for identifying stage II patients who could be candidates for chemotherapy but for screening.

There is a whole other story about SMAD4, juvenile polyposis, bone morphogenetic protein signaling, and CRC--but that will have to wait for another post.

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