Expression of an Activated Mammalian Target of Rapamycin (mTOR) in Gastroenteropancreatic Neuroendocrine Tumors (GEPNETs).
Deepti Dhall, Shikha Bose. Cedars-Sinai Medical Center, Los Angeles
Background: mTOR is an important regulator of cell proliferation, which is activated in various malignancies. A recent phase II trial has revealed the efficacy of mTOR inhibitor (Rapamycin and its derivative RAD001) against advanced low to intermediate grade neuroendocrine tumors. The purpose of this study was to evaluate the expression pattern of mTOR in GEPNETs and to correlate with Ki-67 proliferative index.
Design: Formalin-fixed, paraffin-embedded tissue sections from 27 well-differentiated neuroendocrine tumors, including 9 from pancreas, 11 from gastrointestinal tract, and 7 from metastatic sites (mostly liver), were immunohistochemically stained for phosphorylated mTOR (p-mTOR) using a rabbit monoclonal antibody (Cell Signaling). The percentage of tumor cells positively stained and staining intensity were recorded for each case. Less than 30% staining of tumor cells and weak staining were considered negative.
Results: Eighteen patients presented with a stage IV disease and 9 with either localized or regional metastasis. Twenty-two tumors (81%) showed moderate to strong diffuse staining for p-mTOR, including 6 (67%) pancreatic tumors, all 11 (100%) gastrointestinal tumors, and 5 (71%) metastatic tumors. Of 21 tumors in which Ki-67 proliferative index was available, 11 cases (79%) with a < 5% and 6 cases (85%) with a > 5% Ki-67 labeling index demonstrated positive staining for p-mTOR. The percentage of tumors positively stained for p-mTOR did not differ between cases with and without stage IV disease (78% and 89%, respectively).
Conclusions: 1) p-mTOR is overexpressed in most GEPNETs, irrespective of their site of origin, and whether they are primary or metastatic. 2) p-mTOR staining does not correlate with Ki-67 proliferative index. 3) p-mTOR expression is low in some GEPNETs, which may account for their lack of response to m-TOR inhibitors. 4) Additional studies are warranted to determine the role of p-mTOR in the selection of patients with targeted therapy.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 50, Tuesday Afternoon