Metformin Impact on Progression-Free Survival in Advanced Pancreatic Well-Differentiated Neuroendocrine Tumors (Pwdnets). Retrospective Evaluation in Diabetic Patients Receiving Everolimus Plus Octreotide Lar Treatment

Aim: Abnormal PI3K–Akt–mTOR pathway signaling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor 1 (IGF1), has been implicated in the proliferation of pNET cells. Everolimus (EVE), an inhibitor of mTOR (a central regulator of growth/proliferation, cellular metabolism and angiogenesis) has shown antitumor benefit in pNETs alone and in combination with octreotide LAR (OCT) in RADIANT-1 and RADIANT-3 trials. An increasing number of studies have identified diabetic patients (pts) as having increased risk for the development of cancer and have associated metformin (MET) treatment with a decrease of cancer risk. MET has also been associated with improved outcomes in cancer pts. MET has recently shown some anti-cancer activity, both in vitro and in vivo studies by antisecretory properties to decrease insulin and IGF1 levels and by antitumor effect due to AMPK activation and consequently inhibition to TSC1-2/mTOR complex, mediated to LKB1 oncogene expression. The aims of this retrospective study, even if in a limited number of pts, was to evaluate the effect of concomitant MET administered during EVE plus OCT therapy in pts with pWDNETs and diabetes.