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

Abstract

ABSTRACT 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. Methods: We retrospectively evaluated the difference in terms of progression-free survival (PFS) between consecutive diabetic pts on MET and those on insulin (INS) as concomitant drugs during EVE plus OCT therapy. Normoglycemic pts served as controls. Results: Between 2009 and 2012, 31 pts (age 55.5 years; 22 males) were treated with EVE plus OCT. Six pts received MET, 6 received INS and 19 pts were normogycemic. In the overall population, median PFS was 12 months (mo) (95%CI 6.3-17.7); mPFS was 24 mo (95% CI 8.6-59.9) in diabetic pts and 12 mo (95% CI 8.7- 15.3) in normoglycemic pts (HR 3.17, 95% CI 1.18-8.49; p = 0.016). Median PFS in pts on MET was “not achieved” versus 12.2 mo in pts treated with INS (95% CI 0-28). At the time of this analysis, 4 pts (67%) on MET are still receiving EVE plus OCT, with a median duration of treatment of 19.5 mo (range 10-27+ mo). Conclusions: Although the limited number of pts hampers the analysis, these retrospective results may suggest that the addition of MET to EVE plus OCT can provide clinical benefits to pWDNETs pts. A prospective evaluation is required to either confirm or disprove these preliminary findings. Disclosure: All authors have declared no conflicts of interest.