Abstract
Abstract Introduction: 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 is 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 normolgycemic. 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). Conclusion: Although the limited number of pts hampers the analysis, a prospective evaluation is required to either confirm or discard these preliminary findings. With the aim to evaluate the antiproliferative effect of MET in combination with EVE and OCT LAR in pWDNET pts, a single arm, prospective, single center phase II study was designed (MetNET-1 trial; NCT02294006). Forty-three patient will expect to be evaluated. The study is currently ongoing, and the recruitment is estimated to be completed in August 2016. The results will be anticipated in 2017. Citation Format: Sara Pusceddu, Roberto Buzzoni, Laura Concas, Cristina Bregant, Livia Leuzzi, Massimo Milione, Ettore Seregni, Barbara Formisano, Paola Consonni, Filippo De Braud. The impact of metformin on progression-free survival in patients with advanced pancreatic well differentiated neuroendocrine tumor receiving everolimus plus somatostatin analogue treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1189. doi:10.1158/1538-7445.AM2015-1189
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