Abstract LB-256: Impact of metformin on progression-free survival in diabetic patients with advanced pancreatic neuroendocrine tumors (pNETs) receiving everolimus and/or somatostatin analogues: A sensitivity analysis of the PRIME-NET (pancreatic multicentric, retrospective, italian metformin) study
Authors: Pusceddu Sara , Vernieri Claudio , Maio Massimo Di , Daniela Femia , Prinzi Natalie , Marconcini Riccardo , Spada Francesca , Massironi Sara , Bongiovanni Alberto , Brizzi Maria Pia , Campana Davide , Faggiano Antongiulio , Giuffrida Dario , Fave Gianfranco Delle , Cingarlini Sara , Aroldi Francesca , Antonuzzo Lorenzo , Berardi Rossana , Catena Laura , Buzzoni Roberto , Braud Filippo de 
Published: July 2017

Abstract
Introduction: Several studies have correlated the diabetic status with increased cancer risk and worse cancer prognosis, while metformin (MET) use is associated with a better prognosis. MET could display antitumor effects by modifying systemic metabolism, e.g. by decreasing of blood glucose, insulin and IGF1 levels, or by affecting cancer cell metabolism and proliferation, e.g. through AMPK activation and inhibition of protein/lipid synthesis. Preliminary findings of the PRIME-net retrospective study, conducted on 445 Italian pts, suggested that the addition of MET to EVE and/or SSAs provides clinical benefit in diabetic patient with advanced pancreatic NETs.
Methods: To exclude the possibility that the “time-on-treatment bias” could affect our results, with the risk that an early interruption of EVE or SSA-therapy due to early disease progression may result in lower pt exposure to these drugs and a consequently lower incidence of diabetes in poor responders, a sensitivity analysis on the PRIME-net study population was performed. The analysis considered only diabetics at baseline (BD), thus excluding pts who developed on-treatment diabetes as an adverse event (AE). All statistical tests were two-tailed and p-values&lt;0·05 were considered significant.
Results: Out of 445 pts, 237 were diabetics. Of them, 179 had baseline diabetes (BD) while 57 developed on-treatment diabetes as an adverse event. Among pts with BD, 80 (44.7%) received MET, while 99 (55.3%) were not treated with MET, but received other treatments including insulin. mPFS was 24.7 mo in pts with BD and 15.1 mo in normoglycemic ones (HR 0.70, 95%CI 0.55-0.91; p=0.007). In pts on MET therapy, mPFS was 43.7 mo (HR vs normoglycemic pts 0.52, 95%CI 0.36-0.76, p=0.0006), while it was 20.8 mo in pts not receiving MET (HR vs normoglycemic pts 0.87, 95%CI 0.65-1.17, p=0.37).
Conclusions: This sensitivity analysis confirms results emerged from the main analysis, thus demonstrating a mPFS advantage in diabetic patients with advanced pNETs patients receiving MET in combination with EVE and/or SSAs. Prospective investigations are ongoing to test the antitumor activity of MET in combination with everolimus and SSAs in normoglycaemic pts with advanced pNETs. Protocol number INT 85/15, approved by Ethical committee of fondazione IRCCS Istituto Tumori Milano on 15 June 2015.
Citation Format: Sara Pusceddu, Claudio Vernieri, Massimo Di Maio, Femia Daniela, Natalie Prinzi, Riccardo Marconcini, Francesca Spada, Sara Massironi, Alberto Bongiovanni, Maria Pia Brizzi, Davide Campana, Antongiulio Faggiano, Dario Giuffrida, Gianfranco Delle Fave, Sara Cingarlini, Francesca Aroldi, Lorenzo Antonuzzo, Rossana Berardi, Laura Catena, Roberto Buzzoni, Filippo de Braud. Impact of metformin on progression-free survival in diabetic patients with advanced pancreatic neuroendocrine tumors (pNETs) receiving everolimus and/or somatostatin analogues: A sensitivity analysis of the PRIME-NET (pancreatic multicentric, retrospective, italian metformin) study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-256. doi:10.1158/1538-7445.AM2017-LB-256