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ESMO 2016: Metformin Significantly Lowers the Risk of Cancer Progression in Patients with Diabetes and Advanced pNETs

Large retrospective analysis shows diabetic patients with pNETs on metformin have prolonged PFS
10 Oct 2016
Endocrine and neuroendocrine tumours;  Anticancer agents & Biologic therapy

A retrospective evaluation of patients receiving treatment for pancreatic neuroendocrine tumours (pNETs) showed that patients with diabetes had longer progression-free survival (PFS) than non-diabetic (normoglycaemic) patients.

Patients treated with metformin for diabetes also had the lowest risk of pNETs progression compared to non-diabetic patients, according to findings reported by an Italian team of investigators on 10 October at the ESMO 2016 Congress in Copenhagen.

According to lead author Sara Pusceddu, Medical Oncology Department, Fondazione IRCCS - Istituto Nazionale dei Tumori in Milan, Italy, previous studies have suggested that patients with diabetes have an increased risk of developing cancer. Metformin, the most widely used treatment in type 2 diabetes mellitus, has been associated with a decrease in cancer risk and has recently emerged as a potential anti-proliferation agent in cancer. She pointed out that metformin indirectly decreases both glucose, insulin and insulin-like growth factor 1 (IGF1) levels, and further explained that metformin promotes AMPK activation and mTOR inhibition by TSC1-2.

Together with collegues, Dr. Pusceddu conducted this multicentre, retrospective study to assess the impact of hyperglycaemic versus normoglycaemic status on PFS in patients with pNETs, and to evaluate the impact of concomitant metformin administered during everolimus and/or somatostatin analogue therapy. The hazard ratio (HR) for risk of progression was calculated at 90% statistical power, with α error of 0.05 to detect risk of 0.67 in 445 hyperglycaemic versus normoglycaemic patients. The statistical power in the analysis of smaller subgroups of hyperglycaemic versus normoglycaemic patients on metformin and hyperglycaemic versus normoglycaemic on insulin was 77% to detect a HR of 0.67.

Investigators consulted the database of 24 Italian centres that included 445 patients who received everolimus and/or somatostatin analogues treatment for pNETs between 1999 and 2015. The patients’ median age was 59 (range: 49 to 69) years and 53.5% of patients were male.

Of the patients with pNETs, 209 (46.7%) patients were normoglycaemic and 236 were hyperglycaemic. Of the latter, 112 (25.2%) diabetic patients received metformin, 91 (20.4%) received insulin, and 33 (7.7%) patients were given dietetic counselling.

Metformin Significantly Lowers the Risk of Cancer Progression in Patients with Diabetes and Advanced pNETs

THE PRIME-NET Pancreatic Retrospective Italian MEtformin (NET study) - PFS (normoglycemia vs hyperglycemia). © Sara Pusceddu

In the overall population of patients treated for pNETs, median PFS was 23.4 months (95% confidence interval [CI] 19.1, 27.9). However, PFS was prolonged to 32 months in the subgroup of patients who were hyperglycaemic and had diabetes compared to just 15.1 months in normoglycaemic patients, HR 0.63; 95%CI 0.50, 0.80 (p = 0.0002).

Metformin Significantly Lowers the Risk of Cancer Progression in Patients with Diabetes and Advanced pNETs

THE PRIME-NET Pancreatic Retrospective Italian MEtformin (NET study) - PFS according to glycemia and hypoglyc drugs. © Sara Pusceddu. 

Further subgroup analysis revealed that diabetic patients who received insulin modulating therapy had a prognosis more similar to normoglycemic patients, with difference on PFS which is not statistically significant; the median PFS was 20.8 months (95% CI 15.6-36.3) in patients receiving insulin, (HR versus normoglycaemic patients 0.81; 95% CI 0.60, 1.1 (p = 0.18). However, patients on metformin showed the most prolonged PFS and a lower risk that was statistically significantly; PFS was 44.2 months (95% CI 36.4, 61.9) and the HR for progression versus normoglycaemic patients was 0.45; 95% CI 0.32, 0.62 (p< 0.0001). These results are highly statistically significant.


The authors noted that this study had the limitations of any retrospective analysis but concluded that findings from this large study suggest that adding metformin to either everolimus or a somatostatin analougue may provide clinical benefit in patients with diabetes and advanced pNETs.

They called for a prospective study to confirm these preliminary findings.



Metformin impact on progression-free survival in diabetic patients with advanced pancreatic neuroendocrine tumors (pNET) receiving everolimus and/or somatostatin analogues. The PRIME-NET (Pancreatic multicentric, Retrospective, Italian MEtformin) study

S. Pusceddu, R. Marconcini, F. Spada, S. Massironi, A. Bongiovanni, M.P. Brizzi, N. Brighi, A. Colao, D. Giuffrida, G. Delle Fave, S. Cingarlini, F. Aroldi, L. Antonuzzo, R. Berardi, L. Catena, C. de divitis, P. Ermacora, M. Di Maio, R. Buzzoni, F. de Braud 

Last update: 10 Oct 2016

This trial was sponsored by the Fondazione IRCCS Istituto Nazionale Tumori di Milano.

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