Impact of Diabetes and Metformin Use on Enteropancreatic Neuroendocrine Tumors: Post Hoc Analysis of the CLARINET Study

Abstract

The prognostic role of diabetes mellitus (DM) in advanced enteropancreatic neuroendocrine tumors (NETs) is unclear. Progression free survival (PFS) was assessed in post-hoc analyses of the 96-week, phase III, double-blind, placebo-controlled CLARINET study of lanreotide 120 mg in patients with advanced non-functional enteropancreatic NETs with DM (with/without metformin) and without DM. Of 204 patients, there were 79 with DM (lanreotide, n = 42 {metformin, n = 14}; placebo, n = 37 {metformin, n = 10}) and 125 without DM (lanreotide, n = 59; placebo, n = 66). Median PFS was 96.0 and 98.0 weeks with and without DM, respectively (hazard ratio 1.20 {95% confidence interval 0.79 to 1.82}; p = 0.380). No difference in PFS was observed in lanreotide-treated patients with/without DM (p = 0.8476). In the placebo group, median PFS was numerically shorter with versus without DM (p = 0.052) and was significantly longer in patients with DM and metformin (85.7 weeks) versus without metformin (38.7 weeks; p = 0.009). Multivariable Cox analyses showed that DM at baseline was not associated with PFS (p = 0.079); lanreotide was significantly associated with lower disease progression risk (p = 0.017). Lanreotide efficacy was confirmed in patients with advanced enteropancreatic NETs, regardless of diabetic status; DM was not a negative prognostic factor. A potential antitumor effect of metformin was observed in patients receiving placebo.

Visceral Obesity Is Associated with Shorter Progression-Free Survival in Well-Differentiated Gastro-Entero-Pancreatic Neuroendocrine Neoplasia

“…A recent post-hoc analysis of the CLARINET study on the impact of diabetes and metformin at GEP-NEN PFS concluded that diabetes was not a negative prognostic factor. However, patients in the placebo group who were under metformin had longer PFS (85.7 weeks for metformin vs. 38.7 weeks for no-metformin, p = 0.017), an effect that was not observed in the lanreotide treatment arm [ 36 ]; a finding which favors the hypothesis that the anti-tumor effect of metformin is abrogated in the presence of mTORC1 axis inhibition by somatostatin analogues. Metformin is an anti-diabetic drug with direct action on phosphoinositide 3-kinase/serine/threonine kinase/mTor (Pi3k/Akt/mTor pathway) via Adenosine Monophosphate-Activated Protein Kinase (AMPK) suppressive activity on Mammalian Target of Rapamycin Complex 1 (mTORC1) and indirect effects on insulin secretion and insulin-like growth factor-1 (IGF-1) activity, which was also demonstrated to depict anti-cancer effects [ 37 ].…”

“…It is noteworthy that our study cohort differs from the ones of the abovementioned studies. When compared to CLARINET post-hoc, the follow-up time is longer (95.0 months vs. 24 months) and included mainly carcinoid syndrome-associated GI-tract primary tumors (55.6% midgut tumors) vs. non-functioning pNEN [ 36 ], a feature that also contrasts with the PRIME-NET study that included only patients with pNEN, some of which in the context of MEN1, while the hormonal status was not described [ 42 ]. Our study is one of the first to describe the association of MetS with functioning GI-NEN, namely midgut NEN, while most of our previous data documented the association of metabolic abnormalities with non-functioning pNEN [ 28 ].…”

Metformin: A promising drug for human cancers (Review)

“…Most ongoing clinical trials are based on the evaluation of changes in biomarkers, including insulin levels, AKT/mTOR signals and Ki67 staining. In addition, the clinical benefit of metformin, which uses response and survival rates as indicators, have also been studied, and retrospective studies have used cancer chemotherapy response and survival time as indicators, proving that metformin has potential clinical benefits ( 103 , 104 ).…”

Estudo de fase II piloto de metformina em pacientes com tumores neuroendócrinos bem diferenciados

“…O papel prognóstico do DM-2 também foi analisado em uma análise post hoc do estudo fase III, duplo cego, placebo controlado, CLARINET, com uso de lanreotide 120 mg, em pacientes com TNE enteropancreático não funcional (68,69) . Do grupo que recebeu lanreotide, 42 pacientes tinham DM-2 e do grupo que recebeu placebo, 37 tinham DM-2.…”

“…Do grupo que recebeu lanreotide, 42 pacientes tinham DM-2 e do grupo que recebeu placebo, 37 tinham DM-2. A SLP foi 96 semanas no grupo intervenção e 98 semanas no grupo placebo, sem significância estatística (p=0,380) (68) . No estudo Prime-NET, dos pacientes com TNE de pâncreas tratados com everolimo, 209 pacientes não diabéticos tiveram uma mediana de SLP de 15,1 meses e 236 pacientes com diabetes tiveram uma SLP mediana de 32 meses (razão de risco: 0,63 [IC] 95%: 0,5 -0,8) (51) .…”