TY - JOUR
T1 - Impact of systemic and tumor lipid metabolism on everolimus efficacy in advanced pancreatic neuroendocrine tumors (pNETs)
AU - Vernieri, Claudio
AU - Pusceddu, Sara
AU - Fucà, Giovanni
AU - Indelicato, Pietro
AU - Centonze, Giovanni
AU - Castagnoli, Lorenzo
AU - Ferrari, Elisa
AU - Ajazi, Arta
AU - Pupa, Serenella
AU - Casola, Stefano
AU - Foiani, Marco
AU - Mazzaferro, Vincenzo
AU - Pruneri, Giancarlo
AU - Milione, Massimo
AU - de Braud, Filippo
PY - 2019/4/1
Y1 - 2019/4/1
N2 - The mTOR inhibitor everolimus is effective against advanced pancreatic neuroendocrine tumors (pNETs). However, it can cause metabolic adverse events, such as hyperglycemia, hypertriglyceridemia and hypercholesterolemia. In this work we aimed at evaluating the impact of systemic and tumor lipid metabolism on everolimus efficacy. We carried out a monocentric, retrospective study to correlate plasma triglyceride and cholesterol levels with the progression free survival (PFS) of advanced pNET patients treated with everolimus. In formalin fixed, paraffin embedded (FFPE) tumor specimens, we also assessed by mRNA quantification and immunohistochemistry the expression of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN), two enzymes crucially involved in fatty acid biosynthesis, and we analyzed their impact on PFS. We evaluated 58 consecutive pNET patients who started everolimus between December 2006 and January 2015. Patients with higher plasma triglycerides during the first 3 months of treatment had an increased risk of disease progression (aHR 3.08, 95% CIs 1.15–8.21; p = 0.025). In 23 FFPE tumor specimens amenable for IHC evaluations, we found a positive correlation between ACC1 and FASN at both mRNA (r = 0.87, p = 0.00045) and protein (r = 0.68, p = 0.0004) level. Patients with higher ACC1 protein expression in metastatic lesions had significantly lower PFS when compared to patients with lower ACC1 levels (5.5 vs. 36 months; aHR 4.49, 95% CIs 1.08–18.72; p = 0.039). In conclusion, systemic and tumor lipid metabolism are associated with the PFS of everolimus-treated patients with advanced pNETs; based on these findings, dietary and pharmacological interventions targeting lipid metabolism could improve everolimus efficacy in this patient population.
AB - The mTOR inhibitor everolimus is effective against advanced pancreatic neuroendocrine tumors (pNETs). However, it can cause metabolic adverse events, such as hyperglycemia, hypertriglyceridemia and hypercholesterolemia. In this work we aimed at evaluating the impact of systemic and tumor lipid metabolism on everolimus efficacy. We carried out a monocentric, retrospective study to correlate plasma triglyceride and cholesterol levels with the progression free survival (PFS) of advanced pNET patients treated with everolimus. In formalin fixed, paraffin embedded (FFPE) tumor specimens, we also assessed by mRNA quantification and immunohistochemistry the expression of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN), two enzymes crucially involved in fatty acid biosynthesis, and we analyzed their impact on PFS. We evaluated 58 consecutive pNET patients who started everolimus between December 2006 and January 2015. Patients with higher plasma triglycerides during the first 3 months of treatment had an increased risk of disease progression (aHR 3.08, 95% CIs 1.15–8.21; p = 0.025). In 23 FFPE tumor specimens amenable for IHC evaluations, we found a positive correlation between ACC1 and FASN at both mRNA (r = 0.87, p = 0.00045) and protein (r = 0.68, p = 0.0004) level. Patients with higher ACC1 protein expression in metastatic lesions had significantly lower PFS when compared to patients with lower ACC1 levels (5.5 vs. 36 months; aHR 4.49, 95% CIs 1.08–18.72; p = 0.039). In conclusion, systemic and tumor lipid metabolism are associated with the PFS of everolimus-treated patients with advanced pNETs; based on these findings, dietary and pharmacological interventions targeting lipid metabolism could improve everolimus efficacy in this patient population.
KW - acetyl-CoA carboxylase 1
KW - everolimus
KW - lipid metabolism
KW - metformin
KW - pancreatic neuroendocrine tumors
KW - triglycerides
UR - http://www.scopus.com/inward/record.url?scp=85059576683&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059576683&partnerID=8YFLogxK
U2 - 10.1002/ijc.32042
DO - 10.1002/ijc.32042
M3 - Article
C2 - 30520016
AN - SCOPUS:85059576683
VL - 144
SP - 1704
EP - 1712
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 7
ER -