title: Prognostic significance of AKT/mTOR signaling in advanced neuroendocrine tumors treated with somatostatin analogs.
abstract: BACKGROUND
  Somatostatin analogs (SSAs) are used as part of standard treatment for advanced neuroendocrine tumors (NETs). The mechanisms behind the antiproliferative action of SSAs remain largely unknown, but a connection with the mammalian target of rapamycin (mTOR) signaling pathway has been suggested. Our purpose was to evaluate the activation status of the AKT/mTOR pathway in advanced metastatic NETs and identify biomarkers of response to SSA therapy.
  
  
  METHODS
  Expression of phosphatase and tensin homolog (PTEN), phosphorylated (p)-AKT(Ser473), and p-S6(Ser240/244) was evaluated using immunohistochemistry in archival paraffin samples from 23 patients. Expression levels were correlated with clinicopathological parameters and progression-free survival under treatment with SSAs.
  
  
  RESULTS
  A positive association between p-AKT and p-S6 expression was identified (P = 0.01) and higher expression of both markers was observed in pancreatic NETs. AKT/mTOR activation was observed without the loss of PTEN expression. Tumors showing AKT/mTOR signaling activation progressed faster when treated with SSAs: higher expression of p-AKT or p-S6 predicted a median progression-free survival of 1 month vs 26.5 months for lower expression (P = 0.02).
  
  
  CONCLUSIONS
  Constitutive activation of the AKT/mTOR pathway was associated with shorter time-to-progression in patients undergoing treatment with SSAs. Larger case series are needed to validate whether p-AKT(Ser473) and p-S6(Ser240/244) can be used as prognostic markers of response to therapy with SSAs.
authors.affiliation: Department of Medical Oncology, Hospital Santa Maria, CHLN, Lisboa, Portugal; ; Clinical and Translational Oncology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal;
authors.forename: Isabel
authors.initials: I
authors.lastname: Fernandes
authors.forename: Teresa R
authors.initials: TR
authors.lastname: Pacheco
authors.forename: Adília
authors.initials: A
authors.lastname: Costa
authors.forename: Ana C
authors.initials: AC
authors.lastname: Santos
authors.forename: Ana R
authors.initials: AR
authors.lastname: Fernandes
authors.forename: Mara
authors.initials: M
authors.lastname: Santos
authors.forename: António G
authors.initials: AG
authors.lastname: Oliveira
authors.forename: Sandra
authors.initials: S
authors.lastname: Casimiro
authors.forename: António
authors.initials: A
authors.lastname: Quintela
authors.forename: Afonso
authors.initials: A
authors.lastname: Fernandes
authors.forename: Madalena
authors.initials: M
authors.lastname: Ramos
authors.forename: Luís
authors.initials: L
authors.lastname: Costa