Investigational New Drugs

, Volume 34, Issue 5, pp 654–662 | Cite as

Prediction of response to everolimus in neuroendocrine tumors: evaluation of clinical, biological and histological factors

  • Noura Benslama
  • Julien Bollard
  • Cécile Vercherat
  • Patrick Massoma
  • Colette Roche
  • Valérie Hervieu
  • Julien Peron
  • Catherine Lombard-Bohas
  • Jean-Yves Scoazec
  • Thomas Walter


Objectives Several targeted therapies are available for metastatic neuroendocrine tumours (NETs) but no predictive factor of response to these treatments has been identified yet. Our aim was to identify and evaluate clinical, biological, histological and functional markers of response to everolimus. Methods We retrospectively reviewed 53 patients with NETs treated with everolimus (68 % in clinical trials). Clinical, biological and histological data were analyzed. The functional marker p-p70S6K, a main effector of the mTOR pathway, was studied by immunohistochemistry in 43 cases. Prognostic factors of progression-free survival (PFS) were studied by Kaplan Meier analysis. Results All patients had metastatic and progressive disease before everolimus treatment. Objective response was 9 % and median PFS was 8.1 (4.7–11.5) months. Hypercholesterolemia (HR = 0.13, p < 0.0001) was associated with longer PFS, whereas presence of bone metastases (HR = 3.1, p < 0.001) and overexpression of p-p70S6K by tumor cells (HR = 2.5, p = 0.01) were associated with shorter PFS under everolimus at multivariate analysis. Conclusion Clinical markers are not useful to predict response to everolimus. However, occurrence of hypercholesterolemia under treatment may be an early marker of response. Prospective studies are required to confirm these results and to assess whether p-p70S6K immunostaining is a prognostic or predictive marker of no-response to everolimus.


Neuroendocrine tumours Everolimus Markers P-p70S6K Hypercholesterolemia 


Author contributions

Study design: NB, CV, CR, JYS, TW

Collection of data: NB, VH, JYS, JB, PM, TW

Writing the manuscript: NB, JYS, TW

Approval of the manuscript: all authors

Compliance with ethical standards

Conflict of interest

T Walter, JY Scoazec have acted as advisory board member for Ipsen, Pfizer and Novartis.

All other authors: no conflict of interest.


This study received financial support from Novartis and la Ligue Contre le Cancer du Rhône, France.

C Vercherat is recipient of a post-doctoral grant from LYric grant INCa-DGOS 4664.


  1. 1.
    Yao JC, Hassan M, Phan A, et al. (2008) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35, 825 cases in the United States. J Clin Oncol Off J Am Soc Clin Oncol 26:3063–3072CrossRefGoogle Scholar
  2. 2.
    Pavel ME, Hainsworth JD, Baudin E, et al. (2011) Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 378:2005–2012CrossRefPubMedGoogle Scholar
  3. 3.
    Yao JC, Fazio N, Singh S et al. (2016) Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387(10022):968–77. doi:  10.1016/S0140-6736(15)00817-X.
  4. 4.
    Yao JC, Shah MH, Ito T, et al. (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Galanis E, Buckner JC, Maurer MJ, et al. (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol Off J Am Soc Clin Oncol 23:5294–5304CrossRefGoogle Scholar
  6. 6.
    Lee CK, Marschner IC, Simes RJ, et al. (2012) Increase in cholesterol predicts survival advantage in renal cell carcinoma patients treated with temsirolimus. Clin Cancer Res: An Official Journal of the American Association for Cancer Research 18:3188–3196CrossRefGoogle Scholar
  7. 7.
    Ravaud A, Urva SR, Grosch K, et al. (2014) Relationship between everolimus exposure and safety and efficacy: meta-analysis of clinical trials in oncology. Eur J Cancer 50:486–495CrossRefPubMedGoogle Scholar
  8. 8.
    Neshat MS, Mellinghoff IK, Tran C, et al. (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 98:10314–10319CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Janku F, Wheler JJ, Westin SN, et al. (2012) PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol Off J Am Soc Clin Oncol 30:777–782CrossRefGoogle Scholar
  10. 10.
    Iyer G, Hanrahan AJ, Milowsky MI, et al. (2012) Genome sequencing identifies a basis for everolimus sensitivity. Science 338:221CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bollard J, Couderc C, Blanc M, et al. (2013) Antitumor effect of everolimus in preclinical models of high-grade gastroenteropancreatic neuroendocrine carcinomas. Neuroendocrinology 97:331–340CrossRefPubMedGoogle Scholar
  12. 12.
    Cho D, Signoretti S, Dabora S, et al. (2007) Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 5:379–385CrossRefPubMedGoogle Scholar
  13. 13.
    Duran I, Kortmansky J, Singh D, et al. (2006) A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95:1148–1154CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Yoon DH, Ryu MH, Park YS, et al. (2012) Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum. Br J Cancer 106:1039–1044CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lombard-Bohas C, Cariou B, Verges B, et al. (2014) Management of metabolic disorders induced by everolimus in patients with differentiated neuroendocrine tumors: expert proposals. Bull Cancer 101:175–183PubMedGoogle Scholar
  16. 16.
    Verges B, Walter T, Cariou B (2014) ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS effects of anti-cancer targeted therapies on lipid and glucose metabolism. Eur J Endocrinol 170:R43–R55CrossRefPubMedGoogle Scholar
  17. 17.
    Bilimoria KY, Talamonti MS, Tomlinson JS, et al. (2008) Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients. Ann Surg 247:490–500CrossRefPubMedGoogle Scholar
  18. 18.
    Khan MS, Kirkwood A, Tsigani T, et al. (2013) Circulating tumor cells as prognostic markers in neuroendocrine tumors. J Clin Oncol Off J Am Soc Clin Oncol 31:365–372CrossRefGoogle Scholar
  19. 19.
    Capurso G, Archibugi L, Delle Fave G (2015) Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci 22(8):594–601. doi: 10.1002/jhbp.210.
  20. 20.
    Missiaglia E, Dalai I, Barbi S, et al. (2009) Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol Off J Am Soc Clin Oncol 28:245–255CrossRefGoogle Scholar
  21. 21.
    Qian ZR, Ter-Minassian M, Chan JA, et al. (2013) Prognostic significance of MTOR pathway component expression in neuroendocrine tumors. J Clin Oncol Off J Am Soc Clin Oncol 31:3418–3425CrossRefGoogle Scholar
  22. 22.
    Sharpe LJ, Brown AJ (2008) Rapamycin down-regulates LDL-receptor expression independently of SREBP-2. Biochem Biophys Res Commun 373:670–674CrossRefPubMedGoogle Scholar
  23. 23.
    Custodio AJ-FP, Alonso-Orduña V, López López C, Alonso T, Guillermo C, Carmona-Bayonas A, Álvarez-Escolá CSM, Capdevila J, Grande E, Barriuso J, Feliu J, Aller J (2015) Everolimus (EVE)-induced hyperglycemia (HG) in patients (pts) with advanced G1-G2 neuroendocrine tumors (NETs): clinical relevance and predictive value. ENETS - The European Neuroendocrine Tumor Society. Barcelona, InGoogle Scholar
  24. 24.
    Rugo HS, Hortobagyi GN, Yao J, Pavel M, Ravaud A, Franz D, Ringeisen F, Gallo J, Rouyrre N, Anak O, Motzer R (2016) Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy. Ann Oncol 27(3):519–525. doi: 10.1093/annonc/mdv595.
  25. 25.
    Templeton AJ, Dutoit V, Cathomas R, et al. (2013) Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08). Eur Urol 64:150–158CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Noura Benslama
    • 1
    • 2
    • 3
  • Julien Bollard
    • 2
  • Cécile Vercherat
    • 2
  • Patrick Massoma
    • 2
  • Colette Roche
    • 2
  • Valérie Hervieu
    • 2
    • 3
    • 4
  • Julien Peron
    • 5
  • Catherine Lombard-Bohas
    • 1
  • Jean-Yves Scoazec
    • 2
  • Thomas Walter
    • 1
    • 2
    • 3
  1. 1.Service d’hépatogastroentérologie et d’oncologie digestiveHospices Civils de Lyon, Hôpital Edouard HerriotLyon cedex 03France
  2. 2.INSERM, UMR 1052, Lyon Cancer Research Center, Faculté LaennecLyon cedex 08France
  3. 3.Université de Lyon, Université Claude Bernard Lyon 1Villeurbanne cedexFrance
  4. 4.Service Central d’Anatomie et Cytologie PathologiquesHospices Civils de Lyon, Hôpital Edouard HerriotLyon cedex 03France
  5. 5.Medical Oncology Department, Centre Hospitalier Lyon SudInstitut de Cancérologie des Hospices Civils de LyonPierre-BéniteFrance

Personalised recommendations