title: Prediction of response to everolimus in neuroendocrine tumors: evaluation of clinical, biological and histological factors.
abstract: 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.
authors.affiliation: Service d'hépatogastroentérologie et d'oncologie digestive, Hospices Civils de Lyon, Hôpital Edouard Herriot, 69437, Lyon cedex 03, France.|INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372, Lyon cedex 08, France.|Université de Lyon, Université Claude Bernard Lyon 1, 69622, Villeurbanne cedex, France.
authors.forename: Noura
authors.initials: N
authors.lastname: Benslama
authors.affiliation: INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372, Lyon cedex 08, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Bollard
authors.affiliation: INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372, Lyon cedex 08, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Vercherat
authors.affiliation: INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372, Lyon cedex 08, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Massoma
authors.affiliation: INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372, Lyon cedex 08, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Roche
authors.affiliation: INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372, Lyon cedex 08, France.|Université de Lyon, Université Claude Bernard Lyon 1, 69622, Villeurbanne cedex, France.|Service Central d'Anatomie et Cytologie Pathologiques, Hospices Civils de Lyon, Hôpital Edouard Herriot, 69437, Lyon cedex 03, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hervieu
authors.affiliation: Medical Oncology Department, Centre Hospitalier Lyon Sud, Institut de Cancérologie des Hospices Civils de Lyon, Pierre-Bénite, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Peron
authors.affiliation: Service d'hépatogastroentérologie et d'oncologie digestive, Hospices Civils de Lyon, Hôpital Edouard Herriot, 69437, Lyon cedex 03, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lombard-Bohas
authors.affiliation: INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372, Lyon cedex 08, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Service d'hépatogastroentérologie et d'oncologie digestive, Hospices Civils de Lyon, Hôpital Edouard Herriot, 69437, Lyon cedex 03, France. thomas.walter@chu-lyon.fr.|INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372, Lyon cedex 08, France. thomas.walter@chu-lyon.fr.|Université de Lyon, Université Claude Bernard Lyon 1, 69622, Villeurbanne cedex, France. thomas.walter@chu-lyon.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walter
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000068338:Everolimus / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism; D011379:Prognosis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: Everolimus; Hypercholesterolemia; Markers; Neuroendocrine tumours; P-p70S6K