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Margaux Foulfoin Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Gastroentérologie et d’Oncologie Médicale, Lyon, France

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Emmanuelle Graillot Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Gastroentérologie et d’Oncologie Médicale, Lyon, France
University of Lyon, Université Lyon 1, Lyon, France

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Mustapha Adham University of Lyon, Université Lyon 1, Lyon, France
Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de chirurgie, Lyon, France

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Pascal Rousset University of Lyon, Université Lyon 1, Lyon, France
Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de radiologie, Lyon, France

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Julien Forestier Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Gastroentérologie et d’Oncologie Médicale, Lyon, France

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Valérie Hervieu University of Lyon, Université Lyon 1, Lyon, France
Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d’Anatomie et Cytologie Pathologiques, Lyon, France

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Philip Robinson Hospices Civils de Lyon, DRCI, Lyon, France

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Jean-Yves Scoazec Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d’Anatomie et Cytologie Pathologiques, Lyon, France

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Catherine Lombard-Bohas Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Gastroentérologie et d’Oncologie Médicale, Lyon, France

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Thomas Walter Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Gastroentérologie et d’Oncologie Médicale, Lyon, France
University of Lyon, Université Lyon 1, Lyon, France

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The choice of first-line treatment for metastatic pancreatic neuroendocrine tumors (mP-NET) is mainly based on prognostic factors. ENETS-2016 guidelines stratified treatment according to 3 groups: Group 1, patients in whom all lesions could be removed; Group 2, patients with Ki67 <10%, low tumor burden, no symptoms and stable disease, for whom a watch-and-wait strategy or somatostatin analogs are proposed; Group 3, symptomatic patients or with Ki67 >10% or significant tumor burden or progressive disease, for whom a systemic chemotherapy is proposed. This retrospective study aimed to determine patient distribution, characteristics and outcome among these 3 groups. Patients with mP-NET diagnosis from 2004 to 2016 were categorized into the three groups. Prognosis was calculated using the Kaplan–Meier method. All treatments were recorded, and consistency with ENETS guidelines was explored. 104 patients were analyzed: 64% synchronous mP-NET, 80% grade 2 tumors and median overall survival (OS) of 104 (95% CI: 65–143) months. There were 15 patients in ENETS Group 1, 16 in Group 2 and 73 in Group 3. Median OS was not reached in Groups 1 and 2 and was 64 months (35–93) in Group 3. High liver tumor volume, high-grade tumor and progressive disease were associated with worse OS in multivariate analysis. The first-line treatment was in accordance with guidelines in 82%. 77% percent of deceased patients received less than 4 lines of treatment. Most patients are in Group 3 and do not receive all available treatments. Thus, trials are warranted to improve first-line chemotherapy. Alternative treatments may be considered for less aggressive disease.

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Laura Gerard Service de Gastroentérologie et d’Oncologie Médicale, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France
Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Céline Patte Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Laurence Chardon Service de Biochimie Biologie Moléculaire, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France

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Valérie Hervieu Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France
Service Central d’Anatomie et Cytologie Pathologiques, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France

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Léa Payen Institut de Cancérologie des Hospices Civils de Lyon, CIRculating CANcer Program (CIRCAN), Lyon, France

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Marion Allio Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Claire Marx Service d'Endocrinologie-Diabète-Nutrition, Hospices Civils de Lyon, Hôpital Lyon Sud, Lyon, France

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Hugo Clermidy Service de Chirurgie Thoracique, Vidéothoracoscopie et Transplantation Pulmonaire, Hospices Civils de Lyon, Hôpital Louis Pradel, Lyon, France

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Alice Durand Service de Gastroentérologie et d’Oncologie Médicale, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France

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Patrick Mehlen Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Julien Bollard Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Gilles Poncet Service de Chirurgie Digestive, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France

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Colette Roche Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Benjamin Gibert Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Thomas Walter Service de Gastroentérologie et d’Oncologie Médicale, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France
Gastroenterology and Technologies for Health, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Lyon, France

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Neuropilin 2 (NRP2), a transmembrane non-tyrosine kinase receptor, has been described as a potential critical player in the tumourigenesis of several solid cancers and particularly in neuroendocrine neoplasms (NENs). A soluble form of NRP2 (sNRP2) has been previously described and corresponds to a truncated splice isoform. Its prognostic value has never been studied in NEN. NRP2 expression was studied by immunochemistry on tissue microarrays (n = 437) and on circulating tumour cells (CTCs, n = 5 patients with neuroendocrine carcinoma, NEC). We described the levels of sNRP2 in 229 patients with NEN using the ELISA method to identify the factors associated with sNRP2 levels and to evaluate its prognostic role; 90 blood donors represented the healthy control group. NRP2 was found in 97% of neuroendocrine tumours (396/410) and in 74% of NEC (20/27). NRP2 was also expressed in CTC of all the studied patients. The receiver operating characteristic (ROC) analysis showed that sNRP2 had a weak capacity to discriminate between NEN patients and healthy controls (area under curve (AUC) = 0.601, P = 0.053). Abnormal sNRP2 levels were associated with inflammatory syndrome, bone and peritoneal metastases, and abnormal chromogranin A levels. Patients with high sNRP2 levels (sNRP2Q3–Q4) had significantly poorer overall survival in multivariate analysis (HR 0.16, 95% CI (0.04–0.67), P = 0.015). In conclusion, the present study found that sNRP2 and NRP2 could represent a new prognostic biomarker and a therapeutic target, respectively, particularly in aggressive NEN.

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Julien Hadoux Oncologie Endocrinienne, Département d’Imagerie, Gustave Roussy, Villejuif, France

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Thomas Walter Service d’Oncologie, ENETS Centre of Excellence, Hospices Civils de Lyon et Université de Lyon, Lyon, France

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Christina Kanaan Service de Pathologie, Département de Biologie et Pathologie Médicale, Gustave Roussy, Villejuif, France

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Ségolène Hescot Département d’Oncologie, Institut Curie, Paris, France

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Vincent Hautefeuille Service d’Hépato-gastro-entérologie et Cancérologie Digestive, CHU Amiens Picardie, Amiens, France

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Marine Perrier Département d’Hépato-gastro-entérologie, CHU de Reims, Reims, France

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Igor Tauveron Service d'Endocrinologie, Diabétologie et Maladies Métaboliques, CHU Clermont-Ferrand, Clermont-Ferrand, France
Laboratoire GReD, Université Clermont Auvergne, Clermont-Ferrand, France

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Sandrine Laboureau Département d’Endocrinologie-Diabétologie-Nutrition, CHU d’Angers, Angers Cedex 9, France

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Christine Do Cao CHU de Lille, Service d’Endocrinologie, Lille, France

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Caroline Petorin CHU Clermont-Ferrand, Service de Chirurgie Digestive et Hépatobiliaire, Clermont-Ferrand, France

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Odile Blanchet CRB, CHU d’Angers, Angers Cedex 9, France

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Matthieu Faron Département de Chirurgie, Gustave Roussy, Villejuif, France

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Emmanuelle Leteurtre CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Université de Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277, Lille, France

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Marie-Christine Rousselet Département de Pathologie, CHU d’Angers, Angers Cedex 9, France

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Juliette Joubert Zakeyh Laboratoire d’Anatomie Pathologique, CHU Clermont-Ferrand, Clermont-Ferrand, France

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Aude Marchal Service d’Anatomo-Pathologie, CHU Reims, Reims, France

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Denis Chatelain Service d’Anatomo-Pathologie, CHU Amiens, Amiens, France

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Clément Beaulaton Service d’Anatomo-Pathologie, Institut Curie, Paris, France

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Valérie Hervieu Service d’Anatomo-Pathologie, ENETS Centre of Excellence, Hospices Civils de Lyon et Université de Lyon, Lyon, France

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Catherine Lombard-Bohas Service d’Oncologie, ENETS Centre of Excellence, Hospices Civils de Lyon et Université de Lyon, Lyon, France

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Michel Ducreux Service d’Oncologie Digestive, Département de Médecine, Gustave Roussy, Villejuif, France
Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France

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Jean-Yves Scoazec Service de Pathologie, Département de Biologie et Pathologie Médicale, Gustave Roussy, Villejuif, France
Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France

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Eric Baudin Oncologie Endocrinienne, Département d’Imagerie, Gustave Roussy, Villejuif, France

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the Groupe d’Etude des Tumeurs Endocrines (GTE)
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the Groupe d’Etude des Tumeurs Endocrines (GTE)
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the ENDOCAN-RENATEN network
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the ENDOCAN-RENATEN network

Neuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of RB transcriptional corepressor 1 (RB1) status in second-line chemotherapy (2L) have not been studied. The objectives of this study were to report the results of 2L including EBR as well as prognostic factors in a national retrospective multicentre study. NEC patients treated with 2L and further, with tissue samples available, were included. RB1 status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61 years) included, there were 73 small-cell NEC (60%), 34 large-cell NEC (28%) and 14 NEC (not otherwise specified, 12%). Primary sites were lung (39%), gastroenteropancreatic (36%), other (13%) and unknown (12%). Median Ki-67 index was 80%. Median progression-free survival (PFS) and overall survival (OS) under 2L were 2.1 and 6.2 months, respectively. No difference was observed between patients who received an ‘adenocarcinoma-like’ or a ‘neuroendocrine-like’ 2L or according to the RB1 status. Thoracic NEC primary was the only adverse prognostic factor for OS. EBR, administered to 31 patients, resulted in a 62% disease control rate with a median PFS and OS of 3.2 and 11.7 months, respectively. In the 94 patients with a relapse-free interval of ≥3 months after first-line platinum–etoposide chemotherapy, the median OS was 12 months in patients who received EBR as compared to 5.9 months in patients who did not (P = 0.043). EBR could be the best 2L option for patient with initial response to first-line platinum–etoposide lasting at least 3 months. RB1 status does not provide prognostic information in this setting.

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