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Mairéad G McNamara Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
Division of Cancer Sciences, University of Manchester, Manchester, UK

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Jean-Yves Scoazec Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, France
Université Paris Sud, Faculté de Médecine de Bicêtre, Le Kremlin-Bicêtre, France

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Thomas Walter Department of Gastroenterology and Medical Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France

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Patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PD-NECs) have a poor prognosis. Surgery is offered for those with localised disease, but the majority of patients present with advanced disease. Treatment strategies adopted are analogous to that of high grade NECs of the lung, with platinum/etoposide-based regimens advocated in the first-line setting for advanced disease. There is no standard second-line therapy. Research into their molecular and immune pathways may pave the way for novel drug discovery. The molecular drivers of NEC are best identified in small cell lung carcinoma, which present with near universal genomic alterations in TP53 and RB1. The genetics of EP-PD-NEC remain poorly understood; TP53, KRAS, PIK3CA/PTEN and BRAF mutations have been identified, with alterations in the BRCA pathway reported additionally in small cell NEC of the cervix and absence of argininosuccinate synthetase 1 expression in NEC of the urinary bladder. The use of cell lines and patient-derived xenografts (PDX) to predict response to treatment in NEC and the emergence of alternative biomarkers, such as circulating tumour cells and cell-free DNA, will also be explored. Despite limited published data on the immune microenvironment of EP-NEC, there are a number of clinical trials investigating the use of immune-targeted agents in this disease category, with conflicting emerging data from studies thus far. This review will summarise the treatment and available molecular and immune data in this under researched diagnosis and may stimulate the direction of future exploratory studies.

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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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Ophélie De Rycke Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France
Université de Paris, Centre de Recherche sur l’Inflammation, INSERM, Paris, France

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Thomas Walter Department of Gastro-enterology and oncology, Hospices Civils de Lyon, Edouard Herriot University Hospital, Lyon, France

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Marine Perrier Department of Hepato-Gastroenterology and Digestive Oncology, Robert Debré University Hospital, Reims, France

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Olivia Hentic Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France

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Catherine Lombard-Bohas Department of Gastro-enterology and oncology, Hospices Civils de Lyon, Edouard Herriot University Hospital, Lyon, France

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Romain Coriat Department of Gastroenterology, Cochin University Hospital, Paris, France

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Guillaume Cadiot Department of Hepato-Gastroenterology and Digestive Oncology, Robert Debré University Hospital, Reims, France

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Anne Couvelard Université de Paris, Centre de Recherche sur l’Inflammation, INSERM, Paris, France
Department of Pathology, ENETS Centre of Excellence, Bichat/Beaujon University Hospital, Paris/Clichy, France

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Philippe Ruszniewski Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France
Université de Paris, Centre de Recherche sur l’Inflammation, INSERM, Paris, France

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Jérôme Cros Université de Paris, Centre de Recherche sur l’Inflammation, INSERM, Paris, France
Department of Pathology, ENETS Centre of Excellence, Bichat/Beaujon University Hospital, Paris/Clichy, France

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Louis de Mestier Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France
Université de Paris, Centre de Recherche sur l’Inflammation, INSERM, Paris, France

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A rechallenge is common after the initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with a lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET, and to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause of > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (cohort A). The primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (cohort B). We found that Cohort A included 62 patients (median Ki67 8%), for whom ALK1 followed by a pause achieved an objective response rate of 55% and a PFS1 of 23.7 months (95% IC, 19.8–27.6). ALK2 achieved no objective response and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1–11.3). At multivariable analysis, a hormonal syndrome (P = 0.032) and a pause longer than 12 months (P = 0.041) were associated with a longer PFS2. In cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18–105) before ALK to 100 (IQR 56–180) after ALK (P = 0.003). We conclude that after the initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain the low efficacy of ALK rechallenge.

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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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Nicola Fazio Division of gastrointestinal medical oncology and neuroendocrine tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy

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Lorenzo Gervaso Division of gastrointestinal medical oncology and neuroendocrine tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy
Molecular Medicine Program, University of Pavia, Pavia, Italy

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Thorvardur R Halfdanarson Division of Medical Oncology Mayo Clinic, Rochester, Minnesota, USA

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Mohamad Sonbol Department of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona, USA

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Rachel A Eiring Division of Medical Oncology Mayo Clinic, Rochester, Minnesota, USA

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Sara Pusceddu Division of Medical Oncology, National Cancer Institute, Milan, Italy

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Natalie Prinzi Division of Medical Oncology, National Cancer Institute, Milan, Italy

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Benedetta Lombardi Stocchetti Division of Medical Oncology, National Cancer Institute, Milan, Italy

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Simona Grozinsky-Glasberg Neuroendocrine Tumor Unit, ENETS Center of Excellence, Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, The Hebrew University, Jerusalem, Israel

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David J Gross Neuroendocrine Tumor Unit, ENETS Center of Excellence, Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, The Hebrew University, Jerusalem, Israel

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Thomas Walter Medical Oncology Department, Hopital Edourad Herriot, Hospices civils de Lyon, Lyon, France

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Patrick Robelin Medical Oncology Department, Hopital Edourad Herriot, Hospices civils de Lyon, Lyon, France

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Catherine Lombard-Bohas Medical Oncology Department, Hopital Edourad Herriot, Hospices civils de Lyon, Lyon, France

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Samuele Frassoni Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy

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Vincenzo Bagnardi Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy

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Lorenzo Antonuzzo Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Clotilde Sparano Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences ’Mario Serio’, University of Florence, Florence, Italy

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Sara Massironi Division of Gastroenterology, and Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, University of Milano-Bicocca School of Medicine, Monza, Italy

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Fabio Gelsomino Division of Oncology. Department of Hematology and Oncology, University Hospital of Modena, Modena, Italy

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Alberto Bongiovanni Oncologia medica, IRCCS Istituto Romagnolo per lo Studio dei Tumori ’Dino Amadori’, IRST S.r.l., Meldola, Italy

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Nicoletta Ranallo Oncologia medica, IRCCS Istituto Romagnolo per lo Studio dei Tumori ’Dino Amadori’, IRST S.r.l., Meldola, Italy

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Salvatore Tafuto Oncologia Sarcomi e Tumori rari, I.R.C.C.S. Ist. Naz. Tumori di Napoli ’G. Pascale’, Napoli, Italy

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Maura Rossi Oncology Unit and Centro Documentazione Osteonecrosi, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy

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Mauro Cives Department of Interdisciplinary Medicine, University of Bari ’Aldo Moro’, Bari, Italy

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Ibrahim Rasul Kakil National Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar

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Hytam Hamid Department of Surgery, Al-Moalem Medical City, Khartoum, Sudan

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Alessandra Chirco UO Oncologia Medica ASST Papa Giovanni XXIII, Bergamo, Italy

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Michela Squadroni Oncologia medica, Humanitas Gavazzeni Bergamo, Bergamo, Italy

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Anna La Salvia Medical Oncology Department, Hospital Universitario Doce de Octubre, Imas12, UCM, Madrid, Spain

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Jorge Hernando Vall Hebron University Hospital and Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Johannes Hofland Department of Internal Medicine, Sector Endocrinology, Rotterdam, the Netherlands

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Anna Koumarianou Hematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Sabrina Boselli Data Management-Clinical Trial Office. Scientific Direction. European Institute of Oncology (IEO) IRCCS, Milan, Italy

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Darina Tamayo Data Management-Clinical Trial Office. Scientific Direction. European Institute of Oncology (IEO) IRCCS, Milan, Italy

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Cristina Mazzon Data Management-Clinical Trial Office. Scientific Direction. European Institute of Oncology (IEO) IRCCS, Milan, Italy

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Manila Rubino Division of gastrointestinal medical oncology and neuroendocrine tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy

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Francesca Spada Division of gastrointestinal medical oncology and neuroendocrine tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy

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We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

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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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