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Marianne E Pavel Medical Department, Division of Hepatology and Gastroenterology including Metabolic Diseases, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany

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Marianne E Pavel Medical Department, Division of Hepatology and Gastroenterology including Metabolic Diseases, Campus Virchow Klinikum, Charité University Medicine, Berlin, Germany

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Christine Sers Institute of Pathology, Charité University Medicine, Berlin, Germany

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Neuroendocrine tumors (NETs) are a group of heterogenous neoplasms. Evidence-based treatment options for antiproliferative therapy include somatostatin analogues, the mTOR inhibitor everolimus, the multiple tyrosine kinase inhibitor sunitinib and peptide receptor radionuclide therapy with 177-Lu-octreotate. In the absence of definite predictive markers, therapeutic decision making follows clinical and pathological criteria. As objective response rates with targeted drugs are rather low, and response duration is limited in most patients, numerous combination therapies targeting multiple pathways have been explored in the field. Upfront combination of drugs, however, is associated with increasing toxicity and has shown little benefit. Major advancements in the molecular understanding of NET based on genomic, epigenomic and transcriptomic analysis have been achieved with prognostic and therapeutic impact. New insight into molecular alterations has paved the way to biomarker-driven clinical trials and may facilitate treatment stratification toward personalized medicine in the near future. However, an improved understanding of the complexity of pathway interactions is required for successful treatment. A systems biology approach is one of the tools that may help to achieve this endeavor.

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Andrea Frilling
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Goran Åkerström Department of Surgery and Cancer, Department of Surgery, Department of Surgery University of Verona, Department of Gastroenterology and Hepatology, Department of Surgery, Department of Gastroenterological Surgery, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0HS, UK

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Massimo Falconi Department of Surgery and Cancer, Department of Surgery, Department of Surgery University of Verona, Department of Gastroenterology and Hepatology, Department of Surgery, Department of Gastroenterological Surgery, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0HS, UK

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Marianne Pavel Department of Surgery and Cancer, Department of Surgery, Department of Surgery University of Verona, Department of Gastroenterology and Hepatology, Department of Surgery, Department of Gastroenterological Surgery, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0HS, UK

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Jose Ramos Department of Surgery and Cancer, Department of Surgery, Department of Surgery University of Verona, Department of Gastroenterology and Hepatology, Department of Surgery, Department of Gastroenterological Surgery, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0HS, UK

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Mark Kidd Department of Surgery and Cancer, Department of Surgery, Department of Surgery University of Verona, Department of Gastroenterology and Hepatology, Department of Surgery, Department of Gastroenterological Surgery, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0HS, UK

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Irvin Mark Modlin Department of Surgery and Cancer, Department of Surgery, Department of Surgery University of Verona, Department of Gastroenterology and Hepatology, Department of Surgery, Department of Gastroenterological Surgery, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0HS, UK

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Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a heterogenous group of tumors arising from a variety of neuroendocrine cell types. The incidence and prevalence of GEP-NENs have markedly increased over the last three decades. Symptoms are often absent in early disease, or vague and nonspecific even in advanced disease. Delayed diagnosis is thus common. Chromogranin A is the most commonly used biomarker but has limitations as does the proliferative marker Ki-67%, which is often used for tumor grading and determination of therapy. The development of a multidimensional prognostic nomogram may be valuable in predicting tumor behavior and guiding therapy but requires validation. Identification of NENs that express somatostatin receptors (SSTR) allows for SSTR scintigraphy and positron emission tomography imaging using novel radiolabeled compounds. Complete surgical resection of limited disease or endoscopic ablation of small lesions localized in stomach or rectum can provide cure; however, the majority of GEP-NENs are metastatic (most frequently the liver and/or mesenteric lymph nodes) at diagnosis. Selected patients with metastatic disease may benefit from advanced surgical techniques including hepatic resection or liver transplantation. Somatostatin analogs are effective for symptomatic treatment and exhibit some degree of antiproliferative activity in small intestinal NENs. There is a place for streptozotocin, temozolomide, and capecitabine in the management of pancreatic NENs, while new agents targeting either mTOR (everolimus) or angiogenic (sunitinib) pathways have shown efficacy in these lesions.

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Lena Weindl Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

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Imke Atreya Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

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Peter Dietrich Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

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Sabine Neubeck Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

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Markus F Neurath Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
Deutsches Zentrum Immuntherapie DZI, Erlangen, Germany
Comprehensive Cancer Center CCC-EMN, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

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Marianne Pavel Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
Deutsches Zentrum Immuntherapie DZI, Erlangen, Germany
Comprehensive Cancer Center CCC-EMN, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

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Neuroendocrine neoplasms (NENs) represent a rare and heterogeneous group of malignancies, sharing features of both neural and endocrine cells. NENs G3 appear as a highly aggressive subset with a poor prognosis and limited therapeutic options. The small-molecule inhibitor of the WEE1 tyrosine kinase, adavosertib (AZD1775), has previously demonstrated potent anti-tumor effects on various types of cancer in preclinical and clinical studies. However, the role of adavosertib in NENs G3 had remained elusive. We evaluated the effects of adavosertib on pancreatic (BON-1, QGP-1) and bronchopulmonary (NCI-H720) neuroendocrine tumor cell lines applying 2D and 3D spheroid models. We newly demonstrated that adavosertib is sufficient to reduce cell viability and proliferation in neuroendocrine cell lines with features of high-grade NENs. As underlying mechanisms, we identified adavosertib-mediated DNA double-strand breaks and a G2/M cell cycle checkpoint abrogation leading into mitotic catastrophe and cancer cell apoptosis. Silencing of WEE1 via siRNA transfection resulted in a phenotype similar to adavosertib treatment. Together, inhibition of the WEE1 tyrosine kinase applying adavosertib on NENs G3 outlines a promising novel therapeutic strategy.

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Atsuko Kasajima Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany
Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Marianne Pavel Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Silvia Darb-Esfahani Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Aurelia Noske Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Albrecht Stenzinger Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany
Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Hironobu Sasano Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Manfred Dietel Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Carsten Denkert Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Christoph Röcken Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Bertram Wiedenmann Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Wilko Weichert Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany
Institute of Pathology, Department of Internal Medicine, Department of Pathology, Institute of Pathology, Institute of Pathology, Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany

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Clinical trials indicate efficacy of drugs inhibiting the mammalian target of rapamycin (mTOR) in the treatment of gastroenteropancreatic neuroendocrine tumours (GEP-NET); however, information on detailed expression and activity patterns of mTOR in these tumours is sparse. We investigated the expression of mTOR and expression as well as phosphorylation of its downstream targets 4EBP1, S6K and eIF4E in a cohort of 99 human GEP-NET by immunohistochemistry. We correlated our findings with clinicopathological variables and patient prognosis. We found that 61, 93, 80, 69, 57 and 79% of GEP-NET were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1), nuclear p-4EBP1, phospho-S6K (p-S6K) and phospho-eIF4E (p-eIF4E) respectively. mTOR expression and activity were higher in foregut than in midgut tumours. In foregut tumours, expression of mTOR was higher when distant metastases were present (P=0.035). Strong mTOR activity was associated with higher proliferative capacity. In patients with stage IV midgut tumours, strong p-S6K expression was associated with poor disease-specific survival (P=0.048). In conclusion, mTOR shows considerable variations in expression and activity patterns in GEP-NET in dependence of tumour location and metastatic status. We hypothesise that these differences in mTOR expression and activity might possibly influence response to mTOR inhibitors.

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Jonathan R Strosberg Department of Medicine, Division of Cancer Medicine, Istituto di Oncologia, Novartis International AG, Novartis Pharmaceuticals Corporation, Sarah Cannon Research Institute, University of Paris VII and Beaujon Hospital, Digestive Oncology, Uppsala University Hospital, Department of Hepatology and Gastroenterology, Moffitt Cancer Center, Tampa, Florida, USA

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James C Yao Department of Medicine, Division of Cancer Medicine, Istituto di Oncologia, Novartis International AG, Novartis Pharmaceuticals Corporation, Sarah Cannon Research Institute, University of Paris VII and Beaujon Hospital, Digestive Oncology, Uppsala University Hospital, Department of Hepatology and Gastroenterology, Moffitt Cancer Center, Tampa, Florida, USA

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Emilio Bajetta Department of Medicine, Division of Cancer Medicine, Istituto di Oncologia, Novartis International AG, Novartis Pharmaceuticals Corporation, Sarah Cannon Research Institute, University of Paris VII and Beaujon Hospital, Digestive Oncology, Uppsala University Hospital, Department of Hepatology and Gastroenterology, Moffitt Cancer Center, Tampa, Florida, USA

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Mounir Aout Department of Medicine, Division of Cancer Medicine, Istituto di Oncologia, Novartis International AG, Novartis Pharmaceuticals Corporation, Sarah Cannon Research Institute, University of Paris VII and Beaujon Hospital, Digestive Oncology, Uppsala University Hospital, Department of Hepatology and Gastroenterology, Moffitt Cancer Center, Tampa, Florida, USA

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Bert Bakker Department of Medicine, Division of Cancer Medicine, Istituto di Oncologia, Novartis International AG, Novartis Pharmaceuticals Corporation, Sarah Cannon Research Institute, University of Paris VII and Beaujon Hospital, Digestive Oncology, Uppsala University Hospital, Department of Hepatology and Gastroenterology, Moffitt Cancer Center, Tampa, Florida, USA

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John D Hainsworth Department of Medicine, Division of Cancer Medicine, Istituto di Oncologia, Novartis International AG, Novartis Pharmaceuticals Corporation, Sarah Cannon Research Institute, University of Paris VII and Beaujon Hospital, Digestive Oncology, Uppsala University Hospital, Department of Hepatology and Gastroenterology, Moffitt Cancer Center, Tampa, Florida, USA

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Philippe B Ruszniewski Department of Medicine, Division of Cancer Medicine, Istituto di Oncologia, Novartis International AG, Novartis Pharmaceuticals Corporation, Sarah Cannon Research Institute, University of Paris VII and Beaujon Hospital, Digestive Oncology, Uppsala University Hospital, Department of Hepatology and Gastroenterology, Moffitt Cancer Center, Tampa, Florida, USA

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Eric Van Cutsem Department of Medicine, Division of Cancer Medicine, Istituto di Oncologia, Novartis International AG, Novartis Pharmaceuticals Corporation, Sarah Cannon Research Institute, University of Paris VII and Beaujon Hospital, Digestive Oncology, Uppsala University Hospital, Department of Hepatology and Gastroenterology, Moffitt Cancer Center, Tampa, Florida, USA

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Kjell Öberg Department of Medicine, Division of Cancer Medicine, Istituto di Oncologia, Novartis International AG, Novartis Pharmaceuticals Corporation, Sarah Cannon Research Institute, University of Paris VII and Beaujon Hospital, Digestive Oncology, Uppsala University Hospital, Department of Hepatology and Gastroenterology, Moffitt Cancer Center, Tampa, Florida, USA

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Marianne E Pavel Department of Medicine, Division of Cancer Medicine, Istituto di Oncologia, Novartis International AG, Novartis Pharmaceuticals Corporation, Sarah Cannon Research Institute, University of Paris VII and Beaujon Hospital, Digestive Oncology, Uppsala University Hospital, Department of Hepatology and Gastroenterology, Moffitt Cancer Center, Tampa, Florida, USA

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Somatostatin analogues (SSA) have demonstrated antiproliferative activity in addition to efficacy for carcinoid symptom control in functional neuroendocrine tumors (NET). A post hoc analysis of the placebo arm of the RAD001 In Advanced Neuroendocrine Tumors-2 (RADIANT-2) study was conducted to assess the efficacy of octreotide long-acting repeatable (LAR) on progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan–Meier method. Out of 213 patients randomized to placebo plus octreotide LAR in RADIANT-2, 196 patients with foregut, midgut, or hindgut NET were considered for present analysis. Of these, 41 patients were SSA-treatment naïve and 155 had received SSA therapy before study entry. For SSA-naïve patients, median PFS by adjudicated central review was 13.6 (95% CI 8.2–22.7) months. For SSA-naïve patients with midgut NET (n=24), median PFS was 22.2 (95% CI 8.3–29.5) months. For patients who had received SSA previously, the median PFS was 11.1 (95% CI 8.4–14.3) months. Among the SSA-pretreated patients who had midgut NET (n=119), the median PFS was 12.0 (95% CI 8.4–19.3) months. Median OS was 35.8 (95% CI 32.5–48.9) months for patients in the placebo plus octreotide LAR arm; 50.6 (36.4 – not reached) months for SSA-naïve patients and 33.5 (95% CI 27.5–44.7) months for those who had received prior SSA. This post hoc analysis of the placebo arm of the large phase 3 RADIANT-2 study provides data on PFS and OS among patients with progressive NET treated with octreotide therapy.

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Georg Hilfenhaus Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Andreas Göhrig Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Ulrich-Frank Pape Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Tabea Neumann Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Henning Jann Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Dietmar Zdunek Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Georg Hess Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Jean Marie Stassen Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Bertram Wiedenmann Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Katharina Detjen Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Marianne Pavel Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Christian Fischer Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
Experimental and Clinical Research Center, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Roche Diagnostics, ThromboGenics NV, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

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Placental growth factor (PlGF), a VEGF-homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. Here, we addressed the expression, function, and prognostic value of PlGF in neuroendocrine tumors (NETs). PlGF was determined in NET patients' sera collected retrospectively (n=88) and prospectively (n=87) using Roche-Elecsys and correlated with clinicopathological data. Tumoral PlGF was evaluated by immunohistochemistry, effects of PlGF on proliferation and migration in vitro were assessed using different NET cell lines and effects on tumor growth in vivo in orthotopic xenografts. Circulating and tumoral PlGF was elevated in patients with pancreatic NETs (pNETs) compared with control sera and respective healthy tissue. De novo PlGF expression occurred primarily in the tumor stroma, suggesting paracrine stimulatory circuits. Indeed, PlGF enhanced NET proliferation and migration in vitro and, conversely, neutralizing antibodies to PlGF reduced tumor growth in vivo. Elevated circulating PlGF levels in NET patients correlated with advanced tumor grading and were associated with reduced tumor-related survival in pNETs. Subsequent determinations confirmed and extended our observation of elevated PlGF levels in a prospective cohort of grade 1 and grade 2 pNETs (n=30) and intestinal NETs (n=57). In low-grade pNETs, normal circulating PlGF levels were associated with better survival. In intestinal NETs, circulating PlGF above median emerged as an independent prognostic factor for shorter time-to-progression in multivariate analyses. These data assign to PlGF a novel function in the pathobiology of NETs and propose PlGF as a prognostic parameter and therapeutic target.

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Martyn E Caplin Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Marianne Pavel Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Jarosław B Ćwikła Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Alexandria T Phan Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Markus Raderer Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Eva Sedláčková Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Guillaume Cadiot Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Edward M Wolin Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Jaume Capdevila Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Lucy Wall Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Guido Rindi Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Alison Langley Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Séverine Martinez Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Edda Gomez-Panzani Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Philippe Ruszniewski Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK
Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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on behalf of the CLARINET Investigators
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In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

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James Yao University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Abhishek Garg Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

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David Chen Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

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Jaume Capdevila Vall d’Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Autonomous University of Barcelona, Barcelona, Spain

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Paul Engstrom Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

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Rodney Pommier Oregon Health and Science University, Portland, Oregon, USA

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Eric Van Cutsem University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium

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Simron Singh Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada

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Nicola Fazio European Institute of Oncology, Milan, Italy

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Wei He Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

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Markus Riester Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

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Parul Patel Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

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Maurizio Voi Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

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Michael Morrissey Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

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Marianne Pavel University of Erlangen-Nuremberg, Erlangen, Germany

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Matthew Helmut Kulke Dana Farber Cancer Institute, Boston, Massachusetts, USA

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Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.

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Louis de Mestier Université de Paris, Department of Gastroenterology-Pancreatology, Beaujon University Hospital (APHP), Clichy, France

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Angela Lamarca Division of Cancer Sciences, Department of Medical Oncology, The Christie NHS Foundation, University of Manchester, Manchester, United Kingdom

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Jorge Hernando Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Wouter Zandee Department of Internal Medicine, Sector Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands
Division of Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Teresa Alonso-Gordoa Department of Medical Oncology, Ramon y Cajal University Hospital, IRYCIS, Madrid, Spain

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

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Annemiek ME Walenkamp Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

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Bipasha Chakrabarty Department of Pathology, The Christie, Manchester, United Kingdom

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Stefania Landolfi Department of Pathology, Vall d’Hebron University Hospital, Barcelona, Spain

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Marie-Louise F Van Velthuysen Department of Pathology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Gursah Kats-Ugurlu Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Alejandra Caminoa Department of Pathology, University Hospital Ramon y Cajal, Madrid, Spain

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Maxime Ronot Université de Paris, Department of Radiology, Beaujon University Hospital (APHP), Clichy, France

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Prakash Manoharan Department of Radiology and Nuclear Medicine, The Christie, Manchester, United Kingdom

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Alejandro Garcia-Alvarez Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Tessa Brabander Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

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María Isabel García Gómez-Muriel Department of Radiology, University Hospital Ramon y Cajal, Madrid, Spain

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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, Department of Pathology, Beaujon/Bichat University Hospital (APHP), Clichy/Paris, France

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Jaume Capdevila Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Marianne E Pavel Department of Endocrinology, Erlangen University Hospital, Erlangen, Germany

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Jérôme Cros Université de Paris, Department of Pathology, Beaujon/Bichat University Hospital (APHP), Clichy/Paris, France

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There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from the duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1 = 74; L2 = 52) included alkylating-based (n = 32), etoposide-platinum (n = 22) or adenocarcinoma-like (n = 20) chemotherapy, somatostatin analogs (n = 21), targeted therapies (n = 22) and liver-directed therapies (n = 7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI (1.5–12.2); P = 0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (P < 0.001 and P = 0.008, respectively). The longest median PFS was obtained with adenocarcinoma-like chemotherapy (16.5 months (9.0–24.0)) and targeted therapies (12.0 months (8.2–15.8)), while the shortest PFS was observed with somatostatin analogs (6.2 months (3.8–8.5)) and etoposide-platinum chemotherapy (7.2 months (5.2–9.1)). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 (1.61–8.44), P = 0.002) and alkylating-based chemotherapies (multivariable HR 1.95 (1.01–3.78), P = 0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.

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