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  • Author: Xavier M Keutgen x
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Rushabh Gujarathi Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA

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Sara Abou Azar Section of Endocrine Surgery, Department of Surgery, University of Chicago, Chicago, Illinois, USA

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Joseph Tobias Section of Endocrine Surgery, Department of Surgery, University of Chicago, Chicago, Illinois, USA

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Blase N Polite Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA

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Namrata Setia Department of Pathology, University of Chicago, Chicago, Illinois, USA

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Nicholas Feinberg Department of Radiology, University of Chicago, Chicago, Illinois, USA

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Daniel E Appelbaum Department of Radiology, University of Chicago, Chicago, Illinois, USA

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Xavier M Keutgen Section of Endocrine Surgery, Department of Surgery, University of Chicago, Chicago, Illinois, USA

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Chih-Yi Liao Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA

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Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response rate (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs 12.13 months; P = 0.014) than wild-type (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended toward longer PFS compared to patients without concurrent mutations (31.53 vs 17.97 months; P = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs 9.83 months; P = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs 20.47 months; P = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response.

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Olga Lakiza Endocrine and Neuroendocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA

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Julian Lutze Committee on Cancer Biology, University of Chicago, Chicago, Illinois, USA

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Alyx Vogle Endocrine and Neuroendocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA

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Jelani Williams Endocrine and Neuroendocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA

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Abde Abukdheir Division of Hematology, Oncology, and Cell Therapy, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA

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Paul Miller Endocrine and Neuroendocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA

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Chih-Yi ‘Andy’ Liao Division of Hematology and Oncology, Department of Internal Medicine, University of Chicago, Chicago, Illinois, USA

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Sean P Pitroda Department of Radiation Oncology and Cellular Biology, University of Chicago, Chicago, Illinois, USA

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Carlos Martinez Department of Radiation Oncology and Cellular Biology, University of Chicago, Chicago, Illinois, USA

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Andrea Olivas Department of Pathology, University of Chicago, Chicago, Illinois, USA

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Namrata Setia Department of Pathology, University of Chicago, Chicago, Illinois, USA

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Stephen J Kron Committee on Cancer Biology, University of Chicago, Chicago, Illinois, USA
Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois, USA

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Ralph R Weichselbaum Department of Radiation Oncology and Cellular Biology, University of Chicago, Chicago, Illinois, USA
Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois, USA

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Xavier M Keutgen Endocrine and Neuroendocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA

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Somatic MEN1 mutations occur in up to 50% of pancreatic neuroendocrine tumors (PanNETs). Clinical studies have shown that radiation therapy (IR) is effective in a subset of PanNETs, but it remains unclear why some patients respond better to IR than others. Herein, we study whether MEN1 loss of function increases radiosensitivity of PanNETs and determine its effect on DNA double-strand break (DSB) repair. After creating a MEN1 knockout PanNET cell line, we confirmed reduced DSB repair capacity in MEN1-deficient cells and linked these findings to a defect in homologous recombination, as well as reduced BRCA2 expression levels. Consistent with this model, we found that MEN1 mutant cells displayed increased sensitivity to the highly trapping poly (ADP-ribose) polymerase (PARP) 1 inhibitor talazoparib in vitro. Our results suggest that combining IR with PARP inhibition may be beneficial in patients with PanNETs and MEN1 loss of function.

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