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Recent advances in basic science
Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine?
  1. Anja Rinke1,
  2. Christoph J Auernhammer2,
  3. Lisa Bodei3,
  4. Mark Kidd4,
  5. Sebastian Krug5,
  6. Rita Lawlor6,
  7. Ilaria Marinoni7,
  8. Aurel Perren7,
  9. Aldo Scarpa6,
  10. Halfdan Sorbye8,
  11. Marianne Ellen Pavel9,
  12. Matthias M Weber10,
  13. Irvin Modlin11,
  14. Thomas M Gress1
  1. 1 Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany
  2. 2 Department of Internal Medicine IV and Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Ludwig Maximilian University, LMU Klinikum, Munich, Germany
  3. 3 Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
  4. 4 Wren Laboratories, Branford, Connecticut, USA
  5. 5 Clinic for Internal Medicine I, Martin Luther University, Halle, Germany
  6. 6 Applied Research on Cancer Centre, Department of Pathology and Diagnostics, University of Verona, Verona, Italy
  7. 7 Institute of Pathology, University of Bern, Bern, Switzerland
  8. 8 Department of Oncology, Haukeland University Hospital, Bergen, Norway
  9. 9 Department of Internal Medicine I, Endocrinology, University of Erlangen, Erlangen, Germany
  10. 10 Department of Internal Medicine I, Endocrinology, Johannes Gutenberg University Hospital Mainz, Mainz, Germany
  11. 11 Gastroenterological and Endoscopic Surgery, Yale University School of Medicine, New Haven, Connecticut, USA
  1. Correspondence to Dr Anja Rinke, Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps University Marburg, Marburg, Germany; sprengea{at}uni-marburg.de

Abstract

Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. ‘Targeted’ treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options.

The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour.

This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.

  • neuroendocrine tumors
  • cancer genetics
  • chemotherapy
  • molecular oncology
  • immunotherapy

https://doi.org/10.1136/gutjnl-2020-321300

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    Footnotes

    • IM and TMG are joint senior authors.

    • Twitter @Sebastian_Krug

    • Contributors TMG and AR planned and structured the review and invited all other coauthors. Every coauthor wrote at least one section of the review. AR, RL, AS, IM, MK, LB and CJA also created a figure. AR, TMG and IM deleted overlaps and shortened the manuscript. IrvinM also suggested linguistic improvements. All coauthors read the revised manuscript and gave feedback and consent to submit.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests AR has received honoraria for presentations and advisory boards from AAA, Advanz Pharma, Falk, IPSEN and Novartis. CJA has received research contracts (Ipsen, Novartis), lecture honorarium (AAA, Ipsen, Novartis) and advisory board honorarium (Novartis). LB has been non remunerated consultant or speaker for AAA-Novartis, Ipsen, Curium, Clovis, ITM, Iba and has received research support from AAA-Novartis. MK is Laboratory Director for Wren Laboratories LLC. HS received research grants from Novartis, Amgen and Ipsen, honoraria for advisory board for Novartis, Pfizer, Keocyt, AstraZeneca and Hutchinson, honoraria for presentations from Novartis, BMS, Roche, Amgen, Ipsen, Merck, Shire, Celgene and Bayer. TMG has received funding from IPSEN, Pfizer and Novartis for joined research projects, participation in advisory boards and lectures. IMM is medical and scientific consultant for Clifton Life Sciences. MEP received honoraria for participation in advisory boards and presentations from Novartis, IPSEN, Pfizer Riemser and Lexicon, honoraria for presentations from Prime Oncology and research funding from IPSEN and Novartis. MMW received honoraria for participation in advisory boards and presentations from IPSEN, AAA/Novartis and Advanz Pharma and research funding from Merck.

    • Provenance and peer review Commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.