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
- molecular oncology
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IM and TMG are joint senior authors.
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.
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