AUTHOR=Prisciandaro Michele , Antista Maria , Raimondi Alessandra , Corti Francesca , Morano Federica , Centonze Giovanni , Sabella Giovanna , Mangogna Alessandro , Randon Giovanni , Pagani Filippo , Prinzi Natalie , Niger Monica , Corallo Salvatore , Castiglioni di Caronno Erica , Massafra Marco , Bartolomeo Maria Di , Braud Filippo de , Milione Massimo , Pusceddu Sara 

TITLE=Biomarker Landscape in Neuroendocrine Tumors With High-Grade Features: Current Knowledge and Future Perspective

JOURNAL=Frontiers in Oncology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.780716

DOI=10.3389/fonc.2022.780716

ISSN=2234-943X

ABSTRACT=Neuroendocrine tumors (NETs) are classified based on morphology and graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2-G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in Gastroenteropancreatic (GEP) NETs a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical-pathologic features. Although several mutational analyses have been performed, a molecular classification of NET  is an unmet need in particular for G3, which tend to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited giving the basis for new treatments. Alteration of KRAS, TP53 and RB1 are mainly reported but also druggable alterations, including BRAF and H-MSI, have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming the new standard for G3 NEN discrimination and a predictive biomarker for immunotherapy. In this review we describe the current knowledge available on high grade NETs molecular landscape with a specific focus on those harboring a potentially therapeutic targets in the advanced setting.