Abstract
Neuroendocrine tumors (NETs) are classified based on morphology and are 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 tends 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 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.
Highlights
Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare malignant cancers that arise from diffuse neuroendocrine cells
Retinoblastoma 1 (RB1) mutation and Telomerase Reverse Transcriptase (TERT) gain are shown to be independent unfavorable prognostic markers in all lung NENs, Menin 1 (MEN1) mutation was associated with poor prognosis in atypical carcinoids, and Histone-Lysine NMethyltransferase 2D mutation was associated with longer survival in small cell lung cancer (SCLC) [25, 26]
12 patients with NENs were treated with taletrectinib, a ROS1/neurotrophic receptor tyrosine kinase (NTRK) inhibitor in a phase I study, reporting 1 partial response and 7 stable diseases according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, with a manageable toxicity profile [61]
Summary
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. Several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. New possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. We describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting
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