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

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.

Molecular typing and mutational characterization of rectal neuroendocrine neoplasms

“…This was similar to the findings of Tsuruoka et al's study that PD‐L1 expression was not observed in NETs 22 . Mismatch repair protein deficiency was rare in pancreatic and intestinal NETs 23 . In another study, microsatellite instability (MSI) was confirmed in only 3 (1.3%) of 239 NENs, and all MSI was present in cecal NECs, with MSI being uncommon in other NENs 24 .…”

“… 22 Mismatch repair protein deficiency was rare in pancreatic and intestinal NETs. 23 In another study, microsatellite instability (MSI) was confirmed in only 3 (1.3%) of 239 NENs, and all MSI was present in cecal NECs, with MSI being uncommon in other NENs. 24 Most of the patients in our study had rectal NETs (33 cases), and only three cases were rectal NECs.…”

Comparative Survival Benefits of Surgery and Adjuvant Chemotherapy in Neuroendocrine Carcinoma of the Gallbladder: A Population-Based Study with Insight into Future Personalized Therapeutic Approach

“…Variations in genomic profile aid in differentiating neuroendocrine carcinomas (NECs) and NETs and determining treatment response [ 20 ]. Common mutations reported in the literature involved in NECs include TP53, KRAS, and RB1, and these are associated with poor differentiation of the carcinoma [ 20 ].…”

“…Variations in genomic profile aid in differentiating neuroendocrine carcinomas (NECs) and NETs and determining treatment response [ 20 ]. Common mutations reported in the literature involved in NECs include TP53, KRAS, and RB1, and these are associated with poor differentiation of the carcinoma [ 20 ]. TP53 and RB1 are mutated in about 80% of poorly differentiated neuroendocrine neoplasms (NENs), and data from mouse models indicate that the loss of these two genes is vital to the formation of poorly differentiated NENs [ 21 ].…”

“…These mutations can help differentiate NECs from well-differentiated high-grade NETs; this is especially applicable to pancreatic NENs. Additionally, these biomarkers can predict the response to platinum-based chemotherapy [ 20 ]. MEN1, DAX, and ATRX mutations are associated with well-differentiated neuroendocrine tumors (NETs) [ 22 ].…”