Utility of comprehensive genomic profiling (CGP) to distinguish neoplasms pathologically diagnosed as PanNETs and PanNECs and identify potentially actionable genomic alterations (GA).

Abstract

274 Background: The majority of pancreatic neuroendocrine neoplasms are classified as pancreatic neuroendocrine tumors (PanNETs) or carcinomas (PanNECs). These are distinct entities with respect to clinical presentation, prognosis and treatment; however, locally advanced/metastatic cases may exhibit overlapping histopathologic features and, thus are challenging to differentiate and may result in inappropriate management. Recent sequencing studies have identified key differences between PanNETs and PanNECs. PanNECs often harbor recurrent GA in RB1, and members of the RAS/MAPK and TGF-β pathways. In contrast, PanNETs frequently exhibit GA in chromatin remodeling genes (e.g., MEN1, DAXX and ATRX). The purpose of this study was to evaluate the utility of CGP in the pathologic assessment of locally advanced/metastatic pancreatic neuroendocrine neoplasms. Methods: Hybrid-capture based CGP was performed for up to 315 cancer-related genes and intronic regions of up to 28 genes rearranged in cancer on 318 locally advanced/metastatic pancreatic neuroendocrine neoplasms. Results were correlated with submitting histopathologic diagnoses. Results: Among 50 pathologically-classified PanNETs, 41 (82%) and 9 (18%) cases harbored GA consistent with a PanNET and PanNEC, respectively. In comparison, among 268 pathologically-classified PanNECs, 209 (78%) and 59 (22%) cases had GA compatible with a PanNET and PanNEC, respectively. Commonly altered genes in CGP-classified PanNETs include: MEN1 (37%), DAXX (21%), CDKN2A/B (20%), ATRX (11%), TSC2 (10%), TP53 (8%), PTEN (8%), ARID1A (7%) and SETD2 (5%). Defects in the BRCA pathway were seen in 10% of PanNETs. Conversely, CGP-classified PanNECs had GA in TP53 (54%), RB1 (49%), KRAS (46%), CDKN2A/B (21%), GNAS (10%), PTEN (9%), SMAD4 (7%), MYC (7%) and ARID1A (6%). Conclusions: Pathologic discrimination between PanNETs and PanNECs can be difficult, but incorporating CGP improves the classification of these neoplasms. Further, the identification of recurrent GA in members of the BRCA family highlights a potential therapeutic target for locally advanced/metastatic PanNETs.