Endocrine Abstracts

Background: The well-differentiated grade 3 neuroendocrine tumor (G3NET) category was introduced in the 2017 WHO classification as a new category of high-grade neuroendocrine neoplasm (NEN). G3NET is thought to have worse overall survival (OS) than lower grade NET, but better OS than poorly differentiated neuroendocrine carcinoma (NEC). However, challenges in pathologic diagnosis and changes in terminology have limited our understanding of the G3NET category. We compared outcomes in patients with metastatic and high grade gastroenteropancreatic NEN and assessed whether specific mutations had an impact on outcomes.

Methods: We performed an IRB-approved retrospective chart review of 134 patients with high grade metastatic NEN, formal pathology review at UCSF, and tumor DNA sequencing performed in the context of clinical care. Pathology reports and clinical histories were re-reviewed by a single pathologist and cases were best re-classified as NEC, NET or ambiguous G3NEN. OS, defined from the time of high grade and metastatic NEN diagnosis to death or last follow-up, is measured using Kaplan-Meier methods, and log-rank test is used to compare across G3NET, NEC, and ambiguous G3NEN.

Results: Of the 134 patients, 56 (42%) had NEC, 33 (25%) had G3NET, and 45 (34%) had ambiguous NENs. The median age was 61 and 41% were female, with no differences in NEC vs G3NET vs ambiguous G3NEN. Site of origin was pancreas (n=46, 34%), colorectum (n=30, 22%), other gastrointestinal (n=24, 18%) and unknown (n=34, 25%). The most common recurrently altered genes in NEC were TP53 (75%), RB1 (39%), KRAS (29%), APC (25%), MYC (11%), and CDKN2A (9%). G3NET demonstrated frequent alterations in MEN1 (49%), DAXX (21%), ATRX (9%), TSC1 or TSC2 (18%) SETD2 (18%), CDKN2A (18%), and TP53 (21%). Ambiguous G3NEN had frequent alterations in TP53 (53%), RB1 (31%), CDKN2A (29%), APC (18%), MEN1 (13%), KRAS (9%), and ARID1A (9%). Median OS among G3NET (20 months, 95% CI 10-not calculable), NEC (17 months; 95% CI 10-21), and ambiguous G3NEN (15 months, 95% CI 12-40) was not statistically different (log-rank P=0.411). However, patients with G3NET harboring mutation in TP53 had significantly worse OS (6 months, 95% CI 2-NC) than those without mutation in TP53 (25 months, 95% CI 16-NC; P=0.021).

Conclusions: There is potential to use TP53 mutation status for prognosis of advanced G3NET. Validation of these findings in a larger cohort is needed. Ongoing work is focused on investigating the prognostic value of other mutated genes in this cohort of high grade NEN.

Abstract ID 21470