Validating enhancer signature classifications (ESCs) in pancreatic neuroendocrine tumors (PNETs).

Abstract

627 Background: Predicting recurrence risk (RR) for resected (res) PNET patients (pts) is challenging using existing pathologic criteria. Better predictive models to tailor surveillance for individual pts are needed. A recent study suggests expression patterns of the transcriptomic/epigenomic enhancers ARX and PDX1 may predict RR. In this study, distant metastases occurred almost exclusively in ARX+/PDX1- tumors. Our primary objective was to validate ESCs within our institutional cohort. Methods: We used a tissue microarray generated from res localized PNETs at Vanderbilt University Medical Center (VUMC) between 2002-2012. Clinical, pathological, and outcomes data were extracted from records. Immunohistochemistry was performed with PDX1 by Novus and ARX by Sigma. Patients were grouped as double-positives (DP), ARX+/PDX1-, ARX-/PDX1+ and double-negatives (DN). Time-dependent ROC analysis was performed in R (v3.6.1; survivalROC v1.0.3) to determine ARX and PDX1 positivity. Comparative analyses were performed in SPSS v23.0 (Kruskal-Wallis, Freeman-Halton exact test, Log-rank). Primary outcomes were progression-free survival (PFS) and cancer-specific survival (CSS). Results: 61 PNET specimens had adequate tissue for analysis. Table shows PFS plus CSS data by ESC distribution. Pts with ARX+ (DP & ARX+/PDX1-) tumors were younger (P=0.015) and possessed larger tumors (P=0.065). Pts with ARX+ tumors demonstrated shorter PFS (log-rank P=0.006) and a trend toward lower CSS (log-rank P=0.09). Notably, pts with ARX-/PDX1+ and DN tumors had no deaths and only 1 progression event over a median follow-up period of 91 months (m). Conclusions: Building upon earlier data that ARX+ res PNETs are more likely to relapse, we demonstrate that pts with such tumors have diminished PFS and a trend toward diminished CSS. ESCs need prospective validation but carry the potential to guide surveillance for res PNET patients. [Table: see text]