Abstract C109: Nanostring-based subtyping of pancreatic ductal adenocarcinoma is strongly influenced by the stromal compartment

Abstract

Abstract The prognostic significance of basal-like and classical subtypes of pancreatic ductal adenocarcinoma (PDAC) is well-established, and ongoing clinical trials are poised to validate the predictive utility of such subtypes in guiding first-line treatment decision-making. While the Purity-independent (PurIST)-based subtyping strategy provides a method for PDAC subtype determination based on the Nanostring gene expression quantification platform, the utility of this platform has not been tested in a real-world patient setting. Here, we leverage a retrospective dataset of patients with resectable PDAC (n=299) that received Nanostring sequencing in combination with comprehensive clinical metadata curation and histopathological analysis. All sequencing analyses were performed using formalin-fixed paraffin-embedded (FFPE) tumor whole sections. The proportion of basal-like cases (15%) was comparable with other resectable PDAC cohorts, and patients with basal-like tumors showed reduced overall survival (p=3.9e-4). Histopathological quantification of epithelial, stromal and normal components in each sample revealed significantly (p=0.007) reduced classical gene expression in stroma-high samples. Out of 29 patients with repeat sampling from different FFPE blocks derived from the same tumor and surgery, 31% of tumors received discordant subtypes calls and increases in the amount of stroma sequenced between two samples from the same tumor was negatively correlated with expression of classical subtype genes (p=0.02). Taken together, these data demonstrate the presence of intra-tumoral subtype heterogeneity, highlight the quantity of stroma sequenced as a major contributing factor in PurIST-based subtype determination and generate insight into the reproducibility of this subtyping strategy in a real-world clinical setting. Citation Format: James T. Topham, Steve E. Kalloger, Joanna M. Karasinska, Jenny E. Chu, Hassan Ali, Dongxia Gao, Christine Chow, Andrew Metcalfe, Jonathan M. Loree, David F. Schaeffer, Daniel J. Renouf. Nanostring-based subtyping of pancreatic ductal adenocarcinoma is strongly influenced by the stromal compartment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C109.