PO-521 Gene expression-based subtypes of pancreatic ductal adenocarcinoma offer leads for targeted therapy

Introduction Overall survival (OS) of patients with pancreatic ductal adenocarcinoma (PDAC) is extremely poor. Of patients eligible for surgery (20%), around 15% present with a recurrence within 6 months (m), while 10% survive over 5 years after diagnosis. Detailed clinicopathological and molecular knowledge of factors influencing survival may lead to better prognostic and/or predictive factors and preselection of individual patients for specific treatment strategies. Material and methods Fresh frozen PDAC resection specimens from the Academic Medical Centre Amsterdam (1993–2015) were histopathologically revised, and clinicopathological details were collected. From samples with a tumour cellularity of ≥30% (n=90), mRNA, miRNA, and DNA were used for NGS at multiple levels. Corresponding FFPE blocks were selected for tissue microarrays. Results and discussions Unsupervised consensus clustering of gene expression profiles of 90 PDAC revealed four subgroups with divergent OS rates: secretory (14.7 m), epithelial (31.8 m), compound pancreatic (21.5 m), and mesenchymal (14.0 m) subgroups (p=0.002). The differences between the subgroups suggest that more targeted therapy may be feasible for PDAC. The epithelial and mesenchymal subgroups show an upregulation of genes related to DNA repair and hypoxia, respectively, suggesting sensitivity to hyperthermia, which is known to enhance cytotoxic radio-, and chemotherapy effects through frustration of tumour DNA repair and/or better oxygenation of hypoxic tumours. Immune-related gene expression was observed to be upregulated in the compound pancreatic and mesenchymal subtypes; differences were seen in expression of PDL-1, type I interferon, and MHC Class I, which may explain the difference in OS and suggests differential responses to immunotherapeutic agents. Finally, the epithelial subtype is characterised by prominent increases in metabolic signatures. Differences in metabolic flexibility suggest differences in response to mTOR inhibitors. To determine clinical relevance and identify biomarkers, we are currently characterising the subtypes at the miRNA, mutational, copy number, and immunohistochemical level. Conclusion In our well-defined single-centre set of 90 PDAC, we identified four transcriptomics-based subgroups with different survival outcomes that show a correlation with altered DNA-repair-, hypoxia, immune-, and metabolic features. Complete characterisation of these liabilities may help to further identify prognosticators, and preselect patients for specific treatment strategies.