The cancer fusionome and overexpressed druggable oncogenic signals in <i>K-RAS</i> wild-type pancreatic cancer.

e15180 Background: Pancreatic cancer has apoor prognosis and limited therapeutic options. While K-RAS mutations are prevalent in this malignancy, a subset of patients harboring wild-type K-RAS presents distinct clinical behavior. Gene fusions have been discerned in pancreatic cancer and are promising candidates for administering targeted therapies. Methods: We conducted a retrospective analysis of 926 pancreatic cancer patients of which 165 (18%) carried a wild-type K-RAS gene, by next generation sequencing (NGS) or polymerase chain reaction (PCR) testing. Tumors were analyzed with a clinical-grade hybrid capture-based RNA-seq clinical fusionome test, evaluating gene fusions between 1104 genes or to other known or novel partners as well as gene expression transcript analysis. Single nucleotide variants/insertions deletions (SNV/Indels) were tested with a clinical-grade NGS assay targeting &gt; 300 cancer genes. Results: Gene fusions were detected in 32% of K-RAS wild-type pancreatic cancers, with 75% involving known oncogenic, clinically actionable genes including FGFR (two FGFR2 and one FGFR1 fusion), two NTRK3 and one each of RAF1, RET, ROS1 and BRAF fusions. Deleterious SNVs were frequently found in both fusion-positive and fusion-negative K-RAS wild-type pancreatic cancers. Transcriptomic expression revealed additional potentially druggable targets, e.g., ROS1 and FGFR3 overexpression in a tumor harboring an NTRK3 fusion, BRAF overexpression in the context of an otherwise non-actionable ETV6 fusion, and MET overexpression in a TES::TFEC -fusion bearing cancer. Conclusions: Druggable fusions are frequent in K-RAS wild-type pancreatic cancers. Moreover, RNA fusion assays as well as transcriptomic expression testing can identify candidate personalized therapies for patients with K-RAS wild-type pancreatic cancer.