Identification of Targetable Gene Fusions and Structural Rearrangements to Foster Precision Medicine in <i>KRAS</i> Wild-Type Pancreatic Cancer.

Abstract

It has recently been described that alternative oncogenic drivers may be found in <i>KRAS</i> wild-type (<i>KRAS</i> ^WT) pancreatic cancers. This study aimed to determine the incidence of targetable gene fusions present in <i>KRAS</i> ^WT pancreatic adenocarcinoma and response to targeted therapy. One hundred consecutive patients with pancreatic adenocarcinoma who underwent targeted next-generation sequencing using DNA sequencing with RNA sequencing (n = 47) or without RNA sequencing (n = 53) at a single institution were included in the study. The frequency and landscape of targetable fusions in <i>KRAS</i> ^WT pancreatic adenocarcinoma was characterized and compared with the frequency of fusions in <i>KRAS</i>-mutated (<i>KRAS</i> ^MUT) pancreatic adenocarcinoma. Results were validated in two independent cohorts using data from AACR GENIE (n = 1,252) and TCGA (n = 150). The clinical history of fusion-positive patients who received targeted treatment is described. Pancreatic cancers from 13 of 100 patients (13%) were found to be <i>KRAS</i> ^WT. Targetable fusions were identified in 4/13 (31%) <i>KRAS</i> ^WT tumors compared with 0/87 (0%) <i>KRAS</i> ^MUT pancreatic adenocarcinomas (<i>P</i> = .0002). One patient with a novel <i>MET</i> fusion had a complete response to targeted therapy with crizotinib that is ongoing at 12+ months of treatment. In the validation cohorts, gene fusions were identified in 18/97 (19%) and 2/10 (20%) <i>KRAS</i> ^WT tumors reported in the AACR GENIE and TCGA cohorts, respectively. Oncogene fusions are present in <i>KRAS</i> ^WT pancreatic adenocarcinomas at an increased frequency when compared with <i>KRAS</i> ^MUT pancreatic adenocarcinomas. As these fusions may be susceptible to targeted therapy, molecular analyses for the detection of fusions in <i>KRAS</i> ^WT pancreatic adenocarcinomas may warrant increased consideration.