Identification of targetable gene fusions and structural rearrangements to foster precision medicine in kras wild-type pancreatic cancer

PURPOSE It has recently been described that alternative oncogenic drivers may be found in KRAS wild-type (KRASWT) pancreatic cancers. This study aimed to determine the incidence of targetable gene fusions present in KRASWT pancreatic adenocarcinoma and response to targeted therapy. METHODS One hundred consecutive patients with pancreatic adenocarcinoma who underwent targeted nextgeneration 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 KRASWT pancreatic adenocarcinoma was characterized and compared with the frequency of fusions in KRASmutated (KRASMUT) 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. RESULTS Pancreatic cancers from 13 of 100 patients (13%) were found to be KRASWT. Targetable fusions were identified in 4/13 (31%) KRASWT tumors compared with 0/87 (0%) KRAS MUT pancreatic adenocarcinomas (P = .0002). One patient with a novel MET 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%) KRASWT tumors reported in the AACR GENIE and TCGA cohorts, respectively. CONCLUSION Oncogene fusions are present in KRASWT pancreatic adenocarcinomas at an increased frequency when compared with KRASMUT pancreatic adenocarcinomas. As these fusions may be susceptible to targeted therapy, molecular analyses for the detection of fusions in KRASWT pancreatic adenocarcinomas may warrant increased consideration.