Identification of Targetable Gene Fusions and Structural Rearrangements to Foster Precision Medicine in KRAS Wild-Type Pancreatic Cancer. (2021)

• Record Type: Journal Article
• Authors: Fusco, Michael J.; Saeed-Vafa, Daryoush; Carballido, Estrella M.; Boyle, Theresa A.; Malafa, Mokenge; Blue, Kirsten L.; Teer, Jamie K.; Walko, Christine M.; McLeod, Howard L.; Hicks, J. Kevin; Extermann, Martine; Fleming, Jason B.; Knepper, Todd C.; Kim, Dae Won
• Is Part Of: JCO precision oncology. Volume 5(2021)
• Publication Date: 2021
• Subjects: Precision Medicine; Neoplasms; Pharmacogenetics; Molecular Targeted Therapy; Personalized medicine; Oncology; Pharmacogenomics; Periodical; Periodicals; 616.994
• DOI: 10.1200/PO.20.00265
• Languages: English
• ISSNs: 2473-4284

Abstract

Abstract : PURPOSE: It has recently been described that alternative oncogenic drivers may be found in KRAS wild-type ( KRAS WT ) pancreatic cancers. This study aimed to determine the incidence of targetable gene fusions present in KRAS WT pancreatic adenocarcinoma and response to targeted therapy. METHODS: 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 KRAS WT pancreatic adenocarcinoma was characterized and compared with the frequency of fusions in KRAS -mutated ( KRAS 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. RESULTS: Pancreatic cancers from 13 of 100 patients (13%) were found to be KRAS WT . Targetable fusions were identified in 4/13 (31%) KRAS WT 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%) KRAS WT tumors reported in the AACR GENIE and TCGA cohorts, respectively. CONCLUSION: Oncogene fusions are present in KRAS WT pancreatic adenocarcinomas at an increased frequency when compared with KRAS MUT pancreatic adenocarcinomas. As these fusions may be susceptible to targeted therapy, molecular analyses for the detection of fusions in KRAS WT pancreatic adenocarcinomas may warrant increased consideration.