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Clin Cancer Res. 2019 May 8. doi: 10.1158/1078-0432.CCR-19-0191. [Epub ahead of print]

NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma.

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BC Cancer, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
Pancreas Centre British Columbia, Vancouver, Canada.
BC Cancer, Division of Medical Oncology, Vancouver, British Columbia, Canada.
Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada.
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, British Columbia, Canada.
Pancreas Centre British Columbia, Vancouver, Canada.


Purpose: Gene fusions involving neuregulin 1 (NRG1) have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of NRG1 fusion-positive pancreatic ductal adenocarcinoma is not fully understood.Experimental Design: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving NRG1 received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging.Results: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as KRAS wild type by whole-genome sequencing. All KRAS wild-type tumors were positive for gene fusions involving the ERBB3 ligand NRG1. Two of 3 patients with NRG1 fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy.Conclusions: This work adds to a growing body of evidence that NRG1 gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with KRAS wild-type tumors harboring NRG1 gene fusions may benefit from treatment with afatinib.

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