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

Abstract

Gene fusions involving neuregulin 1 (<i>NRG1</i>) 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 <i>NRG1</i> fusion-positive pancreatic ductal adenocarcinoma is not fully understood. Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving <i>NRG1</i> received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging. Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as <i>KRAS</i> wild type by whole-genome sequencing. All <i>KRAS</i> wild-type tumors were positive for gene fusions involving the ERBB3 ligand <i>NRG1</i>. Two of 3 patients with <i>NRG1</i> fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy. This work adds to a growing body of evidence that <i>NRG1</i> gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with <i>KRAS</i> wild-type tumors harboring <i>NRG1</i> gene fusions may benefit from treatment with afatinib.<i>See related commentary by Aguirre, p. 4589</i>.