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

Abstract

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 fusionpositive pancreatic ductal adenocarcinoma is not fully understood. Experimental Design: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive wholegenome 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 wildtype tumors harboring NRG1 gene fusions may benefit from treatment with afatinib. See related commentary by Aguirre, p. 4589

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

“…The ectopic ERBB signalling pathway, including constitutive activation of MEK, ERK, and PI3K, represents a potentially promising target in NRG1 fusion-initiated KRAS wild-type PDAC [85]. The anti-ERBB3 antibody GSK2849330 and pan-ERBB inhibitors afatinib and neratinib impaired cell proliferation in multiple cancer cell lines with NRG1 rearrangements.…”

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

“…In addition, some studies have demonstrated the actionability of NRG1 fusions in PDAC. Indeed, when patients affected by heavily pretreated PDAC carrying NRG1 fusion received matched therapy with afatinib, an irreversible ERBB1–4 inhibitor, clinical benefit and objective responses were documented [ 65 , 66 ]. However, Drilon at al recently reported four patients affected by IMA of the lung with NRG1 fusion that did not respond to afatinib, but showed an extraordinary clinical response to treatment with a new monoclonal antibody targeting ERBB3 [ 67 ].…”

The Immune Microenvironment in Pancreatic Cancer

“…PDAC driver mutations have proven difficult to target in the clinical setting, with the exception of microsatellite instability with immune check point inhibitors [ 17 ] or BRCA1/2 mutations with platinum-based chemotherapies and PARP-inhibitors [ 18 , 19 ]; however, these concern only a small number of patients. KRAS wild-type patients comprise between 5 and 8% of sporadic PDAC patients [ 20 ] and have been shown to harbor actionable genomic alterations [ 21 ], such as NTRK [ 22 ] or NRG1 [ 23 , 24 ] fusions. While molecular subtypes and actionable genomic alterations may theoretically help guide precision medicine approaches, the molecular characterization of PDAC in patients with advanced disease has not yet entered routine clinical practice.…”