Jones 2019: NRG1 gene fusions are recurrent, clinically actionable rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma
In a Canadian programme sequencing the genomes of advanced pancreatic cancers in real time, tumours without a KRAS mutation repeatedly carried NRG1 fusions, and patients treated with HER-family blockers on the strength of that finding responded. It showed that fusion testing in KRAS wild-type disease changes treatment.
Overview
Analysis of whole-genome and transcriptome sequencing from patients with advanced pancreatic ductal adenocarcinoma in the COMPASS trial and related cohorts at BC Cancer and the Ontario Institute for Cancer Research. NRG1 fusions with several different partner genes were identified in a subset of the KRAS wild-type tumours and in none of the KRAS-mutant cases, and were confirmed at the RNA level.
Patients with NRG1 fusion-positive tumours treated with ERBB-targeting drugs such as afatinib had radiological responses and falls in tumour markers. The authors argue for RNA-based fusion testing in every KRAS wild-type pancreatic cancer.
- NRG1 fusions with multiple partners were recurrent among KRAS wild-type tumours and absent from KRAS-mutant tumours.
- Patients treated with ERBB inhibitors on the basis of an NRG1 fusion responded, with tumour marker declines.
Together with the German MASTER report, this paper is why guidelines recommend comprehensive profiling with fusion detection in KRAS wild-type pancreatic cancer.
- Small numbers of fusion-positive patients; responses were described in a handful of cases.
- DNA panels with limited intron coverage miss many NRG1 fusions, so the frequency depends on the assay.
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