Work

Network analysis of NRG1 variants of uncertain significance (VUSes) in advanced non-small-cell lung cancer and their prognostic role in EGFR-mutant patients treated with first-line osimertinib

Year: 2025

Type: article

Abstract: BACKGROUND: Fusion events involving neuregulin 1 (NRG1), a member of the pan-HER pathway, have been highlighted as a potential therapeutic target; however, little is known about the epidemiological distribution and the prognostic value of NRG1 variants in large real-world datasets. MATERIALS AND METHODS: Data from 878 patients with newly diagnosed advanced non-small-cell lung cancer who had undergone DNA- and RNA-based comprehensive genomic profiling from January 2022 to October 2024 were retrospectively collected in the context of the FPG500 program (interventional monocentric prospective study, NCT06020625). RESULTS: Comprehensive genomic profiling analysis reported NRG1 variants of uncertain significance (VUSes) in 70 samples (8.0%), including 41 deletions (58.6%), 21 sequence variants (33.0%), 2 double genetic hits (2.8%) and 2 amplifications (2.8%). Forty NRG1-mutant patients (57.1%) presented one main actionable genomic alteration, particularly EGFR, HER2 and KRAS mutation. NRG1 VUSes occurred along with genes regulating the RTK/KRAS pathway in 59 samples (84%), the TP53 pathway in 47 samples (67%) and the PI3K pathway in 27 samples (39%). In multivariate analysis carried out in a retrospective cohort of EGFR M+ (del19/L858R) patients treated with osimertinib, EGFRM+/NRG1wt patients showed significantly longer progression-free survival (PFS) and overall survival (OS) compared with EGFRM+/NRG1 M+ patients {PFS 26.07 versus 12.07 months [hazard ratio (HR) 0.34, 95% confidence interval 0.12-0.95, P = 0.0015]; OS 34.06 versus 20.45 months (HR 0.45, 95% confidence interval 0.22-0.93, P = 0.0230)}. CONCLUSIONS: Although retrospective, these data support the hypothesis that NRG1 VUSes are frequently associated with poor prognosis and other oncogene alterations. In EGFR M+ patients treated with osimertinib, concurrent NRG1 alterations were an independent poor prognostic factor for both PFS and OS, raising the need of further validation.

Source: ESMO Open

DOI: 10.1016/j.esmoop.2025.105556