Neuregulin 1 Variants of Uncertain Significance Associated With Poor Prognosis in Advanced Non-Small Cell Lung Cancer

According to a retrospective analysis, neuregulin 1 (NRG1) variants of uncertain significance (VUS) were associated with poor prognosis, and other oncogene alterations, in advanced non-small cell lung cancer (NSCLC).

Emanuele Vita, MD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, and coauthors explained, “Although NRG1 fusions represent a promising field for target therapy in NSCLC, these events remain extremely rare.” They went on to note that NRG1 VUS, such as single nucleotide polymorphisms, deletions, or amplifications, “could play a significant prognostic role for treatments targeting HER family receptors and the MAPK/ERK downstreaming pathway.”

This retrospective analysis included samples from 878 patients who had participated in the FPG500 trial, within the lung cancer cohort. All patients had advanced NSCLC and had undergone DNA- and RNA-based comprehensive genomic profiling. The FPG500 clinical and research program aimed to tailor matched targeted therapies according to biomarkers which could predict response, as identified by comprehensive genome profiling.

Of the samples included, 70 were identified to have an NRG1 VUS. These VUS included 41 deletions, 21 sequence variations, 2 double genetic hits, and 2 amplifications. Of the 70 patients with NRG1 VUS, 40 also had 1 main actionable genomic alteration, including EGFR alterations (n = 19), KRAS mutations (n = 12), oncogenic fusions (n = 6; 2 each of ROS-1, 2 RET, 2 ALK), HER2 activating mutations (n = 2), and MET exon 14 skipping alteration (n = 1). NRG1 VUS occurred concomitant with crucial mutations in genes regulating the RTK/KRAS pathway (n = 59), the TP52 pathway (n = 47), and the PI3K pathway (n = 27).

According to a multivariate analysis of patients with EGFR-mutant NSCLC who were treated with osimertinib, patients who were NRG1 wild-type had a significantly longer progression-free survival and overall survival when compared to those patients who had a concurrent NRG1 alteration.

Dr Vita et al, concluded that their data found NRG1 VUS “are frequently concomitant with EGFR mutations and emerge as an independent poor prognostic factor for survival outcomes in patients treated with first-line osimertinib.” They added that the biological role of NRG1 variants requires further validation.

Source:

Vita E, Scala A, Vitale A, et al. 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. ESMO Open. 2025;10(9). doi:10.1016/j.esmoop.2025.105556