Mutational landscape and characteristics of ERBB2 in non-small cell lung cancer.

Background: Tyrosine kinase domain (TKD) mutation and particularly exon 20 insertion mutations of ERBB2 have been extensively reported in non-small cell lung cancer (NSCLC). Due to the increased accessibility of next-generation sequencing, more ERBB2 mutations within the non-TKD can be detected in clinical practice. Nevertheless, the clinical significance of non-TKD mutations remains unknown. Hence, this study was designed to comprehensively outline the landscape and characteristics of ERBB2 mutations in NSCLC.

Methods: A total of 1934 patients with NSCLC from cBioPortal were included in the study. An ERBB2 mutation cohort was identified, while subsequent analyses revealed clinical and genomic characteristics.

Results: The frequency of ERBB2 mutation was 4.5%, and it was determined to be more likely to occur in never-smokers. ERBB2 mutations occurring in the non-TKD accounted for 57.5% of ERBB2 mutations. In the non-TKD, missense mutation was the most recurrent mutation type, and S310F was the most recurrent mutation variant. ERBB2 mutations within non-TKD also had a strong oncogenic ability where up to 37.5% of ERBB2 oncogenic mutations were within non-TKD. The co-mutation of EGFR or KRAS was higher in the non-TKD mutation compared to the TKD mutation. Shorter overall survival was observed in ERBB2-mutant patients compared with ERBB2 wild-type patients. There was no significant difference in overall survival between patients with non-TKD mutations and TKD mutations.

Conclusions: The present study showed that a considerable portion of non-TKD mutations were oncogenic. ERBB2 mutation was a poor prognostic factor. The non-TKD mutation might also be used as a therapeutic target in ERBB2-directed target therapy.

Key Points: • Significant findings of the study ERBB2 mutations were more abundant within a nontyrosine domain than those within the tyrosine domain. Up to 37.5% of ERBB2 oncogenic mutations were within the nontyrosine domain. ERBB2 mutation was a poor prognostic factor. • What this study adds The frequency of EGFR or KRAS co-mutations were significantly higher in ERBB2 mutations within the nontyrosine kinase domain compared to ERBB2 mutations within the tyrosine kinase domain. Nontyrosine domain mutations confer equal overall survival to tyrosine domain mutations.