HER2 gene mutations in non-small cell lung carcinomas: Concurrence with her2 gene amplification and her2 protein expression and phosphorylation

• We analyzed dysregulation of HER2 signaling pathways in 1275 cases of non-small cell lung carcinoma.
• HER2 mutations were detected in 46 (3.6%) of the non-small cell lung carcinomas, with mutations only present in the ADC.
• All HER2-mutated tumors were negative for other driver gene alterations.
• HER2 mutation status correlated with never-smoker status and patients with smaller tumor size.
• The overall survival rate was not significantly different between patients without and with HER2 mutations. When analyzing only invasive ADCs, HER2 mutation status was an independent factor for an unfavorable outcome.

BackgroundDysregulation of HER2 signaling pathways results in tumor progression in several types of carcinomas. The aim of the current study is to identify clinicopathological characteristics of HER2-mutated non-small cell lung carcinomas (NSCLCs) in conjunction with HER2 protein expression, gene amplification, and phosphorylation.Patients and methodsWe investigated 1275 patients including 1055 adenocarcinomas (ADCs), 146 squamous cell carcinomas, 2 large cell carcinomas, 8 sarcomatoid carcinomas, and 64 adenosquamous carcinomas. High-resolution melting analysis of HER2 hot spot inflame deletion mutations, chromogenic in situ hybridization for HER2 amplification, and immunostaining of wild-type and phosphorylated HER2 was performed.ResultsHER2 mutations were detected in 46 (3.6%) of the NSCLCs, with mutations only present in the ADC. When analyzing ADC cases alone, the incidence of HER2 mutation was increased to 4.3%. All HER2-mutated tumors were negative for other driver gene alterations. HER2 mutation status correlated with never-smoker status and patients with smaller tumor size. HER2 amplifications were also identified in approximately half of the tumors with HER2 mutations. The overall survival rate was not significantly different between patients without and with HER2 mutations. When analyzing only invasive ADCs, HER2 mutation status was an independent factor for an unfavorable outcome. Amongst the 46 patients harboring HER2 mutations, univariate and multivariate analysis revealed that HER2 amplification was an unfavorable prognostic factor, while HER2 phosphorylation was a favorable prognostic factor.ConclusionsHER2 mutations were observed in 3.6% of NSCLCs, particularly in younger patients, those with no history of smoking, and those with small tumors. Amongst the patients with HER2 mutations, HER2 amplification and phosphorylation were independent prognostic factors.