Lung adenocarcinomas with HER2-activating mutations are associated with distinct clinical features and HER2/EGFR copy number gains

Abstract

Introduction: A fraction of lung adenocarcinomas harbor activating mutations in the HER2 kinase domain. HER2-targeted therapies have shown minimal benefit in molecularly unselected patients. We investigated clinical and potential molecular factors associated with HER2-mutant lung adenocarcinoma.

Methods: A total of 224 lung adenocarcinoma samples were examined for activating mutations in epidermal growth factor receptor (EGFR; exons 18-22), V-Ki-ras2 Kirsten rat sarcoma (KRAS; exons 2 and 3), and HER2 (exons 18-21) by direct sequencing. Gene copy number and protein expression of both EGFR and HER2 were further explored in samples harboring HER2 mutations using fluorescence in situ hybridization and immunohistochemistry, respectively.

Results: The mutation rates of EGFR, KRAS, HER2 were 63.39% (142/224), 4.46% (10/224), and 3.57% (8/224), respectively. All mutations were mutually exclusive. All eight HER2 mutations occurred in never smokers and seven were in women. The HER2 mutation rate in samples without EGFR and KRAS mutations was 11.11% (8/72). Seven of eight HER2-mutated tumors showed HER2 copy number gains (CNGs) and five showed EGFR CNGs. All of the HER2-mutated samples showed either HER2 or EGFR CNGs. Gene amplification of HER2 and EGFR was mutually exclusive in HER2-mutated samples.

Conclusion: HER2 mutations in lung adenocarcinoma predominantly occurred in women and never smokers. Most HER2-mutated tumors showed HER2 CNGs. As all of the samples with HER2 mutation showed either HER2 or EGFR CNGs, these patients could potentially benefit from novel EGFR/HER2 dual or pan-erythroblastic leukemia viral oncogene homolog tyrosine kinase inhibitors.