Prognostic and Predictive Implications of HER2/ERBB2/neu Gene Mutations in Lung Cancers

Background: Activating mutation in the kinase domain of the human EGF receptor 2 (HER2) gene (also known as ERBB2 or neu) is reported to be present in a small fraction of lung adenocarcinomas. However its prognostic and predictive implications are not yet established.

Patients And Methods: We examined 504 Japanese lung cancer patients who underwent pulmonary resection for HER2 mutations by direct sequencing and evaluated their prognostic and predictive implications. Updated prognostic data of 14 Japanese patients with HER2 mutation from previous two reports were also gathered.

Results: HER2 mutations were identified in 13 of 504 cases (2.6%). Patients with HER2 mutations were common in female, nonsmokers and adenocarcinomas as those with EGFR mutations. When confined to the subgroup of nonsmokers with adenocarcinoma or adenosquamous cell carcinoma without EGFR mutations, the frequency of HER2 mutations was 14.1% (11/78). There was no difference in the overall survival of patients with HER2 mutations, compared with patients harboring EGFR mutations and patients harboring wild types for both EGFR and HER2. Within the patients with HER2 mutation, two of three with TP53 mutation and one of 13 without TP53 mutation died of the disease, suggesting negative prognostic role of the TP53 mutation. Three patients with HER2 mutations did not respond to platinum-based chemotherapy and EGFR-TKIs. Of note, one patient with the most common HER2 mutations, YVMA776-779ins, responded to trastuzumab plus vinorelbine after failure of multiple round of platinum-based chemotherapy and gefitinib.

Conclusion: HER2 mutations are present in a subset of patients with lung cancer having distinct clinical features. HER2 mutations were not associated with the prognosis of patients with lung cancers. Patients with HER2 mutations might benefit from anti-HER2 therapy.