Abstract
Human epidermal growth factor receptor 2 (HER2 or ErbB2) can be overexpressed, amplified and/or mutated in malignant tumors, and is a candidate for therapeutic targeting. However, molecular associations and clinical significances of these alterations were controversial in lung cancer. In this study, we investigated the frequency and clinicopathological significance of HER2 dysregulation in patients with lung adenocarcinoma. HER2 protein overexpression, gene amplification, and gene mutation were evaluated by immunohistochemistry (IHC), silver in situ hybridization, and direct sequencing, respectively. The H-scoring method and American Society of Clinical Oncology/College of American Pathologists breast cancer guidelines were used to interpret IHC results. Genetic analyses of EGFR and KRAS mutations, and of ALK and ROS1 rearrangements, were also performed. Of the 321 adenocarcinoma patients identified, HER2 overexpression (H-score ≥200) and gene amplification were found in 6 (1.9%) and 46 (14.3%), respectively. HER2 overexpression was correlated with papillary predominant histology; furthermore, it indicated poor overall survival and was an independent prognostic factor. HER2 amplification was associated with pleural invasion and showed a tendency towards shorter overall and disease-free survival. High-level gene amplification (HER2/CEP17 ratio ≥5 or copy number ≥10) was a poor prognostic factor for disease-free survival. HER2 mutations were detected in 6.7% (7 of 104) of driver oncogene-negative adenocarcinomas. Our study suggests that HER2 overexpression or amplification is a poor prognostic factor in lung adenocarcinoma, although the frequency of such events is low. Since molecular targeted agents are being tested in clinical trials, awareness of the specific HER2 status can influence the prognostic stratification and treatment of patients with molecularly defined subsets of lung adenocarcinoma.
Highlights
Lung cancer is estimated to be responsible for more than one-quarter (27%) of all cancerrelated deaths worldwide [1]
We observed that the frequency of HER2 overexpression and gene amplification were 1.9% and 14.3% in adenocarcinomas, respectively, and that protein overexpression and high amplification were associated with poor prognosis
In contrast to previous studies that showed a correlation between HER2 overexpression and both lymph node metastasis and higher tumor stage [25,26], we found that 50% of HER2-overexpressed tumors were papillary predominant adenocarcinomas
Summary
Lung cancer is estimated to be responsible for more than one-quarter (27%) of all cancerrelated deaths worldwide [1]. HER2 alterations in lung adenocarcinoma receptor (EGFR) as well as rearrangements of the anaplastic lymphoma kinase (ALK) gene; tyrosine kinase inhibitors (TKIs) have been developed against the proteins encoded by these genes. Comprehensive molecular profiling of lung adenocarcinoma from The Cancer Genome Atlas data has identified additional driver gene alterations, including amplifications in human epidermal growth factor receptor 2 (HER2 or ERBB2) [2]. HER2 is a receptor tyrosine kinase and a member of the human EGFR (ErbB) family. It is encoded by the HER2 gene located on the long arm of chromosome 17 (17q21), and activates downstream signaling pathways such as those involving PI3K-Akt and MEK/ERK to elicit cell proliferation and migration [3]. Monoclonal antibodies directed against HER2, such as trastuzumab (Herceptin), has improved patient outcomes [4,5]
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