The frequency and clinical impact of HER2 alterations in lung adenocarcinoma.
The frequency and clinical impact of HER2 alterations in lung adenocarcinoma.
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DOI：
10.1371/journal.pone.0171280
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Shim HS
中科院分区：
文献类型：
--
作者：
Kim EK;Kim KA;Lee CY;Shim HS
人表皮生长因子受体 2（HER2 或 ErbB2）可在恶性肿瘤中过度表达、扩增和/或突变，是治疗靶向的候选者。然而，这些改变的分子关联和临床意义在肺癌中存在争议。在这项研究中，我们调查了肺腺癌患者 HER2 失调的频率和临床病理学意义。分别通过免疫组织化学（IHC）、银原位杂交和直接测序评估HER2蛋白过表达、基因扩增和基因突变。 H 评分方法和美国临床肿瘤学会/美国病理学家学院乳腺癌指南用于解释 IHC 结果。还对 EGFR 和 KRAS 突变以及 ALK 和 ROS1 重排进行了遗传分析。在确定的 321 名腺癌患者中，分别有 6 名（1.9%）和 46 名（14.3%）发现 HER2 过度表达（H 评分≥200）和基因扩增。 HER2 过度表达与乳头状为主的组织学相关；此外，它表明总体生存率较差，是一个独立的预后因素。 HER2 扩增与胸膜侵犯相关，并显示出总体生存期和无病生存期较短的趋势。高水平基因扩增（HER2/CEP17 比率≥5 或拷贝数≥10）是无病生存的不良预后因素。 6.7%（104 例中有 7 例）的驱动癌基因阴性腺癌中检测到 HER2 突变。我们的研究表明，HER2 过度表达或扩增是肺腺癌的不良预后因素，尽管此类事件的发生频率较低。由于分子靶向药物正在临床试验中进行测试，因此对特定 HER2 状态的了解可以影响分子定义的肺腺癌亚型患者的预后分层和治疗。
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.