Hou Yating, Xue Xingyang, Zhang Zhuoyun, Mai Dahai, Luo Wei, Zhou Mingyu, Liu Zichuan, Huang Yisheng
Department of Oncology, Maoming People's Hospital, 101 Weimin Road, Maoming, 525000, Guangdong, China.
Department of Thoracic Surgery and Oncology, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Centre for Respiratory Disease, Guangzhou, China.
BMC Cancer. 2025 Apr 22;25(1):752. doi: 10.1186/s12885-025-14125-9.
The objective of this study was to investigate the clinical and genetic characteristics and clinical relevance of HER2 exon 20 oncogenic variants in non-small cell lung cancer (NSCLC) patients.
This prospective study analyzed 51 NSCLC patients with HER2 mutations, identified via next-generation sequencing (NGS) of tissue, blood, cerebrospinal fluid, or pleural effusion samples. Patients were grouped based on the presence of exon 20 mutations (exon 20 vs. non-exon 20) and further divided based on whether they had received prior anti-tumor treatments (baseline vs. non-baseline). Clinical and genetic data, treatment responses were analyzed. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier methods and compared with log-rank tests. Gene ontology (GO) analysis was performed to uncover the biological significance of the mutated genes.
In a cohort of 651 NSCLC patients, 51 (7.83%) harbored HER2 alterations, including 20 (3.08%) with exon 20 mutations. The median age of the HER2-altered subgroup was 58.5 years. Adenocarcinoma was the most prevalent subtype (96.1%), and most patients presented at stage IV (72.5%). The most common metastatic sites were the lungs (68.6%), lymph nodes (52.9%), and brain (43.1%). Among the HER2 mutated patients, 20 (39.3%) had exon 20 mutations. Exon 20 mutations were more prevalent in the non-baseline group (55.0% vs. 29.0%, P = 0.049) and males (75.0%, P = 0.025). These mutations were associated with a higher rate of metastasis to the lungs, lymph nodes (P < 0.001). Patients with exon 20 mutations demonstrated poorer overall survival (OS) outcomes (P = 0.048). No significant differences were observed in age, smoking history, histological subtype, or TNM stage at diagnosis between groups. The majority of exon 20 mutations were in-frame indel mutations (92.0%), with the most common specific mutation being p.Y772_A775dup (70%). Gene Ontology (GO) analysis linked exon 20 mutations to unregulated protein kinase activity and anoikis.
Our study found that NSCLC patients with HER2 exon 20 oncogenic variants have a higher risk of metastasis and drug resistance, leading to worse outcomes than non-exon 20 mutations. This highlights the urgent need for targeted therapies aimed at exon 20 insertions to improve survival and treatment outcomes in this subgroup.
本研究的目的是调查非小细胞肺癌（NSCLC）患者中HER2外显子20致癌变体的临床和遗传特征以及临床相关性。
这项前瞻性研究分析了51例经组织、血液、脑脊液或胸腔积液样本的下一代测序（NGS）鉴定出的HER2突变的NSCLC患者。患者根据外显子20突变的存在情况（外显子20与非外显子20）进行分组，并进一步根据是否接受过先前的抗肿瘤治疗进行划分（基线与非基线）。分析临床和遗传数据、治疗反应。使用Kaplan-Meier方法评估无进展生存期（PFS）和总生存期（OS），并通过对数秩检验进行比较。进行基因本体（GO）分析以揭示突变基因的生物学意义。
在651例NSCLC患者队列中，51例（7.83%）存在HER2改变，其中20例（3.08%）有外显子20突变。HER2改变亚组的中位年龄为58.5岁。腺癌是最常见的亚型（96.1%），大多数患者处于IV期（72.5%）。最常见的转移部位是肺（68.6%）、淋巴结（52.9%）和脑（43.1%）。在HER2突变患者中，20例（39.3%）有外显子20突变。外显子20突变在非基线组中更常见（55.0%对29.0%，P = 0.049），在男性中更常见（75.0%，P = 0.025）。这些突变与肺、淋巴结转移率较高相关（P < 0.001）。有外显子20突变的患者总生存期（OS）结果较差（P = 0.048）。两组在年龄、吸烟史、组织学亚型或诊断时的TNM分期方面未观察到显著差异。大多数外显子20突变是框内插入缺失突变（92.0%），最常见的特定突变是p.Y772_A775dup（70%）。基因本体（GO）分析将外显子20突变与不受调控的蛋白激酶活性和失巢凋亡联系起来。
我们的研究发现，具有HER2外显子20致癌变体的NSCLC患者转移和耐药风险更高，导致的结果比非外显子20突变患者更差。这凸显了迫切需要针对外显子20插入的靶向治疗，以改善该亚组患者的生存率和治疗结果。
