Yang Guangjian, Liu Runze, Li Pei, Yang Yaning, Wang Yajie, Mao Huiqing, Tang Xiaoyong
Department of Respiratory Medical Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, No.440 Jiyan Road, Jinan, 250117, Shandong, China.
Department of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, 250117, Shandong, China.
Discov Oncol. 2024 Jul 16;15(1):285. doi: 10.1007/s12672-024-01154-2.
Unlike human epidermal growth factor receptor 2 (HER2) amplification or exon 20 insertions, missense mutations in the extracellular domain (ECD), transmembrane domain (TMD), and intracellular domain (ICD) of the HER2 protein have been implicated as oncogenic in non-small cell lung cancer (NSCLC). However, their molecular subtypes, structural disparities, and clinical responses to current medical treatments, particularly HER2-targeted tyrosine kinase inhibitors (TKIs), remain unclear in NSCLC and warrant investigation.
A real-world observational ATLAS study was conducted to gather and analyze therapeutic outcomes of chemotherapy or TKIs for heterogeneous HER2 missense mutations in NSCLC. Computational models of typical ECD, TMD, and ICD mutations were utilized to explore their structural variances.
We screened 37 eligible patients with HER2-activating missense mutations, of which 35 patients who had received chemotherapy or HER2-targeted TKIs as first-line therapy were available for response assessment. The median progression-free survival (PFS) for chemotherapy was 4.43 months (95% confidence interval [CI], 3.77-5.10), with an objective response rate (ORR) of 26.1% (6/23) and a disease control rate (DCR) of 17/23 (73.9%). The administration of afatinib, dacomitinib, and pyrotinib, HER2-targeted TKIs, achieved a median PFS of 4.65 months, with an ORR of 33.3% (4/12) and a DCR of 83.3% (10/12). Molecular modeling and computational simulations of ECD, TMD, and ICD mutations revealed their distinct structural characteristics.
In comparison to chemotherapy, HER2-targeted TKIs demonstrated similar activity and PFS benefits for HER2-activating missense mutations in NSCLC.
与人类表皮生长因子受体2（HER2）扩增或外显子20插入不同，HER2蛋白细胞外结构域（ECD）、跨膜结构域（TMD）和细胞内结构域（ICD）中的错义突变在非小细胞肺癌（NSCLC）中被认为具有致癌性。然而，在NSCLC中，它们的分子亚型、结构差异以及对当前医学治疗（尤其是HER2靶向酪氨酸激酶抑制剂（TKIs））的临床反应仍不清楚，值得研究。
开展一项真实世界观察性ATLAS研究，以收集和分析化疗或TKIs治疗NSCLC中异质性HER2错义突变的治疗结果。利用典型ECD、TMD和ICD突变的计算模型来探索其结构差异。
我们筛选了37例符合条件的HER2激活错义突变患者，其中35例接受化疗或HER2靶向TKIs作为一线治疗的患者可用于疗效评估。化疗的中位无进展生存期（PFS）为4.43个月（95%置信区间[CI]，3.77 - 5.10），客观缓解率（ORR）为26.1%（6/23），疾病控制率（DCR）为17/23（73.9%）。给予HER2靶向TKIs阿法替尼、达可替尼和吡咯替尼后，中位PFS为4.65个月，ORR为33.3%（4/12），DCR为83.3%（10/12）。ECD、TMD和ICD突变的分子建模和计算模拟揭示了它们独特的结构特征。
与化疗相比，HER2靶向TKIs对NSCLC中HER2激活错义突变显示出相似的活性和PFS获益。
