Anaplastic lymphoma kinase (ALK)是非小细胞肺癌(NSCLC)中最常见的融合基因，并使用ALK酪氨酸激酶抑制剂 (ALK-TKIs) 取得了显著的治疗效果。然而，其临床疗效高度不可预知。已证明，预先存在的肿瘤异质性(ITH)对于治疗反应不佳以及对靶向治疗的耐药性做出了贡献。在这项工作中，我们调查了ALK融合基因的等位基因频率(VAFs)是否有助于评估ITH和预测靶向治疗效果。通过采用下一代测序(NGS)技术，检测到7.2%（326/4548）的患者为ALK阳性。在四种不同阈值(adjVAF < 50%、40%、30%或20%)的调整VAF (adjVAF，肿瘤纯度的VAF正常化)的基础上，评估了ALK亚克隆性与克唑替尼疗效的关联性。然而，在评估ALK亚克隆性的adjVAF与中位无进展生存期 (PFS)之间未观察到统计学关联，并且在接受首线克唑替尼治疗的85名患者中，adjVAF与PFS之间的相关性很差。结果表明，基于杂交捕获的NGS测定的ALK VAF在NSCLC的ITH评估和靶向治疗疗效预测上可能不可靠。© 2022. 高等教育出版社。

Anaplastic lymphoma kinase (ALK) is the most common fusion gene involved in non-small cell lung cancer (NSCLC), and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors (ALK-TKIs). However, the clinical efficacy is highly variable. Pre-existing intratumoral heterogeneity (ITH) has been proven to contribute to the poor treatment response and the resistance to targeted therapies. In this work, we investigated whether the variant allele frequencies (VAFs) of ALK fusions can help assess ITH and predict targeted therapy efficacy. Through the application of next-generation sequencing (NGS), 7.2% (326/4548) of patients were detected to be ALK positive. On the basis of the adjusted VAF (adjVAF, VAF normalization for tumor purity) of four different threshold values (adjVAF < 50%, 40%, 30%, or 20%), the association of ALK subclonality with crizotinib efficacy was assessed. Nonetheless, no statistical association was observed between median progression-free survival (PFS) and ALK subclonality assessed by adjVAF, and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib. Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.© 2022. Higher Education Press.