PDF(Pubmed)
Abstract：
Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have been found to significantly improve the quality of life and survival in ALK-positive non-small cell lung cancer (NSCLC) patients. However, the duration of responses is limited by drug resistance. Genetic heterogeneity of ALK-positive tumors could potentially explain the differences in individual patient outcomes. We performed next-generation sequencing (NGS) on plasma samples, pleural effusion samples, and tissue re-biopsy obtained at various treatment milestones from an ALK rearrangement lung adenocarcinoma patient undergoing targeted therapy. The liver metastases of the EML4-ALK NSCLC patient presented rapid progression after 3.5 months of alectinib, while the other lesions showed good partial response. Targeted NGS identified the newly emerged MET amplification except for EML4-ALK in plasma ctDNA and liver lesions. Subsequently, a clinical benefit was achieved one month after the commencement of crizotinib, a dual ALK and MET inhibitor; however, the patient experienced disease progression another month later. Several rounds of ALK-TKI combination therapy were tried but failed. Concurrent genetic alterations, including loss-of-function mutations in FBXW7 and MLL3, may mainly contribute to poor prognosis in the patient. It highlighted the molecular profiling by using NGS can be useful in identifying the heterogeneity across lesions and the resistance mechanism of targeted treatments.
摘要：
已发现间变性淋巴瘤激酶酪氨酸激酶抑制剂（ALK-TKIs）显着改善ALK阳性非小细胞肺癌（NSCLC）患者的生活质量和生存率。然而,反应的持续时间受到耐药性的限制。ALK阳性肿瘤的遗传异质性可能解释了个体患者预后的差异。我们对血浆样本进行了下一代测序（NGS），胸腔积液样本,以及接受靶向治疗的ALK重排肺腺癌患者在不同治疗阶段获得的组织再活检。EML4-ALKNSCLC患者的肝转移在3.5个月的阿来替尼后呈现快速进展，而其他病变表现出良好的部分反应。靶向NGS鉴定了新出现的MET扩增,除了血浆ctDNA和肝脏病变中的EML4-ALK。随后，克唑替尼开始后一个月实现了临床获益，ALK和MET双重抑制剂；然而，患者在一个月后出现疾病进展.尝试了几轮ALK-TKI联合治疗，但失败了。同时遗传改变，包括FBXW7和MLL3的功能缺失突变,可能主要导致患者预后不良.它强调了通过使用NGS的分子谱分析可以用于识别跨病变的异质性和靶向治疗的耐药机制。
