Sánchez-Herrero Estela, Blanco Clemente Mariola, Calvo Virginia, Provencio Mariano, Romero Atocha
Molecular Oncology Laboratory, Biomedical Sciences Research Institute, Puerta de Hierro-Majadahonda University Hospital, Madrid, Spain.
Medical Oncology Department, Puerta de Hierro-Majadahonda University Hospital, Madrid, Spain.
Transl Lung Cancer Res. 2020 Apr;9(2):366-372. doi: 10.21037/tlcr.2020.02.07.
Tyrosine kinase inhibitors (TKIs) of the anaplastic lymphoma kinase gene () have significantly improved the quality of life and survival of non-small cell lung cancer (NSCLC) patients whose tumors harbor an translocation. However, most of these patients relapse within 2 to 3 years as the tumor acquires resistance mutations. Unlike beaming and digital PCR (dPCR), which only allow a few mutations to be analyzed, next-generation sequencing (NGS) approaches enable the simultaneous screening of multiple genetic alterations even when the frequencies of the variants are very low. We present the case of a 52-year-old man who was diagnosed with an -positive NSCLC and was treated with crizotinib and, subsequently, ceritinib. The analysis of serial liquid biopsies by NGS detected two asynchronous mutations arising in the locus during disease progression, namely p.Gly1269Ala (c.3806G>C) and p.Gly1202Arg (c.3604G>A), that conferred resistance to crizotinib and ceritinib, respectively. The resistance mutations were detected independently at different times, and could be imputed to different metastatic lesions, thereby highlighting the importance of heterogeneity in advance disease. Plasma levels of resistance mutations correlated well with tumor responses assessed by CT scans and bone scintigraphy, demonstrating that non-invasive tumor molecular profiling by NGS allows the efficient dynamic monitoring of -positive NSCLC patients, and outperforms dPCR and beaming because more somatic mutations can be tracked over the course of the treatment. In conclusion, this case report illustrates the usefulness NGS to guide therapeutic decisions in -positive NSCLC patients based tumor molecular profile upon disease progression.
间变性淋巴瘤激酶基因（）的酪氨酸激酶抑制剂（TKIs）显著改善了肿瘤携带 易位的非小细胞肺癌（NSCLC）患者的生活质量和生存率。然而，这些患者中的大多数在2至3年内复发，因为肿瘤获得了耐药性突变。与仅允许分析少数突变的荧光定量PCR和数字PCR（dPCR）不同，新一代测序（NGS）方法能够同时筛查多个基因改变，即使变异频率非常低。我们报告了一例52岁男性患者，他被诊断为 阳性NSCLC，接受了克唑替尼治疗，随后接受了色瑞替尼治疗。通过NGS对系列液体活检进行分析，在疾病进展过程中检测到 基因座出现了两个不同时发生的突变，即p.Gly1269Ala（c.3806G>C）和p.Gly1202Arg（c.3604G>A），分别赋予了对克唑替尼和色瑞替尼的耐药性。耐药性突变在不同时间独立检测到，可能归因于不同的转移病灶，从而突出了晚期疾病异质性的重要性。 耐药性突变的血浆水平与CT扫描和骨闪烁显像评估的肿瘤反应密切相关，表明通过NGS进行的非侵入性肿瘤分子谱分析能够有效动态监测 阳性NSCLC患者，并且优于dPCR和荧光定量PCR，因为在治疗过程中可以追踪更多的体细胞突变。总之，本病例报告说明了NGS在根据疾病进展时的肿瘤分子谱指导 阳性NSCLC患者治疗决策方面的有用性。
