Xing Puyuan, Yang Nong, Hu Xue, Mu Yuxin, Wang Shouzheng, Guo Yiying, Hao Xuezhi, Hu Xingsheng, Zhang Xinwei, Li Junling
National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Transl Cancer Res. 2020 Oct;9(10):6455-6463. doi: 10.21037/tcr-20-754.
The incidence of lung cancer is growing fast in China, however, the prognosis remains dismal due to the limited therapeutic approaches. The "ret proto-oncogene mutation" () fusions have been proven to be the driver gene in lung cancer development and the therapeutic target of several multi-target tyrosine kinase inhibitors.
We applied formalin-fixed, paraffin-embedded (FFPE) samples of 39 patients with non-small cell lung cancer (NSCLC) using the Lung Plasma panel covering 168 cancer-associated genes and performed capture-based targeted deep sequencing to identify the fusion partners and concurrent gene mutation with Miseq. The log-rank test was used to compare the survival difference of patients according to treatment strategies. Statistical analyses and graphs were performed using R language and GraphPad Prism.
Most of the samples were advanced (stage IIIb and IV) lung adenocarcinomas (80.77%). fusions were identified in 52% of the samples and K15-E12 was the most common variant. 6 (15%) samples harbored concurrent mutation and 3 samples were positive with mutation including a mutation in exon 19. Of these patients included, ten received cabozantinib, two received anlotinib, and one received crizotinib. Two (20%; 0-45) samples achieved stable disease and two were progressed in the cabozantinib treated group. Median progression-free survival (PFS) was 4 months (95% CI: 3.2-4.8) and median overall survival (OS) was 25 months (95% CI: 1.5-48.5). Three (11.54%; 0-24) samples achieved partial response in patients without RET inhibitor treatment and 4 (15.38%; 2-29) were stable disease. The median PFS was 11 months (95% CI: 1.2-20.8). There was no significant difference in PFS and OS between groups with or without RET inhibitors treatment.
This study provided insight into the fusions patients treatment. The survival benefit of current RET inhibitors was limited. More precise and potent RET inhibitors should be developed in the near future.
肺癌在中国的发病率正在快速上升，然而，由于治疗方法有限，其预后仍然不容乐观。“原癌基因ret突变”（）融合已被证明是肺癌发展中的驱动基因以及几种多靶点酪氨酸激酶抑制剂的治疗靶点。
我们应用福尔马林固定、石蜡包埋（FFPE）的39例非小细胞肺癌（NSCLC）患者样本，使用覆盖168个癌症相关基因的肺癌血浆检测板，并通过基于捕获的靶向深度测序，利用Miseq鉴定融合伙伴和并发基因突变。采用对数秩检验根据治疗策略比较患者的生存差异。使用R语言和GraphPad Prism进行统计分析和绘图。
大多数样本为晚期（IIIb期和IV期）肺腺癌（80.77%）。在52%的样本中鉴定出融合，K15 - E12是最常见的变体。6个（15%）样本存在并发突变，3个样本为突变阳性，包括外显子19中的一个突变。在这些纳入的患者中，10例接受卡博替尼治疗，2例接受安罗替尼治疗，1例接受克唑替尼治疗。在卡博替尼治疗组中，2个（20%；0 - 45）样本病情稳定，2个病情进展。中位无进展生存期（PFS）为4个月（95%CI：3.2 - 4.8），中位总生存期（OS）为25个月（95%CI：1.5 - 48.5）。在未接受RET抑制剂治疗的患者中，3个（11.54%；0 - 24）样本获得部分缓解，4个（15.38%；2 - 29）病情稳定。中位PFS为11个月（95%CI：1.2 - 20.8）。接受或未接受RET抑制剂治疗的组之间在PFS和OS方面没有显著差异。
本研究为融合患者的治疗提供了见解。当前RET抑制剂的生存获益有限。在不久的将来应开发更精确、更有效的RET抑制剂。
