Circulating Tumor Cells with Aberrant ALK Copy Number Predict Progression-Free Survival during Crizotinib Treatment in ALK-Rearranged Non-Small Cell Lung Cancer Patients
Circulating Tumor Cells with Aberrant ALK Copy Number Predict Progression-Free Survival during Crizotinib Treatment in ALK-Rearranged Non-Small Cell Lung Cancer Patients
复制标题
DOI：
10.1158/0008-5472.can-16-3072
复制
发表时间：
2017-05-01
期刊：
影响因子：
11.2
通讯作者：
Farace, Francoise
中科院分区：
文献类型：
--
作者：
Pailler, Emma;Oulhen, Marianne;Farace, Francoise
在接受克唑替尼治疗的alk重排非小细胞肺癌（NSCLC）患者中，临床反应的持续时间和程度是不可预测的，尽管所有患者都会出现耐药性。在这里，我们评估了使用克唑替尼监测具有异常ALK-FISH模式（alk重排，alk拷贝数增益（ALK-CNG））的循环肿瘤细胞（CTC）是否可以预测一组alk重排患者的无进展生存期（PFS）。前瞻性招募39例以克唑替尼作为首个ALK抑制剂治疗的ALK重排NSCLC患者。在基线和使用克唑替尼的早期时间点（2个月）采集血样。在过滤富集后，使用免疫荧光染色联合滤过鱼检测ctc中异常的ALK-FISH模式。根据是否存在alk -重排和/或ALK-CNG信号，将ctc划分为不同的子集。alk -重排或ALK-CNG CTCs的基线数量与PFS之间无显著关联。然而，我们观察到在克唑替尼上ALK-CNG减少的CTC数和更长的PFS之间有显著的关联（似然比检验，P = 0.025）。在多因素分析中，CTC随ALK-CNG的动态变化是与PFS相关的最强因素（HR, 4.485； 95%可信区间，1.543-13.030,P = 0.006）。虽然不占主导地位，但据报道，ALK-CNG是肿瘤活检中对克唑替尼获得性耐药的机制之一。我们的研究结果表明，ALK-CNG的ctc数量的动态变化可能是克唑替尼对alk重排NSCLC患者疗效的预测性生物标志物。CTC的系列分子分析显示了对该人群进行实时患者监测和临床结果预测的希望。(c) 2017 aacr。
The duration and magnitude of clinical response are unpredictable in ALK-rearranged non-small cell lung cancer (NSCLC) patients treated with crizotinib, although all patients invariably develop resistance. Here, we evaluated whether circulating tumor cells (CTC) with aberrant ALK-FISH patterns [ALK-rearrangement, ALK-copy number gain (ALK-CNG)] monitored on crizotinib could predict progression-free survival (PFS) in a cohort of ALK-rearranged patients. Thirty-nine ALK-rearranged NSCLC patients treated with crizotinib as first ALK inhibitor were recruited prospectively. Blood samples were collected at baseline and at an early time-point (2 months) on crizotinib. Aberrant ALK-FISH patterns were examined in CTCs using immunofluorescence staining combined with filter-adapted FISH after filtration enrichment. CTCs were classified into distinct subsets according to the presence of ALK-rearrangement and/or ALK-CNG signals. No significant association between baseline numbers of ALK-rearranged or ALK-CNG CTCs and PFS was observed. However, we observed a significant association between the decrease in CTC number with ALK-CNG on crizotinib and a longer PFS (likelihood ratio test, P = 0.025). In multivariate analysis, the dynamic change of CTC with ALK-CNG was the strongest factor associated with PFS (HR, 4.485; 95% confidence interval, 1.543-13.030, P = 0.006). Although not dominant, ALK-CNG has been reported to be one of the mechanisms of acquired resistance to crizotinib in tumor biopsies. Our results suggest that the dynamic change in the numbers of CTCs with ALK-CNG may be a predictive biomarker for crizotinib efficacy in ALK-rearranged NSCLC patients. Serial molecular analysis of CTC shows promise for real-time patient monitoring and clinical outcome prediction in this population. (C) 2017 AACR.