Detection of Circulating Tumor Cells Harboring a Unique ALK Rearrangement in ALK-Positive Non-Small-Cell Lung Cancer
Detection of Circulating Tumor Cells Harboring a Unique ALK Rearrangement in ALK-Positive Non-Small-Cell Lung Cancer
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DOI：
10.1200/jco.2012.44.5932
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发表时间：
2013-06-20
影响因子：
45.3
通讯作者：
Farace, Francoise
中科院分区：
文献类型：
--
作者：
Pailler, Emma;Adam, Julien;Farace, Francoise
目的：克唑替尼治疗非小细胞肺癌（NSCLC）时ALK重排的诊断检测目前是通过肿瘤活检或细针穿刺进行的。我们评估是否可以通过使用循环肿瘤细胞（CTCs）进行ALK重排诊断。患者和MethodsThe存在的ALK重排检查在CTCs的18个ALK阳性和14个ALK阴性患者通过使用过滤富集技术和过滤适应荧光原位杂交（FA-FISH），FISH方法优化过滤器。在CTC中确定ALK重排模式，并与肿瘤活检中存在的ALK重排模式进行比较。对ALK重排的CTC和肿瘤标本的上皮（细胞角蛋白，E-钙粘蛋白）和间质（波形蛋白，N-钙粘蛋白）标记物表达进行表征。ALK重排的CTCs进行了监测，在5例患者治疗crizotinib.ResultsAll ALK阳性患者有4个或更多的ALK重排的CTCs每1毫升的血液（中位数，9个CTCs每1毫升;范围，4至34个CTCs每1毫升）。在ALK阴性患者中未检测到或仅检测到1个ALK重排CTC（中位数，1/1 mL;范围，0 - 1/1 mL）。ALK重排的CTC具有独特的（3 '5'）分裂模式，并且在肿瘤中存在不均匀的分裂模式（3 '5'，仅3 '）。ALK重排的CTC表达间充质表型，与肿瘤中异质性上皮和间充质标志物表达形成对比。在接受克唑替尼治疗的患者中检测到ALK重排的CTC水平的变化。结论通过使用过滤技术和FA-FISH可以检测ALK阳性非小细胞肺癌患者的CTC中ALK重排，从而实现克唑替尼治疗的诊断检测和监测。我们的研究结果表明，具有独特ALK重排和间充质表型的CTC可能来自肿瘤细胞的克隆选择，这些肿瘤细胞具有驱动ALK阳性NSCLC转移进展的潜力。(C)2013年美国临床肿瘤学会
PurposeThe diagnostic test for ALK rearrangement in non-small-cell lung cancer (NSCLC) for crizotinib treatment is currently done on tumor biopsies or fine-needle aspirations. We evaluated whether ALK rearrangement diagnosis could be performed by using circulating tumor cells (CTCs).Patients and MethodsThe presence of an ALK rearrangement was examined in CTCs of 18 ALK-positive and 14 ALK-negative patients by using a filtration enrichment technique and filter-adapted fluorescent in situ hybridization (FA-FISH), a FISH method optimized for filters. ALK-rearrangement patterns were determined in CTCs and compared with those present in tumor biopsies. ALK-rearranged CTCs and tumor specimens were characterized for epithelial (cytokeratins, E-cadherin) and mesenchymal (vimentin, N-cadherin) marker expression. ALK-rearranged CTCs were monitored in five patients treated with crizotinib.ResultsAll ALK-positive patients had four or more ALK-rearranged CTCs per 1 mL of blood (median, nine CTCs per 1 mL; range, four to 34 CTCs per 1 mL). No or only one ALK-rearranged CTC (median, one per 1 mL; range, zero to one per 1 mL) was detected in ALK-negative patients. ALK-rearranged CTCs harbored a unique (3'5') split pattern, and heterogeneous patterns (3'5', only 3') of splits were present in tumors. ALK-rearranged CTCs expressed a mesenchymal phenotype contrasting with heterogeneous epithelial and mesenchymal marker expressions in tumors. Variations in ALK-rearranged CTC levels were detected in patients being treated with crizotinib.ConclusionALK rearrangement can be detected in CTCs of patients with ALK-positive NSCLC by using a filtration technique and FA-FISH, enabling both diagnostic testing and monitoring of crizotinib treatment. Our results suggest that CTCs harboring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC. (C) 2013 by American Society of Clinical Oncology