ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research
ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research
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DOI：
10.1093/annonc/mdz204
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发表时间：
2019-09-01
影响因子：
50.5
通讯作者：
Reis-Filho, J. S.
中科院分区：
文献类型：
--
作者：
Marchio, C.;Scaltriti, M.;Reis-Filho, J. S.
背景：NTRK 1、NTRK 2和NTRK 3融合存在于多种不同组织学类型的恶性肿瘤中。这些融合体代表了这些受体酪氨酸激酶的致癌激活的最常见机制，以及用于TRK小分子抑制剂的生物标志物。鉴于NTRK 1/2/3融合的频率不同，NTRK抑制剂给药的关键是开发用于检测携带激活性NTRK 1/2/3融合基因的人类癌症的最佳方法。欧洲医学肿瘤学会（ESMO）转化研究和精准医学工作组招募了来自多个机构的专家（TR和PM WG），以审查可用的方法检测NTRK基因融合，其潜在的应用，并实施一个合理的方法检测NTRK 1/2/3融合基因在人类恶性肿瘤的策略。在肿瘤患者中筛选NTRK融合时，寻求最合理的策略，并进一步审查和批准的ESMO TR和PM WG和ESMO leadership.Results：NTRK融合基因检测采用的主要技术包括免疫组化，荧光原位杂交（FISH），RT-PCR，RNA和DNA为基础的下一代测序（NGS）。每种技术都有其优势和局限性，筛选和最终诊断的检测方法的选择也应考虑资源和临床背景。在NTRK融合高度复发的肿瘤中，FISH、RT-PCR或基于RNA的测序组可用作确认技术，而在测试NTRK 1/2/3融合不常见的肿瘤人群的情况下，应进行一线测序（优选RNA测序）或通过免疫组织化学进行筛查，然后对阳性病例进行测序。
Background: NTRK1, NTRK2 and NTRK3 fusions are present in a plethora of malignancies across different histologies. These fusions represent the most frequent mechanism of oncogenic activation of these receptor tyrosine kinases, and biomarkers for the use of TRK small molecule inhibitors. Given the varying frequency of NTRK1/2/3 fusions, crucial to the administration of NTRK inhibitors is the development of optimal approaches for the detection of human cancers harbouring activating NTRK1/2/3 fusion genes.Materials and methods: Experts from several Institutions were recruited by the European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) to review the available methods for the detection of NTRK gene fusions, their potential applications, and strategies for the implementation of a rational approach for the detection of NTRK1/2/3 fusion genes in human malignancies. A consensus on the most reasonable strategy to adopt when screening for NTRK fusions in oncologic patients was sought, and further reviewed and approved by the ESMO TR and PM WG and the ESMO leadership.Results: The main techniques employed for NTRK fusion gene detection include immunohistochemistry, fluorescence in situ hybridization (FISH), RT-PCR, and both RNA-based and DNA-based next generation sequencing (NGS). Each technique has advantages and limitations, and the choice of assays for screening and final diagnosis should also take into account the resources and clinical context.Conclusion: In tumours where NTRK fusions are highly recurrent, FISH, RT-PCR or RNA-based sequencing panels can be used as confirmatory techniques, whereas in the scenario of testing an unselected population where NTRK1/2/3 fusions are uncommon, either front-line sequencing (preferentially RNA-sequencing) or screening by immunohistochemistry followed by sequencing of positive cases should be pursued.