高静教授:CTC与ctDNA在肿瘤中研究现状与思考

2018-06-15 佚名 ioncology

液体活检由于实时、无创、便捷、及时等优势成为近几年新宠,其中CTC和ctDNA是研究最热的两大液体活检手段。CTC很早就被认识,直到2004年得到爆发式认识与快速发展。

液体活检由于实时、无创、便捷、及时等优势成为近几年新宠,其中CTC和ctDNA是研究最热的两大液体活检手段。CTC很早就被认识,直到2004年得到爆发式认识与快速发展。十余年来,CTC研究方向历经了CTC计数、亚型分析、组学探索、CDX模型的演变,目前逾40种的CTC捕获手段被开发,这也为CTC检出率差异较大(如胃癌检出率18.4-90.5%)埋下伏笔,很多因素会影响CTC的检出结果,如循环内皮细胞(CEC)的干扰、CTC判读误差、上皮型/间质型/混合型CTC及CTM的比例等。基于整个CTC捕获现状,理想的捕获原则是“高低多少”原则(捕获效率高、花费成本低、细胞类型多、杂质细胞少)。

肿瘤组织高度的异质性导致CTC的异质性也很高,关于CTC的形态异质性笔者建议需要与不同凋亡阶段的CTC区分开方可下形态异质性的结论,关于CTC的分子分型异质性,组学手段提供坚实的证据,基于已有的报道,可能不同层面(染色体拷贝数、蛋白表达等)的分子分型异质性具有较大差异,尚需深入探索。虽然CTC来源的CDX模型对研究耐药、转移非常重要,但CTC的成瘤率低是一个自然现象,毕竟大部分成瘤的都是CTM,而且大部分患者中捕获不到CTM。

ctDNA作为另一种液体活检手段,来源于肿瘤细胞凋亡或坏死的DNA碎片,半衰期大约2h,二代测序的快速发展,引领了ctDNA研究热潮,众多前瞻性临床研究也已纳入ctDNA的分层分析。关于ctDNA研究,肺癌一如既往走到最前列,胃癌的研究很少,我们团队的结果证实晚期胃癌中ctDNA可以克服内镜活检取材的空间异质性,并且ctDNA中的HER2拷贝数监控靶向治疗疗效方面不劣于常规肿瘤标志物,这提示ctDNA在晚期患者中的巨大潜在应用价值。

虽然最近JCO发文对ctDNA研究的过度热潮提出质疑,但同时肯定了ctDNA的未来应用前景,尤其最新发表的一篇纳入目前最大ctDNA样本量的文章,也对ctDNA的应用进行了客观评价。总之,ctDNA在癌症筛查、肿瘤复发预测、指导药物选择、动态监测疗效方面具有应用价值,尤其在耐药发现中具有独特优势,并且检测ctDNA中TMB有望成为免疫治疗的新型疗效预测marker。

由于ctDNA具有克服组织异质性特点,因此相对于组织,对ctDNA中的肿瘤驱动克隆、亚克隆分析具有独特优势。当然,在ctDNA研究火热的当下,很多问题尚需冷静对待,由于检测方法、覆盖基因区域、分析方法等的多样性,对样本分析方法有效性及结果解读带来很大的挑战,尤其ctDNA的临床有效性和实用性验证、以及覆盖液体活检的新型TNMB分期验证尚需较长路要走。

作为两大液体活检手段,CTC和ctDNA看起来非常相似,但两者的可比较性很低。基于现有手段,ctDNA的研究较CTC相对容易,且已有证据提示ctDNA在早癌筛查、晚期肿瘤疗效监测方面优于CTC,但在更深层次的研究方面,CTC具有ctDNA无可比拟的优势。肿瘤的精准治疗时代离不开对肿瘤的分子水平认识,这需要各个层面多种手段的齐头并进,除CTC和ctDNA之外,越来越多的液体活检手段被广为研究,如外泌体、各种循环RNA、肿瘤细胞驯化的血小板等,我们期待更多的埋藏在水面之下的冰山露出水面。

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    2019-01-14 kalseyzl
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    2018-06-16 kafei

    学习了谢谢

    0

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    2018-06-16 易水河

    知之为知之.学习学习

    0

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    2018-06-15 惠映实验室

    学习了.谢谢分享.

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    2018-06-15 执着追梦

    学习.谢谢分享

    0

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