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Detection of circulating tumor DNA in early- and late-stage human malignancies. ​

文献信息 ​

DOI10.1126/scitranslmed.3007094
PMID24553385
期刊Science translational medicine
影响因子14.6
JCR 分区Q1
发表年份2014
被引次数2420
关键词循环肿瘤DNA, 早期癌症, 晚期癌症, 生物标志物, KRAS基因突变
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN1946-6234
页码224ra24
期号6(224)
作者Chetan Bettegowda, Mark Sausen, Rebecca J Leary, Isaac Kinde, Yuxuan Wang, Nishant Agrawal, Bjarne R Bartlett, Hao Wang, Brandon Luber, Rhoda M Alani, Emmanuel S Antonarakis, Nilofer S Azad, Alberto Bardelli, Henry Brem, John L Cameron, Clarence C Lee, Leslie A Fecher, Gary L Gallia, Peter Gibbs, Dung Le, Robert L Giuntoli, Michael Goggins, Michael D Hogarty, Matthias Holdhoff, Seung-Mo Hong, Yuchen Jiao, Hartmut H Juhl, Jenny J Kim, Giulia Siravegna, Daniel A Laheru, Calogero Lauricella, Michael Lim, Evan J Lipson, Suely Kazue Nagahashi Marie, George J Netto, Kelly S Oliner, Alessandro Olivi, Louise Olsson, Gregory J Riggins, Andrea Sartore-Bianchi, Kerstin Schmidt, le-Ming Shih, Sueli Mieko Oba-Shinjo, Salvatore Siena, Dan Theodorescu, Jeanne Tie, Timothy T Harkins, Silvio Veronese, Tian-Li Wang, Jon D Weingart, Christopher L Wolfgang, Laura D Wood, Dongmei Xing, Ralph H Hruban, Jian Wu, Peter J Allen, C Max Schmidt, Michael A Choti, Victor E Velculescu, Kenneth W Kinzler, Bert Vogelstein, Nickolas Papadopoulos, Luis A Diaz

一句话小结 ​

本研究利用数字聚合酶链反应技术评估了循环肿瘤DNA（ctDNA）在640名不同癌症患者中的检测能力，发现ctDNA在晚期胰腺癌、卵巢癌等多种癌症患者中检测率超过75%，而在某些类型的癌症中则较低，表明ctDNA与循环肿瘤细胞是不同的生物标志物。此外，ctDNA在监测KRAS基因突变及治疗反应方面表现出高灵敏度和特异性，这为非侵入性肿瘤检测和监测提供了重要的临床意义。

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循环肿瘤DNA · 早期癌症 · 晚期癌症 · 生物标志物 · KRAS基因突变

摘要 ​

非侵入性肿瘤检测和监测方法的发展仍然是肿瘤学中的一个重大挑战。我们使用基于数字聚合酶链反应技术评估循环肿瘤DNA（ctDNA）在640名不同癌症类型患者中检测肿瘤的能力。我们发现，ctDNA在超过75%的晚期胰腺癌、卵巢癌、结直肠癌、膀胱癌、胃食管癌、乳腺癌、黑色素瘤、肝细胞癌和头颈癌患者中可被检测到，而在不到50%的原发性脑癌、肾癌、前列腺癌或甲状腺癌患者中则难以检测到。在局部肿瘤患者中，ctDNA在结直肠癌、胃食管癌、胰腺癌和乳腺腺癌患者中的检测率分别为73%、57%、48%和50%。ctDNA通常在未检测到循环肿瘤细胞的患者中存在，这表明这两种生物标志物是不同的实体。在另一个206名转移性结直肠癌患者的研究中，我们显示ctDNA在检测临床相关的KRAS基因突变方面的灵敏度为87.2%，特异性为99.2%。最后，我们评估了ctDNA是否能够为24名客观对治疗有反应但随后复发的患者提供有关表皮生长因子受体阻断抵抗机制的线索。这23名（96%）患者中出现了一个或多个与丝裂原激活蛋白激酶通路相关的基因突变。综合这些数据表明，ctDNA是一种广泛适用、灵敏且特异的生物标志物，可用于多种临床和研究目的，适用于不同类型癌症的患者。

英文摘要 ​

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

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主要研究问题 ​

  1. ctDNA在不同癌症类型中的检测灵敏度和特异性有何差异？
  2. 除了ctDNA，还有哪些其他非侵入性生物标志物可以用于肿瘤检测？
  3. ctDNA检测在早期癌症筛查中的潜在应用和挑战是什么？
  4. 如何利用ctDNA监测癌症治疗后的复发和耐药机制？
  5. ctDNA检测结果如何影响临床决策和患者管理策略？

核心洞察 ​

研究背景和目的 ​

随着癌症早期检测和治疗监测的需求增加，开发非侵入性方法以检测和监控肿瘤成为肿瘤学领域的一项重大挑战。本研究旨在评估循环肿瘤DNA（ctDNA）在多种癌症类型中的检测能力，特别是在早期和晚期肿瘤患者中的应用潜力。

主要方法/材料/实验设计 ​

本研究使用数字聚合酶链反应（digital PCR）技术，分析了640名不同癌症类型患者的血浆样本，以检测ctDNA的存在。研究分为以下几个主要步骤：

Mermaid diagram
  • 患者招募：选取640名不同类型癌症患者，包括晚期胰腺癌、卵巢癌、结直肠癌等。
  • 样本处理：通过严格的协议提取血浆和肿瘤DNA。
  • ctDNA检测：使用数字PCR技术，评估ctDNA的水平及其与肿瘤特异性突变的关联。
  • 结果分析：比较ctDNA与循环肿瘤细胞（CTCs）的检测率和敏感性。

关键结果和发现 ​

  • 在晚期癌症患者中，ctDNA的检测率超过75%，而在早期肿瘤患者中，ctDNA的检测率为73%（结直肠癌）、57%（胃食管癌）、48%（胰腺癌）和50%（乳腺腺癌）。
  • ctDNA在没有可检测CTCs的患者中也常常存在，表明这两种生物标志物是不同的实体。
  • 在206名转移性结直肠癌患者中，ctDNA对临床相关的KRAS基因突变的敏感性为87.2%，特异性为99.2%。
  • 在24名对表皮生长因子受体（EGFR）阻断治疗有反应但后续复发的患者中，96%出现了与MAPK通路相关的突变。

主要结论/意义/创新性 ​

本研究表明，ctDNA是一种广泛适用、敏感且特异的生物标志物，可用于多种癌症的检测和监测。ctDNA的检测不仅能够帮助早期发现肿瘤，还可以为个体化治疗提供重要的遗传信息，特别是在抗EGFR治疗的耐药机制研究中。

研究局限性和未来方向 ​

  • 局限性：ctDNA的检测在某些类型的癌症（如脑肿瘤、肾癌、前列腺癌等）中的敏感性较低；此外，ctDNA的浓度在不同患者和不同肿瘤类型之间存在显著差异。
  • 未来方向：未来的研究应集中在提高ctDNA检测的敏感性，尤其是在早期癌症筛查中的应用，同时探索ctDNA与其他生物标志物的联合使用，以优化癌症管理策略。

通过对ctDNA的深入研究，本研究为癌症早期检测和治疗监测提供了新的思路和方法，具有重要的临床应用前景。

参考文献 ​

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引用本文的文献 ​

  1. Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. - Daniel A Haber;Victor E Velculescu - Cancer discovery (2014)
  2. Detecting cancer by monitoring circulating tumor DNA. - Paul T Spellman;Joe W Gray - Nature medicine (2014)
  3. Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies. - Simonetta M Leto;Livio Trusolino - Journal of molecular medicine (Berlin, Germany) (2014)
  4. Tumor signatures in the blood. - Michael R Speicher;Klaus Pantel - Nature biotechnology (2014)
  5. Pharmacologic biomarkers in the development of stratified cancer medicine. - William Douglas Figg;David R Newell - Clinical cancer research : an official journal of the American Association for Cancer Research (2014)
  6. Modeling platinum sensitive and resistant high-grade serous ovarian cancer: development and applications of experimental systems. - Paula Cunnea;Euan A Stronach - Frontiers in oncology (2014)
  7. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. - Cassandra L Hodgkinson;Christopher J Morrow;Yaoyong Li;Robert L Metcalf;Dominic G Rothwell;Francesca Trapani;Radoslaw Polanski;Deborah J Burt;Kathryn L Simpson;Karen Morris;Stuart D Pepper;Daisuke Nonaka;Alastair Greystoke;Paul Kelly;Becky Bola;Matthew G Krebs;Jenny Antonello;Mahmood Ayub;Suzanne Faulkner;Lynsey Priest;Louise Carter;Catriona Tate;Crispin J Miller;Fiona Blackhall;Ged Brady;Caroline Dive - Nature medicine (2014)
  8. Acquired resistance to EGFR-targeted therapies in colorectal cancer. - Beth O Van Emburgh;Andrea Sartore-Bianchi;Federica Di Nicolantonio;Salvatore Siena;Alberto Bardelli - Molecular oncology (2014)
  9. The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? - Anne Marie Lennon;Christopher L Wolfgang;Marcia Irene Canto;Alison P Klein;Joseph M Herman;Michael Goggins;Elliot K Fishman;Ihab Kamel;Matthew J Weiss;Luis A Diaz;Nickolas Papadopoulos;Kenneth W Kinzler;Bert Vogelstein;Ralph H Hruban - Cancer research (2014)
  10. Circulating tumor DNA moves further into the spotlight. - Mark Sausen;Sonya Parpart;Luis A Diaz - Genome medicine (2014)

... (2410 更多 篇文献)

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