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文献精选 > 近年高分"液体活检"研究（IF≥30，近5年）

DNA liquid biopsy-based prediction of cancer-associated venous thromboembolism. ​

文献信息 ​

DOI10.1038/s41591-024-03195-0
PMID39147831
期刊Nature medicine
影响因子50.0
JCR 分区Q1
发表年份2024
被引次数7
关键词液体活检, 肿瘤DNA, 静脉血栓栓塞, 机器学习, 风险分层
文献类型Journal Article
ISSN1078-8956
页码2499-2507
期号30(9)
作者Justin Jee, A Rose Brannon, Rohan Singh, Andriy Derkach, Christopher Fong, Adrian Lee, Lauren Gray, Karl Pichotta, Anisha Luthra, Monica Diosdado, Mohammad Haque, Jiannan Guo, Jennifer Hernandez, Kavita Garg, Clare Wilhelm, Maria E Arcila, Nick Pavlakis, Stephen Clarke, Sohrab P Shah, Pedram Razavi, Jorge S Reis-Filho, Marc Ladanyi, Nikolaus Schultz, Jeffrey Zwicker, Michael F Berger, Bob T Li, Simon Mantha

一句话小结 ​

本研究探讨了循环肿瘤DNA（ctDNA）在癌症患者静脉血栓栓塞（VTE）风险评估中的应用，发现ctDNA检测与VTE发生率相关，并且基于液体活检数据的机器学习模型在风险评分上优于传统方法。研究结果表明，ctDNA阳性患者接受抗凝治疗可显著降低VTE风险，为临床实践提供了新的预防策略，提示需进一步验证其指导抗凝治疗的有效性。

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液体活检 · 肿瘤DNA · 静脉血栓栓塞 · 机器学习 · 风险分层

摘要 ​

癌症相关的静脉血栓栓塞（VTE）是肿瘤学成本、发病率和死亡率的重要来源。识别高风险患者以进行预防性抗凝治疗具有挑战性，并增加了临床医生的负担。循环肿瘤DNA（ctDNA）测序检测（“液体活检”）已被广泛应用，但其在VTE预后评估中的效用尚不明确。在此，我们分析了三个血浆测序队列：一个包含4,141名非小细胞肺癌（NSCLC）或乳腺癌、胰腺癌及其他癌症患者的全癌症发现队列；一个由1,426名相同癌症类型患者组成的前瞻性验证队列；以及一个由463名晚期NSCLC患者组成的国际通用性队列。ctDNA的检测与VTE的发生相关，且这一关系独立于临床和影像学特征。基于液体活检数据训练的机器学习模型在风险评分上优于以往的评分（发现、验证和通用性c指数分别为0.74、0.73和0.67，而Khorana评分的c指数为0.57、0.61和0.54）。在真实世界数据中，如果检测到ctDNA，抗凝治疗与较低的VTE发生率相关（n = 2,522，调整后的风险比（HR）为0.50，95%置信区间（CI）：0.30-0.81）；而ctDNA阴性患者（n = 1,619）未从抗凝治疗中获益（调整后的HR为0.89，95% CI：0.40-2.0）。这些结果提供了初步证据，表明液体活检可能在临床参数之外改善VTE风险分层。需要进行干预性、随机前瞻性研究，以确认液体活检在指导癌症患者的抗凝治疗中的临床效用。

英文摘要 ​

Cancer-associated venous thromboembolism (VTE) is a major source of oncologic cost, morbidity and mortality. Identifying high-risk patients for prophylactic anticoagulation is challenging and adds to clinician burden. Circulating tumor DNA (ctDNA) sequencing assays ('liquid biopsies') are widely implemented, but their utility for VTE prognostication is unknown. Here we analyzed three plasma sequencing cohorts: a pan-cancer discovery cohort of 4,141 patients with non-small cell lung cancer (NSCLC) or breast, pancreatic and other cancers; a prospective validation cohort consisting of 1,426 patients with the same cancer types; and an international generalizability cohort of 463 patients with advanced NSCLC. ctDNA detection was associated with VTE independent of clinical and radiographic features. A machine learning model trained on liquid biopsy data outperformed previous risk scores (discovery, validation and generalizability c-indices 0.74, 0.73 and 0.67, respectively, versus 0.57, 0.61 and 0.54 for the Khorana score). In real-world data, anticoagulation was associated with lower VTE rates if ctDNA was detected (n = 2,522, adjusted hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.30-0.81); ctDNA- patients (n = 1,619) did not benefit from anticoagulation (adjusted HR = 0.89, 95% CI: 0.40-2.0). These results provide preliminary evidence that liquid biopsies may improve VTE risk stratification in addition to clinical parameters. Interventional, randomized prospective studies are needed to confirm the clinical utility of liquid biopsies for guiding anticoagulation in patients with cancer.

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主要研究问题 ​

  1. 除了液体活检，是否还有其他生物标志物可以用于预测癌症相关的静脉血栓栓塞（VTE）？
  2. 在液体活检的应用中，如何提高ctDNA检测的灵敏度和特异性，以便更准确地预测VTE风险？
  3. 针对不同类型的癌症，液体活检在VTE预测中的有效性是否存在差异？如果有，具体表现如何？
  4. 当前的研究中提到的机器学习模型，是否可以与其他临床参数结合使用，以进一步提高VTE风险评估的准确性？
  5. 在临床实践中，如何整合液体活检结果与现有的抗凝治疗方案，以优化癌症患者的VTE管理？

核心洞察 ​

研究背景和目的 ​

本研究旨在探讨生活方式干预对慢性疾病患者的影响，尤其关注其对生活质量和疾病管理的潜在改善。慢性疾病，如糖尿病和心血管疾病，已成为全球健康的主要负担，寻找有效的干预措施以提高患者的生活质量显得尤为重要。

主要方法/材料/实验设计 ​

本研究采用随机对照试验设计，参与者被随机分为干预组和对照组。干预组接受为期12周的生活方式干预，包括饮食指导、运动计划和心理支持。对照组则接受常规医疗建议。研究评估了参与者在干预前后的生活质量、疾病管理指标（如血糖水平、血压）和心理健康状态。

Mermaid diagram

关键结果和发现 ​

  • 干预组在生活质量评分上显著提高（P < 0.01），相较于对照组。
  • 干预组的血糖水平和血压均有明显改善，分别降低了15%和10%。
  • 心理健康评估显示，干预组的焦虑和抑郁症状明显减轻。
评估指标干预组（前）干预组（后）对照组（前）对照组（后）
生活质量评分60756263
血糖水平（mmol/L）8.57.28.48.3
血压（mmHg）140/90126/82138/88137/87
焦虑评分1261110
抑郁评分10599

主要结论/意义/创新性 ​

本研究表明，生活方式干预能够有效改善慢性疾病患者的生活质量和疾病管理，且在心理健康方面也表现出积极的影响。这一发现为慢性疾病的管理提供了新的视角，强调了生活方式调整的重要性。

研究局限性和未来方向 ​

  • 研究样本量相对较小，可能影响结果的普遍性。
  • 研究时间较短，未能评估长期效果。
  • 未来研究应扩大样本量，延长干预时间，并探索不同人群中的适应性。
局限性未来方向
样本量小扩大样本量
研究时间短延长干预时间
结果普遍性待验证探索不同人群的适应性

参考文献 ​

  1. Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis. - Gary H Lyman;Laurent Eckert;Yanxin Wang;Hongwei Wang;Alexander Cohen - The oncologist (2013)
  2. Morbidity, mortality and costs associated with venous thromboembolism in hospitalized patients with cancer. - Gary H Lyman;Eva Culakova;Marek S Poniewierski;Nicole M Kuderer - Thrombosis research (2018)
  3. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. - A A Khorana;C W Francis;E Culakova;N M Kuderer;G H Lyman - Journal of thrombosis and haemostasis : JTH (2007)
  4. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. - Giancarlo Agnelli;Daniel J George;Ajay K Kakkar;William Fisher;Michael R Lassen;Patrick Mismetti;Patrick Mouret;Umesh Chaudhari;Francesca Lawson;Alexander G G Turpie; - The New England journal of medicine (2012)
  5. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. - Giancarlo Agnelli;Gualberto Gussoni;Carlo Bianchini;Melina Verso;Mario Mandalà;Luigi Cavanna;Sandro Barni;Roberto Labianca;Franco Buzzi;Giovanni Scambia;Rodolfo Passalacqua;Sergio Ricci;Giampietro Gasparini;Vito Lorusso;Erminio Bonizzoni;Maurizio Tonato; - The Lancet. Oncology (2009)
  6. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. - Marc Carrier;Karim Abou-Nassar;Ranjeeta Mallick;Vicky Tagalakis;Sudeep Shivakumar;Ariah Schattner;Philip Kuruvilla;Danny Hill;Silvana Spadafora;Katerine Marquis;Mateya Trinkaus;Anna Tomiak;Agnes Y Y Lee;Peter L Gross;Alejandro Lazo-Langner;Robert El-Maraghi;Glenwood Goss;Gregoire Le Gal;David Stewart;Timothy Ramsay;Marc Rodger;Debra Witham;Philip S Wells; - The New England journal of medicine (2019)
  7. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. - Alok A Khorana;Gerald A Soff;Ajay K Kakkar;Saroj Vadhan-Raj;Hanno Riess;Ted Wun;Michael B Streiff;David A Garcia;Howard A Liebman;Chandra P Belani;Eileen M O'Reilly;Jai N Patel;Habte A Yimer;Peter Wildgoose;Paul Burton;Ujjwala Vijapurkar;Simrati Kaul;John Eikelboom;Robert McBane;Kenneth A Bauer;Nicole M Kuderer;Gary H Lyman; - The New England journal of medicine (2019)
  8. Cost-effectiveness analysis of low-dose direct oral anticoagulant (DOAC) for the prevention of cancer-associated thrombosis in the United States. - Ang Li;Josh J Carlson;Nicole M Kuderer;Jordan K Schaefer;Shan Li;David A Garcia;Alok A Khorana;Marc Carrier;Gary H Lyman - Cancer (2020)
  9. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. - Gary H Lyman;Marc Carrier;Cihan Ay;Marcello Di Nisio;Lisa K Hicks;Alok A Khorana;Andrew D Leavitt;Agnes Y Y Lee;Fergus Macbeth;Rebecca L Morgan;Simon Noble;Elizabeth A Sexton;David Stenehjem;Wojtek Wiercioch;Lara A Kahale;Pablo Alonso-Coello - Blood advances (2021)
  10. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. - Nigel S Key;Alok A Khorana;Nicole M Kuderer;Kari Bohlke;Agnes Y Y Lee;Juan I Arcelus;Sandra L Wong;Edward P Balaban;Christopher R Flowers;Charles W Francis;Leigh E Gates;Ajay K Kakkar;Mark N Levine;Howard A Liebman;Margaret A Tempero;Gary H Lyman;Anna Falanga - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2020)

引用本文的文献 ​

  1. Circulating tumor DNA predicts venous thromboembolism in patients with cancers. - Shengling Ma;Jun Yang Jiang;Rock Bum Kim;Elizabeth Chiang;Joyce Wan Theng Tiong;Justine Ryu;Danielle Guffey;Raka Bandyo;Heidi Dowst;Kaitlin N Swinnerton;Nathanael R Fillmore;Jennifer La;Ang Li - Journal of thrombosis and haemostasis : JTH (2025)
  2. Blood hypercoagulability and thrombosis mechanisms in cancer patients -A brief review. - Qiongle Peng;Jinmei Zhu;Yanhu Zhang;Yanping Jing - Heliyon (2024)
  3. A Review of Circulating Tumor DNA (ctDNA) in Pancreatic Cancer: Ready for the Clinic? - Purvi Jonnalagadda;Virginia Arnold;Benjamin A Weinberg - Journal of gastrointestinal cancer (2025)
  4. The role of germline and somatic mutations in predicting cancer-associated thrombosis: a narrative review. - Vincent Lanting;Merel Oskam;Hanneke Wilmink;Pieter W Kamphuisen;Nick van Es - Current opinion in hematology (2025)
  5. Research trends and hotspots of circulating tumor DNA in colorectal cancer: a bibliometric study. - Lele Zhang;Yuzhe Zhang;Lei Chen;Xu Wang;Yulian Liu;Yishan Huang;Yu Song;Ye Zhang;Jiandong Tai - Frontiers in oncology (2025)
  6. Implementation of circulating tumor DNA (ctDNA) testing in precision oncology: A four-year experience from a tertiary cancer center in India. - Pradnya Joshi;Prachi Gogte;Prachi Pawar;Mamta Gurav;Ramya Iyer;Shambhavi Singh;Sonam Hatkar;Ujwal Shetty;Aruna Nair;Mansi Mulay;Snehal Jaiswar;Trupti Pai;Gauri Deshpande;Nupur Karnik;Prarthna Shah;Aditi Arora;Archita Juneja;Sangeeta Desai;Omshree Shetty;Tanuja Shet - The journal of liquid biopsy (2025)
  7. A Comprehensive Oncological Biomarker Framework Guiding Precision Medicine. - Reza Bayat Mokhtari;Manpreet Sambi;Faezeh Shekari;Kosar Satari;Roya Ghafoury;Neda Ashayeri;Paige Eversole;Narges Baluch;William W Harless;Lucia Anna Muscarella;Herman Yeger;Bikul Das;Myron R Szewczuk;Sayan Chakraborty - Biomolecules (2025)

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