基于DNA液体活检的癌症相关静脉血栓栓塞症预测
DNA liquid biopsy-based prediction of cancer-associated venous thromboembolism
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影响因子:50
分区:医学1区 Top / 生化与分子生物学1区 细胞生物学1区 医学：研究与实验1区
发表日期:2024 Sep
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
DOI:
10.1038/s41591-024-03195-0
keywords:
摘要
癌症相关的静脉血栓栓塞（VTE）是肿瘤治疗中的主要成本、发病率和死亡原因。识别高危患者以进行预防性抗凝治疗具有挑战性，也增加了临床医生的负担。循环肿瘤DNA（ctDNA）测序检测方法（“液体活检”）已广泛应用，但其在VTE预后中的实用性尚不清楚。本研究分析了三个血浆测序队列：一是包含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泛癌症发现队列；二是由1,426名具有相同癌症类型的患者组成的前瞻性验证队列；三是来自国际的先进NSCLC患者463名的普遍性队列。ctDNA检测与VTE呈相关性，且与临床和影像学特征无关。基于液体活检数据训练的机器学习模型优于以往的风险评分（发现队列、验证队列和普遍性队列的c指数分别为0.74、0.73和0.67，而Khorana评分为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VTE发生率较低相关（n=2,522，调整后风险比（HR）=0.50，95%置信区间（CI）：0.30-0.81）；未检测到ctDNA的患者（n=1,619）则未从抗凝中获益（调整HR=0.89，95% CI：0.40-2.0）。这些结果提供了初步证据，表明液体活检可能改善VTE风险分层，超越临床参数。需要进行干预性、随机的前瞻性研究，以确认液体活检在指导癌症患者抗凝中的临床应用价值。
Abstract
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.