基于DNA液体活检的癌症相关静脉血栓栓塞的预测
DNA liquid biopsy-based prediction of cancer-associated venous thromboembolism
影响因子:50.00000
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
摘要
癌症相关的静脉血栓栓塞（VTE）是肿瘤成本，发病率和死亡率的主要来源。识别高危患者进行预防性抗凝治疗是具有挑战性的，增加了临床医生负担。循环肿瘤DNA（CTDNA）测序测定法（“液体活检”）已广泛实现，但是它们的VTE预后效用尚不清楚。在这里，我们分析了三个血浆测序队列：4,141例非小细胞肺癌（NSCLC）或乳腺癌，胰腺和其他癌症患者的PAN-CANCER发现队列；一个前瞻性验证队列，由1,426例具有相同癌症类型的患者组成；以及463例晚期NSCLC患者的国际概括性队列。 CTDNA检测与与临床和放射学特征无关的VTE相关。经过液体活检数据培训的机器学习模型的表现优于先前的风险评分（发现，验证和概括性C-Indices 0.74、0.73和0.67，而Khorana分数为0.57、0.61和0.54）。在实际数据中，如果检测到ctDNA，则与VTE率较低有关（n = 2,522，调整危险比（HR）= 0.50，95％置信区间（CI）：0.30-0.81）； CTDNA-患者（n = 1,619）没有受益于抗凝治疗（调整后的HR = 0.89，95％CI：0.40-2.0）。这些结果提供了初步证据表明，除临床参数外，液体活检还可以改善VTE风险分层。需要介入的随机前瞻性研究来确认液体活检的临床效用，以指导癌症患者的抗凝治疗。
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.