Moik Florian, Horváth-Puhó Erzsébet, Ay Cihan, Pabinger Ingrid, Mulder Frits, van Es Nick, Sørensen Henrik Toft
Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
EClinicalMedicine. 2025 Aug 21;87:103440. doi: 10.1016/j.eclinm.2025.103440. eCollection 2025 Sep.
Emerging data suggest a substantial risk of arterial and venous thromboembolic events (ATE/VTE) associated with targeted cancer therapies. We examined the association between selected targeted therapies and ATE/VTE-risk using Danish population-based healthcare data.
We identified 41,744 patients with cancer treated with selected targeted therapies between January 2004 and December 2020. We computed cumulative incidence functions and 95% confidence intervals (CIs) of ATE/VTE after therapy initiation, considering death as competing event. A multivariable Cox proportional hazards regression analysis with time-varying exposure to targeted therapy was conducted for selected cancers, calculating hazard ratios (HRs) and 95% CIs for ATE/VTE, enabling the comparison of the time periods with and without targeted therapy, adjusting for age, sex, comorbidity burden, cancer stage, and year of diagnosis.
The three-year cumulative ATE-incidence was 3.7% (95% CI: 3.2-4.2) with immune checkpoint inhibitors (ICI; n = 7880), 3.4% (95% CI: 2.8-4.1) with multi-kinase inhibitors (MKI; n = 3394), 2.6% (95% CI: 1.9-3.5) with cyclin dependent kinase (CDK) 4/6-inhibitors (n = 1966), 2.5% (95% CI: 1.0-5.4) with anaplastic lymphoma kinase (ALK)-/ROS1-targeted therapies (n = 199), 2.6% (95% CI: 2.2-2.9) with epidermal growth factor receptor (EGFR)-targeted therapies (n = 8603), 2.4% (95% CI: 2.1-2.7) with vascular endothelial growth factor (VEGF)-targeted therapies (n = 12,802), and 1.4% (95% CI: 1.2-1.6) with human epidermal growth factor receptor 2 (HER2)-targeted therapies (n = 11,683). The three-year VTE-incidence was highest for EGFR- (9.3% [95% CI: 8.7-9.9]), ALK/ROS- (9.2% [95% CI: 5.7-13.8]), VEGF-targeted therapies (8.8% [95% CI: 8.3-9.3]), and ICI (8.1% [95% CI: 7.5-8.8]), followed by 7.5% (95% CI: 6.7-8.5) with MKI, 6.9% (95% CI: 5.7-8.3) with CDK4/6-inhibitors, and 3.4% (95% CI: 3.1-3.8) with HER2-targeted therapies. Among patients with selected cancer types, time-dependent exposure to certain targeted therapies was associated with an increased risk of ATE and/or VTE.
Selected targeted therapies pose a clinically meaningful risk of ATE and VTE in patients with cancer.
Department of Clinical Epidemiology, Center for Population Medicine, Aarhus University and Aarhus University Hospital, Denmark and the Independent Research Fund Denmark (3101-00102B).
新出现的数据表明，与靶向癌症治疗相关的动脉和静脉血栓栓塞事件（ATE/VTE）风险很大。我们使用丹麦基于人群的医疗保健数据研究了选定的靶向治疗与ATE/VTE风险之间的关联。
我们确定了2004年1月至2020年12月期间接受选定靶向治疗的41744例癌症患者。我们计算了治疗开始后ATE/VTE的累积发病率函数和95%置信区间（CI），将死亡视为竞争事件。对选定的癌症进行了多变量Cox比例风险回归分析，采用随时间变化的靶向治疗暴露，计算ATE/VTE的风险比（HR）和95%CI，以便比较有和没有靶向治疗的时间段，并根据年龄、性别、合并症负担、癌症分期和诊断年份进行调整。
免疫检查点抑制剂（ICI；n = 7880）的三年累积ATE发病率为3.7%（95%CI：3.2 - 4.2），多激酶抑制剂（MKI；n = 3394）为3.4%（95%CI：2.8 - 4.1），细胞周期蛋白依赖性激酶（CDK）4/6抑制剂（n = 1966）为2.6%（95%CI：1.9 - 3.5），间变性淋巴瘤激酶（ALK）/ROS1靶向治疗（n = 199）为2.5%（95%CI：1.0 - 5.4），表皮生长因子受体（EGFR）靶向治疗（n = 8603）为2.6%（95%CI：2.2 - 2.9），血管内皮生长因子（VEGF）靶向治疗（n = 12802）为2.4%（95%CI：2.1 - 2.7），人表皮生长因子受体2（HER2）靶向治疗（n = 11683）为1.4%（95%CI：1.2 - 1.6）。EGFR靶向治疗（9.3%[95%CI：8.7 - 9.9]）、ALK/ROS靶向治疗（9.2%[95%CI：5.7 - 13.8]）、VEGF靶向治疗（8.8%[95%CI：8.3 - 9.3]）和ICI（8.1%[95%CI：7.5 - 8.8]）的三年VTE发病率最高，其次是MKI为7.5%（95%CI：6.7 - 8.5），CDK4/6抑制剂为6.9%（95%CI：5.7 - 8.3），HER2靶向治疗为3.4%（95%CI：3.1 - 3.8）。在选定癌症类型的患者中，特定靶向治疗的时间依赖性暴露与ATE和/或VTE风险增加相关。
选定的靶向治疗对癌症患者构成了具有临床意义的ATE和VTE风险。
丹麦奥胡斯大学和奥胡斯大学医院临床流行病学系、人群医学中心以及丹麦独立研究基金（3101 - 00102B）。
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