The relationship between cancer and thromboembolic events as been widely studied since 1895. As we know, venous thromboembolism (VTE) is a well-recognized complication of malignancy, including pulmonary embolism (PE), deep-vein thrombosis (DVT), and migratory thrombophlebitis (Trousseau syndrome). It is reported that patients with cancer have a 4-fold greater risk to suffer from VTE than the general population.1
Additionally, the occurrence of VTE in various patients with cancer is associated with a worse prognosis.2
The VTE risk factors are divided into three categories: cancer (histologic type and TNM stage), treatment (surgery, chemotherapy, and targeted therapy), and patient-related factors (physical status and previous thrombosis). Among various cancer types, lung cancer, especially NSCLC, may be responsible for the most occurrences of VTE due to its high prevalence in the global population.3
During the past decade, the therapeutic landscape has dramatically evolved for patients with advanced NSCLC. Precision medicine is used in clinical practice, in which, different molecularly targeted TKIs are used for patients with advanced NSCLC regarding a variety of EGFR,ALK,ROS1, and NTRK mutations, as well as MET skipping mutations, resulting in a significantly improved objective response rate and prolonged overall survival. Besides that, recent studies further found that different genomic alternations also are associated with the different risk of thromboembolic events in patients with NSCLC.
ALK Fusions
ALK rearrangements are detected in 2% to 7% of patients with NSCLC.4
Isolated reports demonstrated that patients harboring ALK-rearranged NSCLC might have a higher incidence of thromboembolism throughout the course of the disease. In a retrospective cohort study of 55 patients diagnosed with ALK-rearranged NSCLC at Princess Margaret Cancer Centre, Toronto, Canada, 23 patients (42%) experienced VTE events, which is 3- to 5-fold greater than previously reported in advanced NSCLC. This finding was confirmed in a validation cohort from two other tertiary centers, with an VTE rate of 28% (12 out of 43). Combining the results of two cohorts, the overall VTE rate is 36%. What’s more, the occurrence of VTE was associated with a worse prognosis (HR for OS = 2.88, p = 0.059).5
Al-Samkari et al.6
reported comparable results in the advanced-stage NSCLC cohorts. In this analysis, 422 patients with ALK rearrangement and 385 patients with ALK wild-type NSCLC were enrolled. After time-to-event analyses controlling for relevant thrombosis risk factors, the results showed a 4-fold increase of VTE risk in patients with ALK rearrangements. As can be seen in this study, the initial VTE rate for patients with ALK rearrangements was 42.7% vs. 28.6% for patients with no ALK mutations; recurrent VTE rates were 13.5% and 3.1%, respectively. In addition, the VTE risk attributable to ALK rearrangement was significant (HR = 3.70; 95% CI: 2.51-5.44; p < 0.001), and OR for recurrent VTE was 4.85 (95% CI: 2.60- 9.52; p < 0.001). Recently, Dou and colleagues7
drew a similar conclusion in a prospective cohort study. In their analysis of 341 qualified patients diagnosed with NSCLC, those with ALK mutations demonstrated a significantly elevated rate of VTE than those with wild-type ALK (26.9% vs. 9.2%). All of these data consistently support that ALK fusion associated with higher thromboembolic events in patients with NSCLC.
ROS1 Fusion
ROS1 fusion accounts for less than 2% in patients with NSCLC. The relationship between VTE risk and ROS1-positive NSCLC has been observed in several different studies, highlighting that ROS1 rearrangement increases the odds of VTE. A multicenter study conducted by Ng et al.8
reported that the incidence of first thromboembolic event was 34.7% within 90 days before or after diagnosis of ROS1-positive advanced NSCLC, which was significantly higher than incidence for the EGFR-positive (13.7%) and KRAS-positive cohorts (18.4%). When comparing a ROS1-positive cohort with an ALK-positive cohort in univariable analyses, the difference in thromboembolic rate is statistically significant (34.7% vs. 22.3%), but no difference was observed in multivariate analyses (p = 0.229). Moreover, another study performed by Chiari et al.9
demonstrated the incidence of VTE in patients with ROS1-positive NSCLC was 3- to 5-fold higher than that of the general patient population for NSCLC. In this prospective METROS trial, 41.6% of patients with ROS1-positive disease developed at least one VTE event. Among them, 35.7% of VTE events occurred during the progression period, 32.1% at the diagnosis, 17.8% during chemotherapy, and 14.2% during crizotinib therapy. In addition, Alexander et al.10
have reported thromboembolic events in 42 cases of ROS1-rearranged NSCLC. Among 42 patients recruited in this study, 20 patients (48%) experienced venous or arterial thromboembolic events: 1 patient (2%) had arterial thrombosis, 13 patients (31%) developed PE, and 12 patients (29%) developed DVT. Taken together, ROS1 fusion is associated with an elevated risk of thromboembolic events in patients with NSCLC.
Clinical Application
Although lung cancer has been associated with an intermediate risk of VTE compared with other types of malignancies, the cancer-associated VTE risk-assessment model, the Khorana Risk Score, performs poorly in patients with lung cancer because it does not adequately distinguish between patients at intermediate versus high risk of VTE.11
As a result, pharmacologic thromboprophylaxis is still not widely used in clinical practice for patients with NSCLC. The discrepancy in incidence of thromboembolic events found between patients with NSCLC with and without ALK/ROS1 fusion would provide the rationale for next steps in improving VTE risk prognostication.
However, the mechanisms underlying these association are still unknown. Given the crucial role that specific molecular drivers play in the behavior and prognosis of malignant tumors, the risk of coagulation might be associated with these oncogenic driver genes. However, this must be further explored. In addition, other druggable oncogene driver mutations such as NTRK1 and RET fusion have been recently recommended for targeted therapy in clinical practice. The association of these rare mutations with thromboembolic events needs further clarification.
In conclusion, thrombotic events are reported to be the second leading cause of death in patients with cancer.12
Patients diagnosed with NSCLC harboring ALK or ROS1 fusion have a high incidence of thromboembolic events and may benefit from use of thromboprophylaxis.
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