The association between pulmonary embolism and the cancer-related genomic alterations in patients with NSCLC

Lung cancer has high morbidity and mortality [1]. It is one of many cancers which carry the highest risk of acute pulmonary embolism (PE). PE that is one of the subtypes of venous thromboembolism (VTE), is the third acute cardiovascular syndrome behind myocardial infarction and stroke in the world [2, 3].

A series of previous studies suggested that the risk of PE occurrence was prevalently high in patients with lung cancer especially non-small cell lung cancer (NSCLC) [4‐7]. NSCLC especially adenocarcinoma were considered to be the independent risk factors for the occurrence of PE [4, 7]. For NSCLC patients who are concomitant with thrombosis, their survival rate was lower than those without thrombosis [5].

In the advanced NSCLC, molecular tests are frequently used for the detection of cancer-related genomic alterations to identify whether or not targeted therapies or immunotherapy are applicable. The predictive genomic alterations for NSCLC mainly include the anaplastic lymphoma kinase (ALK) fusion oncogene, the C-ros oncogene 1 receptor tyrosine kinase (ROS1) gene rearrangements, the sensitizing epidermal growth factor receptor (EGFR) gene mutations, the B-rapidly accelerated fibrosarcoma (BRAF) V600E point mutations, and the programmed cell death 1-ligand 1 (PD-L1) expression [8]. To date, the association between the aforementioned cancer-related genomic alterations and PE in patients with NSCLC has been understudied yet. Therefore the present study was aimed at this subject.

In the current study, it was discovered that the positive ALK and PD-L1 may indicate an increased risk of pulmonary embolism in patients with NSCLC. The reason why we chose the newly-diagnosed patients with NSCLC was that the newly-diagnosed patients may reflect the natural relationship between PE and the results of molecular tests in patients with NSCLC, since the incidence of PE will be interfered with surgery, chemotherapy and so on, along with the initiation of the oncotherapy [12].

With respect to the results of a handful of comparable studies, part results of the current study are basically consistent with the most of them. In the study of Lee et al., no relation was revealed between EGFR mutation or ALK rearrangements and the VTE risk of Asian patients with NSCLC. However, the correlation was assessed between the molecular mutation and clinically diagnosed PE without the confirmation via CTPA in the study of Lee et al. [13] In the study of Corrales-Rodriguez et al. [14] and of Verso et al. [15], EGFR was not associated with an increased risk of VTE in patients with NSCLC, being consistent with the current study. In the study of Zer et al., the rate of VTE in an ALK-rearranged cohort was 3 to 5 fold higher than previously reported in NSCLC population [16]. In the study of Dou et al., the presence of ALK rearrangement was associated with increased risk of VTE in patients with NSCLC [17]. In a most recent study, the time-to-event analyses indicated that the ALK rearrangement resulted in a 4-fold increase of VTE risk and 3-fold increase of arterial thrombosis risk in NSCLC [18]. These findings are consistent with our findings. To date, the possible reason why ALK causes VTE may be due to that the ALK rearrangement may increase the risk of VTE by enhancing tissue factor procoagulant activity via NF-κB signaling pathway, or by mucin abundance, or by heparin [16, 17].

With regard to ROS-1, being inconsistent with our finding, a recent study reported that the incidence of VTE which included 46.4% of PE, was 3 to 5 fold higher in patients with ROS1-rearrangment than that in general population with NSCLC [19]. Nevertheless, the study merely measured 48 patients, making large-scale investigation necessary to confirm the conclusion. For BRAF and PD-L1, there have been no comparable studies. The underlying mechanism of the high incidence of pulmonary embolism in PD-L1-positive patients is still unclear. A previous study demonstrated that there was a positive correlation between sPD-1 levels and platelet counts [20]. As a result, thrombocytosis in PD-L1-positive patients may be the predisposing factor of pulmonary embolism. It was also observed that the risk of having a PE increased along with the increase of platelets in the present study. Nevertheless, this is merely a hypothesis that needs to be further verified.

Some clinical implications may derive from the current study. On account of the current findings, clinicians are suggested to be vigilant and thinking of the higher probability of PE incidence in NSCLC patients with positive ALK and PD-L1, in comparison to those without them. Accordingly, the clinicians’ awareness of screening, prophylaxis, and follow-up for underlying PE should be enhanced for this patient population. As a result, the monitoring of C-PTP of PE and D-dimer level should be more frequently performed to rule out the underlying PE, for NSCLC patients with positive ALK and PD-L1, in comparison with the opposite. Meanwhile, the implementation of prophylactic anticoagulation should be taken into account more often in NSCLC patients with positive ALK and PD-L1 than in those without them, especially when there is a moderate or high C-PTP of PE and/or an elevated D-dimer level.

This study suffers from some limitations. First of all, this is a retrospective study which may have certain bias. A prospective study is warranted in the future. Secondly, the exclusion of PE was implemented by using CTPA in the current study, however, some most distally peripheral sub-segmental embolism may not be detected on CTPA. The combined examination of CTPA and pulmonary ventilation perfusion scan may be applicable if a prospective study is carried out.

In conclusion, the current study suggests that the positive results of ALK and PD-L1 among existing genomic alterations of NSCLC may indicate an increased risk of pulmonary embolism in patients with NSCLC. The message being delivered hereby may be conducive to the screening and prophylaxis of pulmonary embolism in patients with NSCLC in daily clinical practice.