Risk of thromboembolism in patients with ALK‐ and EGFR‐mutant lung cancer: A cohort study

Abstract

Introduction Thromboembolism (TE) is common in patients with non‐small cell lung cancer (NSCLC) and is associated with worse outcomes. Recent advances in the understanding of NSCLC have led to the identification of molecular subtypes such as anaplastic lymphocyte kinase (ALK) and epidermal growth factor receptor (EGFR) mutations. The association of these subtypes with risk of TE has not been fully explored. Methods We conducted a retrospective cohort study of consecutive NSCLC patients seen at the Cleveland Clinic from July 2002 through July 2017 for whom molecular classification and follow‐up were available. TE events included deep vein thrombosis (DVT), pulmonary embolism (PE), visceral vein thrombosis (VVT), and arterial events. TE‐free survival and overall survival rates for each of the molecular subtypes (wild‐type, ALK‐mutant, and EGFR‐mutant) were estimated by the Kaplan‐Meier method. Cox proportional hazard regression analysis was used to identify factors associated with the endpoints TE and overall survival. TE was analyzed as a conditional, time‐dependent covariate to assess its impact with respect to overall survival. Results The study population consisted of 461 patients. Approximately half were females (n = 263, 57%) and 58% (n = 270) were older than 65 years. TE occurred in 98 of 461 patients (21.3%) during a median follow‐up of 33.1 months. The highest cumulative rates of TE were observed in patients with ALK‐mutant NSCLC (N = 20/46, 43.5%) followed by patients with EGFR‐mutant cancers (N = 35/165, 21.2%) and wild‐type cancers (N = 43/250, 17.2%) P < .05. Cumulative incidence of TE at 6 months of follow‐up was 15.7% (95% confidence interval [CI]: 5.0%‐26.4%) for ALK‐mutant cancers, 8.8% (95% CI: 4.4%‐13.2%) for EGFR‐mutant cancers, and 9.2% (95% CI: 5.4%‐12.9%) for wild‐type cancers. Patients who experienced TE had worse overall survival (all patients: hazard ratio = 2.8 95% CI 2.1‐3.6, P < .001). Conclusions Patients with ALK‐mutant advanced lung adenocarcinoma have the highest rate of TE. TE is associated with worse survival across molecular subtypes. These findings should be taken into consideration in decision‐making regarding thromboprophylaxis.

Validation of the Khorana score for predicting venous thromboembolism in 40 218 patients with cancer initiating chemotherapy

“…Other studies also found limited clinical value of the Khorana score in patients with lung cancer, indicating the need for considering other risk markers for this subgroup. 52,53 Indeed, refined risk stratification to guide primary prevention of venous thromboembolism remains an unmet need among cancer patients. Cancer-specific Khorana score thresholds or development of cancer-specific risk scores are needed for improving individualized risk assessment, while also considering patient preferences.…”

Coagulome and the tumor microenvironment: an actionable interplay

“…Mitogenic signaling and the presence of a stressful microenvironment, as is commonly found in human tumors, regulate the expression of F3 [120,121]. Some of the somatic mutations that play a driver role in tumor progression, such as those found in MET or RAS, might directly regulate F3 expression [122,123]. Genomic instability also directly regulates F3 expression, as described by Bakhoum et al who identified F3 as a transcriptional target of NF-kB activated by the innate immune mechanisms sensing cytosolic DNA, cGAS-STING [124].…”

CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in women with breast cancer in real‐world practice

“…The Khorana score was not a useful tool to predict thrombosis in our mostly HR + HER2 negative breast cancer population while on CDK4/6 inhibitors. Increasingly, the role of the tumor mutational profile as an independent predictor of cancer‐associated thrombosis is being described 29‐32 . For example, non‐small cell lung cancers (NSCLCs) driven by aberrant anaplastic lymphoma kinase (ALK) rearrangements have been shown to be at increased risk for arterial and venous thrombosis compared to non‐ALK rearranged NSCLC 29,31 .…”

“…Increasingly, the role of the tumor mutational profile as an independent predictor of cancer‐associated thrombosis is being described 29‐32 . For example, non‐small cell lung cancers (NSCLCs) driven by aberrant anaplastic lymphoma kinase (ALK) rearrangements have been shown to be at increased risk for arterial and venous thrombosis compared to non‐ALK rearranged NSCLC 29,31 . Another recent publication that evaluated over 14 000 pooled solid tumor samples, including 14% from breast tumors, identified seven somatic tumor mutations independently associated with VTE risk.…”