Molecular Subtyping to Predict Risk of Venous Thromboembolism in Patients with Advanced Lung Adenocarcinoma: A Cohort Study
Authors: Gervaso Lorenzo , Poudel Shyam K , Roopkumar Joanna , Reddy Chandana A , Pennell Nathan A , Velcheti Vamsidhar , McCrae Keith R , Khorana Alok A 
Published: November 2019

Background
Venous thromboembolism (VTE) is a common complication in cancer care and can be predicted based on validated risk assessment tools. Innovative new therapeutics in non-small cell lung cancer (NSCLC) have changed practice patterns and mortality, and new predictors of VTE are therefore needed to better identify high risk patients in this setting. The incidence of VTE according to specific molecular subtypes of NSCLC has not been fully evaluated. The aim of this study was to evaluate rates of VTE in lung adenocarcinoma in relation to their molecular subtype and the association of VTE with survival.
Methods
We conducted a retrospective cohort study at Cleveland Clinic Taussig Cancer Institute, approved by the institutional review board. We identified advanced lung adenocarcinoma patients from 7/2002 through 07/2017 for whom molecular classification was available and treatment/follow-up was at the Cleveland Clinic. VTE diagnoses including deep-vein thrombosis (DVT) and pulmonary embolism (PE) were identified by electronic medical record review. Patients were classified according to their molecular subtype: wild-type, ALK-mutant or EFGR-mutant. VTE-free survival and overall survival (OS) rates for these categories were estimated by the Kaplan-Meier method and evaluated for association with VTE using Cox proportional hazard regression in each cohort. VTE was analyzed as a conditional, time-dependent covariate with respect to OS.
Results
The study population included 461 patients, 43.0% male, with a median age at diagnosis of 67 (range, 27-90) years. Of these, 157 (34.1%) were never-smokers. According to molecular subtypes, 165 patients were EGFR-mutant (35.8%), 46 (10.0%) ALK-mutant and 250 (54.2%) were wild-type. All patients had adenocarcinoma and 158 of 211 (74.9%) received a specific tyrosine kinase inhibitor according to their driver mutation. VTE occurred in 98/461 (21.3%) during a follow up of 33.1 months. Highest rates of VTE were observed in patients with ALK-mutant cancers (43.5%, N=20/46) followed by patients with EGFR-mutant cancers (21.2% N=35/165) and wild-type cancers (17.2%, N=43/250) (P &lt; 0.05) (Figure 1). Cumulative rates of VTE at one year of follow-up were 20.7 % for ALK-mutant cancers, 11.1% for EGFR-mutant cancers, and 10.7% for wild-type cancers. The most common VTE event was DVT (49.0%, N=48/98) followed by PE (45.9%, N=45)). Overall survival was significantly worse in patients who experienced VTE in each molecular subgroup: ALK-mutant [HR 2.44 95% CI 1.03 - 5.79, p = 0.043], EGFR-mutant [HR 2.27 95% CI 1.43 - 3.59 p = 0.0005] and wild-type [HR 3.84 95% CI 2.67 - 5.52 p &lt; 0.0001])
Conclusions
VTE complicates more than one fifth of advanced lung adenocarcinoma patients. Nearly half of VTE events are PE. VTE is associated with worse survival across molecular subtypes. Patients with ALK-mutant advanced lung adenocarcinomas have the highest rates of VTE, exceeding those observed in patients with pancreas cancers and myeloma. These findings should be taken into consideration in decision-making regarding thromboprophylaxis.
Figure 1

Disclosures
Velcheti: Foundation Medicine: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Genentech: Consultancy; BMS: Consultancy; Reddy Labs: Consultancy; Alkermes: Consultancy; Boston Scientific: Consultancy; Merck: Consultancy. McCrae:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Khorana:Janssen: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy.