Somatic Tumor Mutations and Risk for Thrombosis

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. Cancer patients have a 4-7 fold increased risk of thrombosis, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging.

The etiology of thrombosis in cancer is multifactorial, and the vascular system is an important interface between the malignant cells and their systemic and external environments. Genetic alterations in malignant cells, as they respond to their microenvironment, can result in inflammation, angiogenesis, and tissue repair. This in turn leads to the local and systemic activation of the coagulation system. It has been postulated that the procoagulant effect of malignant cells may be related to the release of soluble mediators such as G-CSF into the circulation or by the shedding of procoagulant Extracellular Vesicles (EVs) harboring Tissue Factor. Previously published studies had entertained the notion that certain oncogenic mutations may deregulate hemostatic genes (coagulome) in cancer cells.

The researchers conducted this study to assess potential associations between tumor molecular signatures and Cancer Associated Thrombosis, including tumor-specific mutations, and the presence of Clonal Hematopoiesis. The authors analyzed deep-coverage targeted DNA-sequencing data of more than 14,000 solid tumor samples from 11,695 patients, using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform, to identify somatic alterations associated with Venous ThromboEmbolism (VTE). Among the patients included, more than 15 different solid tumor types were represented and 72% had metastatic disease at time of analysis.
Among these patients, there were 693 episodes of Cancer Associated Thrombosis, and the authors in addition to looking for associations with standard clinical variables such as diagnosis, stage and therapy, also assessed potential linkage of Cancer Associated Thrombosis with oncogenic mutations. The Primary endpoint was defined as the first instance of cancer-associated Pulmonary Embolism and/or proximal/distal lower extremity Deep Vein Thrombosis.

It was noted that several genes were found to be significantly associated with the VTE risk, regardless of tumor type. Independent of tumor type, the following mutations were associated with increased risk of Cancer Associated Thrombosis: KRAS (HR=1.34 suggesting 1.34 times higher risk), STK11 (HR=2.12), KEAP1 (HR=1.84), CTNNB1 (HR=1.73), CDKN2B (HR=1.45) and MET (HR=1.83). Mutations in SETD2 were associated with a decreased risk of Cancer Associated Thrombosis (HR=0.35). Clonal Hematopoiesis (CH) is an aging associated biologic state, with genetic mutations occurring in the background of active malignancies. The presence of Clonal Hematopoiesis was not associated with an increased risk of Cancer Associated Thrombosis.

The authors from this study concluded that this is the first large-scale study to explore the link between cancer genomics and thrombosis. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B, and MET were associated with an increased risk of VTE in patients with solid tumors. It remains unclear whether drugs targeting these genetic alterations would alter the course of Cancer Associated Thrombosis.

Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors. Dunbar A, Bolton KL, Devlin SM, et al. Blood 2021;137:2103-2113.