Impact of Tumor Genomic Mutations on Thrombotic Risk in Cancer Patients

Abstract

Venous thromboembolism (VTE) is common in patients with cancer and is an important contributor to morbidity and mortality in these patients. Early thromboprophylaxis initiated only in those cancer patients at highest risk for VTE would be optimal. Risk stratification scores incorporating tumor location, laboratory values and patient characteristics have attempted to identify those patients most likely to benefit from thromboprophylaxis but even well-validated scores are not able to reliably distinguish the highest-risk patients. Recognizing that tumor genetics affect the biology and behavior of malignancies, recent studies have explored the impact of specific molecular aberrations on the rate of VTE in cancer patients. The presence of certain molecular aberrations in a variety of different cancers, including lung, colon, brain and hematologic tumors, have been associated with an increased risk of VTE and arterial thrombotic events. This review examines the findings of these studies and discusses the implications of these findings on decisions relating to thromboprophylaxis use in the clinical setting. Ultimately, the integration of tumor molecular genomic information into clinical VTE risk stratification scores in cancer patients may prove to be a major advancement in the prevention of cancer-associated thrombosis.

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

“…In contrast, inconsistent findings have been observed in studies that looked at mutations in KRAS and EGFR genes in the context of VTE risk being lower when compared to patients with ROS1 and ALK rearrangements. 31,32 Our study took into consideration the use of TKI in conjunction with the ALK mutation for the evaluation of VTE in our cohort of NSCLC (PD-L1) expression is observed. Our study population pre-dated consistent identification of these molecular targets and rates of TE across these molecular subtypes were not evaluated in our report.…”

“…Although patients with the ALK rearrangement were nearly two decades younger on average than the non‐ ALK control group, with fewer co‐morbidities and lower rates of accepted arterial and venous thrombotic risk factors, they still had higher rates of thrombotic events, strongly suggestive of a role for ALK rearrangement in increasing thrombotic risk. In contrast, inconsistent findings have been observed in studies that looked at mutations in KRAS and EGFR genes in the context of VTE risk being lower when compared to patients with ROS1 and ALK rearrangements 31,32 …”

Risk Prediction and New Prophylaxis Strategies for Thromboembolism in Cancer

“…In this context, the advent of tumor genomic profiling has strongly contributed not only to a deeper comprehension of cancer biology, but also to the discovery of potential VTE risk genomic factors. The subject is addressed in the review by Leiva and colleagues discussing the potential mechanisms by which the tumor mutational status may influence thrombogenesis [ 11 ]. Molecular aberrations involving various targetable driver mutations may, in fact, impact thrombotic risk in many tumor types, possibly through a disregulation of tumor tissue factor (TF) expression.…”

“…Molecular aberrations involving various targetable driver mutations may, in fact, impact thrombotic risk in many tumor types, possibly through a disregulation of tumor tissue factor (TF) expression. This is the case of mutated KRAS in colorectal and lung cancer and IDH1 in brain cancer patients, the former being positively associated with TF upregulation, the latter being associated with hypermethylation of the F3 promoter of the TF gene leading to decreased TF expression and a decreased risk of VTE [ 11 ]. Other tumor mutations that have been involved in the prothrombotic state in carcinoma patients include ALK , ROS1 , and JAK2 , all participating in downstream signaling of inflammatory cytokines [ 11 ], while the burden of breast cancer mutational events, using a next-generation sequencing approach, is currently the focus of an ongoing trial [ 12 ].…”

Management of Cancer-Associated Thrombosis: An Evolving Area

“…Larger sample size studies are needed to confirm these findings. In addition, tumors specific mutations have been recently associated with the risk of VTE in some cancers, including non-small cell lung carcinoma, colon cancer, and myeloproliferative neoplasms, and integration of tumors mutational signature into VTE RAMs may also significantly improve VTE risk prediction in the near future [ 29 , 30 ].…”