In a single-institution study reported in JACC: CardioOncology, Feldman et al found that somatic KRAS and STK11 alterations were associated with increased risk of arterial thromboembolism in patients with solid tumors, irrespective of tumor type.
Study Details
The retrospective cohort study used tumor genetic alteration data from adults with solid cancers who underwent Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing between 2014 and 2016. Arterial thromboembolism was defined as myocardial infarction, coronary revascularization, ischemic stroke, peripheral arterial occlusion, or limb revascularization, and was identified through systematic assessment of electronic medical records. Patients with prior arterial thromboembolism were excluded from the analysis.
Patients were followed from date of tumor-matched blood sample receipt for MSK-IMPACT testing until first arterial thromboembolism event, death, or for up to 1 year. The analysis included the 25 most commonly altered genes; CDKN2B was also included due to a known association with risk of venous thromboembolism. Multivariate analysis was performed for each mutation; all models were adjusted for receipt of cytotoxic chemotherapy in the prior year, age, and presence of metastatic disease, and were stratified by tumor type.
Incidence of Arterial Thromboembolism Events
A total of 11,871 eligible patients were included in the analysis, with 74% having metastatic disease. Within 1 year of observation, a total of 160 arterial thromboembolism events were recorded, including 106 strokes, 1 peripheral embolic event, and 53 myocardial infarction or coronary revascularization events. The 12-month cumulative incidence of arterial thromboembolism was 1.9% (95% confidence interval [CI] = 1.6%–2.2%). The highest cumulative incidence of arterial thromboembolism events was observed in the subgroups of patients with lung cancer (31% of events; 49 events in 1,908 patients), those with ‘other’ cancers (16% of events; 25 events in 1,916 patients), and those with pancreatic cancer (7% of events; 11 events in 508 patients).
Nongenomic Factors Associated With Arterial Thromboembolism on Univariate Analysis
Factors associated with increased risk of arterial thromboembolism on univariate analysis consisted of:
- Increased age (hazard ratio [HR] = 1.02 per 1-year increase, 95% confidence interval [CI] = 1.01–1.03, P = .001)
- Metastatic disease (HR = 1.77, 95% CI = 1.11–2.82, P= .017)
- Use of vasculotoxic chemotherapy (HR = 1.61, 95% CI = 1.14–2.28, P = .007)
- Use of beta blockers (HR = 1.72, 95% CI = 1.15–2.59, P =0.009).
On individual assessment, none of the traditional cardiovascular risk factors—such as diabetes, hypertension, hypercholesterolemia, and smoking history—were associated with an increased risk of arterial thromboembolism; when these factors were combined into a single risk variable, the presence of one or more cardiovascular risk factor(s) was associated with increased risk of arterial thromboembolism (HR = 1.19, 95% CI = 1.03–1.38, P = .019). Use of systemic anticoagulation was associated with reduced risk (HR = 0.57, 95% CI = 0.36–0.89, P = .013). Radiation to the head, neck, brain, and thorax was not significantly associated with increased risk (HR = 1.48, 95% CI = 0.87–2.51, P = .15).
Multivariate Analyses of Genomic Alterations
TP53 alterations (43%) and KRAS alterations (17%) had the highest prevalence among all tumor samples. On multivariate analyses, alterations in KRAS (n = 2,058; HR = 1.98, 95% CI = 1.34–2.94, P = .0006, P = .015 after adjustment for multiple comparisons) and alterations in STK11 (n = 374; HR = 2.51, 95% CI = 1.44–4.38, P = .0012, P = .015 after adjustment for multiple comparisons) were independently associated with significantly increased risk of arterial thromboembolism, independent of tumor type.
Presence of a KRAS alteration was significantly associated with increased risk of arterial thromboembolism both among lung cancers (HR = 1.96, 95% CI = 1.10–3.46, P= .021) and non–lung cancers (HR = 1.95, 95% CI = 1.28–2.97, P = .002).
Analysis limited to ischemic strokes showed a similar effect of genomic alterations. The hazard ratio for stroke was 2.22 (95% CI = 1.38–3.58) among patients with vs without a KRAS alteration and 3.48 (95% CI = 1.87–6.46) among patients with vs without a STK11 alteration.
The investigators concluded, “In a large genomic tumor-profiling registry of patients with solid cancers, alterations in KRAS and STK11 were associated with an increased risk of arterial thromboembolism independent of cancer type. Further investigation is needed to elucidate the mechanism by which these mutations contribute to arterial thromboembolism in this high-risk population.”
Simon Mantha, MD, MPH, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the JACC: CardioOncology article.
Disclosure: The study was supported by the National Cancer Institute and others. For full disclosures of the study authors, visit jacc.org.
