Targeted Therapies Associated with Increased Risk for and Incidence of Thrombosis in the Treatment of Breast Cancer

Background Breast cancer is the most common cancer in women and second-leading cause of cancer-related death. The landscape of breast cancer treatment has changed rapidly with the integration of targeted molecular therapies, including pharmacologic inhibitors of CDK4/6, PARP, mTOR and PI3K. These medications are associated with an increased risk of thrombosis. For CDK4/6i, rates of thrombosis have been reported in clinical trials between 0.60-6.1%, with abemaciclib seeming to demonstrate the highest incidence (Curr Probl Cancer 2022;46(2)). According to one meta-analysis, patients taking PARPi had an incidence of thrombosis of 4.1% (ESMO Op 2023;8(2)). In clinical trials evaluating both everolimus and alpelisib in breast cancer, there was no increase in thrombotic risk compared to placebo (Eur Heart J 2022;22; N Engl J Med 2019;380(20):1929-1940). Additionally, risk factors associated with thrombosis with targeted therapies have not yet been well described. The aim of this study was to determine the incidence of thrombosis in women with breast cancer being treated with targeted therapies and to investigate associated risk factors for development of thrombosis. Methods We conducted a retrospective cohort study using a de-identified national database with 85 contributing health care organizations, including over 129 million patients (TriNetX Research Network, Cambridge, MA). We identified adults (≥18 years old) with a breast cancer diagnosis (ICD-10 C50) who were treated with CDK 4/6i (ribociclib, abemaciclib, or palbociclib), PARPi (olaparib), mTORi (everolimus), or P13Ki (alpelisib) between March 2012-April 2024. Thrombotic events were defined as arterial thrombosis (myocardial infarction and cerebral infarction) and venous thrombosis (venous embolism and pulmonary embolism) occurring ≥1 day after initiation of treatment with medications of interest. Patients using anticoagulants were excluded. We collected demographic, clinical, and treatment characteristics from our cohort. Baseline differences were calculated using independent t-test for continuous variables, and chi-square test or fisher's exact test for categorical variables. Comparison was made with a cohort of patients with breast cancer who are not on treatment with the listed medications (776,940 patients). Logistic regression was used to assess the association between the outcome of thrombosis (ICD-10: I63, I21, I26, I82, I74) and covariates of breast cancer medication (CDK4, PARP, mTOR, or PI3K; ICD-10:1873916, 1601374, 1946825, 1597582, 2099704, 141704, 2169285), nicotine dependence (ICD-10: F17), prior thrombosis (ICD-10: I63, I21, I26, I82, I74), malignant neoplasm of brain (ICD-10: C79.31). Results Our study included 13,717 patients diagnosed with breast cancer and were described as taking one of the medications of interest. The overall incidence of any thrombosis in patients taking CDK 4/6i was 13.96%; specifically, ribociclib 7.3%, palbociclib 16.4%, and abemaciclib 12.3%. Patients taking olaparib had 7.5% incidence of thrombosis, while everolimus and alpelisib demonstrated the highest thrombosis risks (19.5% and 20.7%, respectively). Both CDK4/6i and everolimus were associated with an increased risk of arterial clots (OR 1.86, 95% CI 1.34-2.6, p<0.001; OR 1.68, 95% CI 1.36-2.07, p<0.001, respectively). Venous thromboembolism was increased among patients on CDK4/6i, everolimus, alpelisib (OR 1.88, 95% CI 1.51-2.34, p<0.001; OR 2.28, 95% CI 1.97-2.63, p<0.001; OR 1.84, 95% CI 1.47-2.28, p<0.001, respectively), but not among those taking olaparib. Risk factors associated with thrombosis development were nicotine dependence (OR 1.51, 95% CI 1.29, 1.76 p < 0.001), prior venous thrombosis (OR 6.21, 95% CI 4.91, 7.84 p < 0.001), prior arterial thrombosis (OR 4.41, 95% CI 3.45, 5.61 p < 0.001), and brain metastases (OR 1.41, 95% CI 1.13, 1.74 p = 0.002). Discussion Our study demonstrates that the incidence of thrombosis is increased in patients with breast cancer who are utilizing targeted therapies at a significantly higher rate than reported in prior studies. We also found several risk factors associated with thrombosis in patients taking these targeted therapies. Our data contributes to the overarching question of whether patients who are taking these medications would benefit from prophylactic anticoagulation given the significant risk of thrombosis. Prospective studies are needed.