Risk of venous thromboembolism associated with CDK 4/6 inhibitors and adjuvant hormonal therapy in non-metastatic breast cancer: A systematic review and meta-analysis

Abstract Background: Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), non-metastatic breast cancer represents a significant proportion of early-stage breast cancer cases and remains a therapeutic challenge despite advances in treatment strategies. Standard adjuvant therapies, such as tamoxifen and aromatase inhibitors (AIs), have effectively reduced recurrence rates and improved survival outcomes in this population. More recently, the introduction of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors, Abemaciclib, Palbociclib, and Ribociclib, has led to new treatment for high-risk patients. Combined with endocrine therapy, these agents have significantly improved disease-free survival by targeting cell cycle dysregulation. However, these new options of therapy also present some challenges, particularly concerning safety. Existing studies suggest that both tamoxifen and CDK 4/6 inhibitors are associated with an increased risk of venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT). Despite their increasing clinical use, significant research gaps related to side effects and adverse events still exist. This review addresses these gaps by synthesizing the available evidence and providing a better understanding of VTE risks associated with these therapies. Evaluating incidence rates, exploring patient characteristics, and comparing treatment regimens will help clinicians balance the efficacy and safety of these therapies. This study seeks to support the development of evidence-based recommendations that enhance patient outcomes while minimizing adverse events. Methods: The databases Medline, Embase, and Cochrane Central Register of Controlled Trials (Central) were searched. Publications included studied adult patients who have had a diagnosis of local or locally advance, non-metastatic breast cancer and have received treatment with CKD 4/6 inhibitors and/or adjuvant hormonal therapy. Major exclusion criteria included patient age <18 years-old, metastatic cancer, and patients already diagnosed with a hypercoagulable disorder (such as antiphospholipid syndrome, or specific constitutional thrombophilia). The statistical analysis was performed using OpenMeta[Analyst]. We reported information in Risk Ratio (RR) with 95% confidence intervals. We pooled the information with a binary fixed-effect meta-analysis according to the heterogeneity expected. We assessed heterogeneity using the I2 test. For the interpretation, it was determined that the values of <50% and >50% in the I2 test corresponded to low and high levels of heterogeneity, respectively. Results: In total, 4,623 publications were identified through the database search. An additional publication was identified through manual search. Of these publications, seven studies were selected for data extraction and analysis after screening for inclusion criteria was performed. From those studies, we observed the incidence of VTE in the group of patients treated with CDK 4/6 inhibitors to be larger (68/3165) than the incidence of VTE in the comparator group (11/2205). The comparator group in this analysis consisted of patients treated with endocrine therapy alone with aromatase inhibitors (AI), tamoxifen, or fulvestrant. We found that the relative risk of developing VTE was significantly higher with CDK 4/6 inhibitor treatment than with treatment with endocrine therapy alone (RR 3.7, 95% CI 1.9 to 7.0). Overall, there was not a significant variability in effect estimates from the included studies (I2=0 %). Conclusion: Results from this study show that for adult patients with local and locally advanced breast cancer, there is increased risk of VTE development when treated with CDK 4/6 inhibitors compared to treatment with endocrine therapy alone. Limitations to this analysis include exclusion of metastatic disease, limited data available on mortality associated with VTE incidence, and varying degrees of patient-specific thromboembolic risk factors. As the use of CDK 4/6 inhibitors in the treatment of breast cancer grows, this information will provide further information for conversations about risks and benefits when selecting treatment plans.