Abstract P3-14-02: Incidence of venous thromboembolism in patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK 4/6 inhibitors: A systematic review and meta- analysis of randomized controlled trials
Authors: Thein KZ , Zaw MH , Tun AM , Jones C , Radhi S , Hardwicke F , Oo TH 
Published: February 2018

Abstract
Background:
The cyclin dependent kinases (CDK) along with their partners, the cyclins, have a crucial role in regulation of the cell cycle. Several CDK-targeted agents have been employed in hormone receptor positive metastatic breast cancer (MBC) with noteworthy safety concerns. Nevertheless, the impact of this agent on risk of venous thromboembolism (VTE) remains uncertain. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of VTE among patients with hormone receptor-positive HER2-negative MBC treated with CDK 4/6 inhibitors.
Methods:
We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through June 2017. Trials that mention deep vein thrombosis and pulmonary embolism as adverse effects were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Pooled VTE rates were estimated as follows: we multiplied the median follow-up duration by the sample size. Crude study-specific VTE rates were then calculated by dividing the number of incident VTE cases by the total number of person-months follow-up.
Results:
A total of 2671 patients with hormone receptor-positive HER2-negative MBC from four phase 3 studies and one phase 2 study were eligible for analysis. The study arm used palbociclib-letrozole, palbociclib-fulvestrant, ribociclib-letrozole and abemaciclib-fulvestrant while the control arm utilized placebo in combination with letrozole or fulvestrant. The I2 statistic for heterogeneity was 13.6, and the heterogeneity X2 (Cochran's Q) was 4.6 (P= 0.3), suggesting homogeneity of results among the randomized trials. The VTE incidence was 24 (1.46%) in CDK 4/6 group vs 4 (0.39%) in control group. The pooled RR for VTE was 2.736 (95% CI: 1.115 – 6.714, P = 0.028) and the absolute RD was 0.010 (95% CI: 0.002 – 0.018, P = 0.010) according to the fixed effects model. By the random effects model, the pooled RR was 2.411 (95% CI: 0.809 – 7.181, P = 0.114) and RD was 0.009 (95% CI: 0.0 – 0.019, P = 0.048). Over median follow up of 36 months, the RR for VTE was 3.792 (95% CI: 1.838 – 7.822, P &lt; 0.0001) and RD was 0.024 (95% CI: 0.014 – 0.034, P &lt; 0.0001) with the fixed effects model. By the random effects model, the pooled RR for VTE was 4.248 (95% CI: 0.952- 18.959, P = 0.058) and RD was 0.026 (95% CI: 0.004 – 0.021, P &lt; 0.0001). The pooled rate of VTE among CDK 4/6 group was 2.99 per person years compared to 0.50 per person years among control arm.
Conclusion:
Approximately 1% of patients on letrozole or fulvestrant alone developed VTE in previous studies. Our meta-analysis demonstrated that the addition of CDK 4/6 inhibitors to letrozole or fulvestrant, contribute to higher incidence of VTE. More randomized trials are required to determine the actual relation and definitive incidence of VTE, a major cause of morbidity and mortality among these patients.
Citation Format: Thein KZ, Zaw MH, Tun AM, Jones C, Radhi S, Hardwicke F, Oo TH. Incidence of venous thromboembolism in patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK 4/6 inhibitors: A systematic review and meta- analysis of randomized controlled trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-02.