Updated meta-analysis of randomized controlled trials (RCTs) to determine the CDK 4/6 inhibitors associated venous thromboembolism (VTE) risk in hormone receptor-positive breast cancer (BC) patients

Abstract

Background: Majority of BC express hormone receptors and cyclin dependent kinases especially CDK4/6 have been proven to mediate hormone therapy resistance. Many CDK 4/6 inhibitors have shown survival benefits. Yet, the VTE risk remains considerable. We undertook an updated meta-analysis of RCTs to determine the VTE risk among patients with hormone receptor-positive metastatic BC treated with CDK 4/6 inhibitors. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018 were queried. RCTs that mention VTE as adverse effect were incorporated in themeta-analysis. The primarymeta- analytic approach was a fixed effectsmodel 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). Results: Five phase III studies and one phase II study with a total of 3,159 patients were eligible. The study arms used palbociclib-letrozole, palbociclib-fulvestrant, ribociclibletrozole, abemaciclib-fulvestrant, abemaciclib-letrozole/anastrozole while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant. The I2 statistic for heterogeneity was 16.452, and the heterogeneity X2 (Cochran's Q) was 5 (P=0.308), suggesting homogeneity among RCTs. The VTE incidence was 40 (2.03%) in CDK 4/6 inhibitors group vs 5 (0.42%) in control group. The pooled RR for VTE in CDK 4/6 inhibitors group was 3.561 (95% CI: 1. 574 to 8.057, P=0.002) and the absolute RD was 0.014 (95% CI: 0.002 to 0.027, P=0.022) according to the fixed effects model. By the random effects model, the pooled RR was 3.072 (95% CI: 1.138 to 8.294, P=0.027) and RD was 0.015 (95% CI: 0.007 to 0.023, P<0.0001). Conclusions: Our meta-analysis showed that the addition of CDK 4/6 inhibitors to letrozole or fulvestrant, contribute to higher incidence of VTE. Patients on CDK 4/6 inhibitors group experienced a significant increase in the VTE risk with a RR of 3.56. VTE remains the second leading cause of death in cancer patients receiving antineoplastic therapy and close monitoring is required.