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.
MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018 were queried. RCTs that mention VTE as adverse effect were incorporated in the meta-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).
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, ribociclib-letrozole, 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).
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.
Clinical trial identification
Legal entity responsible for the study
Kyaw Zin Thein, Texas Tech University Health Sciences Center.
Has not received any funding.
All authors have declared no conflicts of interest.