A comparison of fulvestrant plus a targeted agent with fulvestrant alone in hormone receptor-positive advanced breast cancer that progressed on prior endocrine therapy: a meta-analysis

Abstract

Fulvestrant is recommended for the hormone receptor-positive metastatic breast cancer (MBC) patients progressed during or after prior endocrine therapy. Notably, recent evidence has also demonstrated that adding a targeted agent to fulvestrant conferred a significantly clinical benefit in these patients. Since these results were inconsistent among the studies, this meta-analysis herein was conducted to compare the efficacy and toxicities of the fulvestrant-based combination therapy with fulvestrant monotherapy. Thus, a systemic research was performed in PubMed, Embase, and Cochrane library to identify relevant Phase II or Phase III randomized controlled trials. The progression-free survival (PFS), overall response rate (ORR), and toxicities were evaluated. And HR, risk ratio (RR), and their 95% CIs were employed to complete the pooled analyses. In total, 13 studies with 3,910-hour positive MBC patients progressed on prior endocrine therapy were included in our meta-analysis. Improvements of doublet-agents group were proven in terms of PFS (HR 0.73, 95% CI =0.63-0.86, P=0.000) and ORR (RR 2.07, 95% CI =1.67-2.58, P=0.000). And the further subgroup analysis also demonstrated that fulvestrant in combination with a cyclin-dependent kinase (CDK4/6) inhibitor or a PI3K/mTOR inhibitor was associated with a superior efficacy (RR 2.72, 95% CI =1.93-3.83, P=0.000 and RR 1.60, 95% CI =1.15-2.23, P=0.005, respectively). However, the efficacy was comparable between the other combination strategies and fulvestrant alone. With respect to the adverse effects, adding a targeted agent to fulvestrant also produced more frequent grade 3/4 toxicities (RR 3.86, 95% CI =2.66-5.61, P=0.000). Taken together, combination of fulvestrant with a targeted agent, especially inhibitors targeting CDK4/6 or PI3K/mTOR pathway, may open a new avenue for more effective therapies in relapse or metastatic hormone receptor-positive breast cancer after prior aromatase inhibitors or tamoxifen treatment. In addition, identifying reliable biomarkers to delineate which subgroup of patients will specially benefit from fulvestrant-based combination therapy is warranted.

Keywords: breast cancer; combination therapy; endocrine resistance; fulvestrant.

Figure 1

Flow diagram and results of our literature identification. Abbreviation: RCT, randomized controlled trial.

Figure 2

The pooled HR and 95% CI for PFS following fulvestrant in combination with a targeted agent and fulvestrant alone. Note: Weights are from random effect analysis. Abbreviations: PFS, progression-free survival; CDK4/6, cyclin-dependent kinase 4/6.

Figure 3

The pooled risk ratio (RR) and 95% CI for overall response rate. Abbreviations: ORR, overall response rate; CDK4/6, cyclin-dependent kinase 4/6.

Figure 4

Forest plot of relative risk of treatment induced grade 3/4 toxicities. Note: Weights are from random effects analysis. Abbreviations: RR, risk ratio; CDK4/6, cyclin-dependent kinase 4/6.

Figure 5

Funnel plot of publication bias in the meta-analysis. Notes: (A) PFS. (B) ORR. Abbreviations: PFS, progression-free survival; ORR, overall response rate.