Clinical value of circulating ESR1 mutations for patients with metastatic breast cancer: a meta-analysis

Abstract

Background: The clinical implication of plasma ESR1 mutations in the estrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who had progressed after prior aromatase inhibitor (AI)-based therapy remains controversial. We conducted the first meta-analysis to investigate the prognostic significance and predictive role of plasma ESR1 mutations in MBC patients with prior exposure to AI therapy.

Materials and methods: We searched PubMed, Embase, and Cochrane Library databases for eligible studies. Meta-analysis was conducted to calculate combined hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). Subgroup and sensitivity analyses were also performed.

Results: This study enrolled a total of 1,530 patients with ER-positive MBC cases from six articles, including 429 ESR1 mutation carriers (28.04%). Meta-analysis demonstrated that plasma ESR1 mutation carriers had significantly worse PFS (HR: 1.40, 95% CI: 1.17-1.66; P<0.0001) and OS (HR: 1.65, 95% CI: 1.36-2.01; P<0.0001) compared to wild-type ESR1. Subgroup analysis showed that plasma ESR1 mutations were associated with shorter PFS after AI-based treatment, but were not significantly predictive of outcome on fulvestrant-containing therapy (HR: 1.26, 95% CI: 0.98-1.62; P=0.077). As for different ESR1 mutations, D538G mutation implied significantly worse PFS (HR: 1.50, 95% CI: 1.18-1.91; P=0.01), while Y537S mutation was not correlated with PFS (HR: 1.65, 95% CI: 0.87-1.73; P=0.134).

Conclusion: The meta-analysis indicated that plasma ESR1 mutation assessment may have prognostic significance and clinical value in guiding further endocrine therapy choice in ER+ MBC patients who received prior AI therapy.

Keywords: ESR1 mutations; breast carcinoma; cfDNA; ctDNA; meta analysis.

Figure 1

Flow diagram of literature review and study selection. Notes: ^aThe report presented by Fribbens et al included data from two randomized studies (SoFEA and PALOMA3), which were analyzed independently. Therefore, six eligible studies were enrolled in the meta-analysis. Abbreviations: OS, overall survival; PFS, progression-free survival.

Figure 2

Forest plot for PFS between plasma ESR1 mutation and wild-type ESR1. Abbreviations: HR, hazard ratio; PFS, progression-free survival.

Figure 3

Forest plot for OS between plasma ESR1 mutation and wild-type ESR1. Abbreviations: HR, hazard ratio; OS, overall survival.

Figure 4

Funnel plot to detect publication bias for PFS in the plasma ESR1 mutations vs wild-type ESR1. Abbreviations: PFS, progression-free survival; SE, standard error; HR, hazard ratio.