Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial

Abstract

Importance: Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models. The prevalence of these mutations and their potential impact on clinical outcomes has not been established.

Objective: To determine the prevalence of ESR1 mutations (Y537S and D538G) in estrogen receptor (ER)-positive MBC and determine whether mutation is associated with inferior outcomes.

Design, setting, and participants: From December 16, 2014, to August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples from participants in the BOLERO-2 double-blind phase 3 study that randomized patients from 189 centers in 24 countries with MBC to exemestane plus placebo or exemestane plus everolimus. The study enrolled postmenopausal women with a diagnosis of MBC and prior exposure to an aromatase inhibitor. Baseline plasma samples were available from 541 of 724 patients (74.7%). We assessed the effect of mutation on overall survival of the population and the effect of mutation on progression-free survival (PFS) by treatment arm.

Interventions: Patients were randomized to treatment with exemestane (25 mg oral daily) together with everolimus (10 mg oral daily) or with placebo.

Main outcomes and measures: The 2 most frequent mutations in ESR1 (Y537S and D538G) were analyzed from cfDNA using droplet digital polymerase chain reaction and samples scored as wild-type, D538G, Y537S, or double mutant. Cox-proportional hazards model was used to assess PFS in patient subgroups defined by mutations, and the effect of each mutation on overall survival.

Results: Of 541 evaluable patients, 156 (28.8%) had ESR1 mutation D538G (21.1%) and/or Y537S (13.3%), and 30 had both. These mutations were associated with shorter overall survival (wild-type, 32.1 months [95% CI, 28.09-36.40 months]; D538G, 25.99 months [95% CI, 19.19-32.36 months]; Y537S, 19.98 months [13.01-29.31 months]; both mutations, 15.15 months [95% CI, 10.87-27.43 months]). The D538G group (hazard ratio, 0.34 [95% CI, 0.02-0.57]) derived a similar PFS benefit as wild type from addition of everolimus to exemestane.

Conclusions and relevance: ESR1 mutations are prevalent in ER-positive aromatase inhibitor-treated MBC. Both Y537S and D538G mutations are associated with more aggressive disease biology.

Trial registration: clinicaltrials.gov Identifier: NCT00863655.

Figure 1.. Kaplan-Meier Curves for Overall Survival (OS) According to Mutation Status

A, Superior overall survival (OS) is shown for patients without mutation (MT) in ESR1 (wild-type [WT]) compared with those with D538G and/or Y537S mutation. B, Overall survival results are shown for WT or D538G alone or Y537S alone or both D538G and Y537S (double MT).

Figure 2.. Kaplan-Meier Curves for Effect of Addition of Everolimus to Exemestane

A, Progression-free survival (PFS) for patients without ESR1 mutation (wild-type [WT]) or with the D538G mutation (D538G). B, Results for patients without ESR1 mutation (WT) or with the Y537S mutation (Y537S). Addition of everolimus (EVE) was associated with improved progression-free survival (PFS) for patients with WT or D538G mutation but not for those with Y537S mutation. PBO indicates placebo.