Estrogen receptor α (ESR1) mutations are highly prevalent in women receiving aromatase inhibitors for metastatic breast cancer (MBC), according to a secondary analysis from a clinical trial.
ESR1 mutations found in MBC have been known to promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models; however, the prevalence of these mutations as well as their potential impact on clinical outcomes has not yet been clearly defined.
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Therefore, investigators led by Sarat Chandarlapaty, MD, PhD, Memorial Sloan Kettering Cancer Center (New York, NY), analyzed the prevalence of ESR1 in patients with estrogen receptor (ER)-positive MBC who participated in the BOLERO-2 phase III clinical trial to determine whether the mutations are associated with inferior outcomes. They published their results in Jama Oncology.
The phase III double-blind BOLERO-2 trial was conducted to compare the effectiveness of exemestane plus a placebo with exemestane plus everolimus in patients with MBC. It enrolled 724 postmenopausal women who were diagnosed with MBC prior to exposure to an aromatase inhibitor.
To determine how ESR1 affected patient outcomes, investigators analyzed cell-free DNA from baseline plasma samples, which were available in 541 (74.7%) of the study participants. Overall and progression-free survival were the primary outcome measures in both treatment arms.
Of the 541 patients deemed eligible for study inclusion, 156 (28.8%) had D538G (21.1%) and/or Y537S (13.3%), two of the most common ESR1 mutations. Median overall survival was significantly shorter among these patients (20.7 months) than it was in those who presented with neither mutation (32.1 months). Those with both mutations had the shortest median overall survival (15.15 months) followed by patients harboring the Y537S mutation (19.98 months). Patients with the D538G mutation had a median overall survival of 25.99 months.
Additional analysis revealed that patients who harbored D538G and were treated with placebo achieved a shorter median progression-free survival than those who did not have either mutation (2.69 months vs 3.94 months, respectively).
Among those assigned to receive everolimus, progression-free survival was 8.48 months in those without a mutation and 5.78 months in those with D538G.
Comparative analysis of these treatment groups in those harboring Y537S or both mutations could not be definitively assessed due to the small number of patients presenting with these conditions.
Still, investigators concluded that ESR1 mutations were highly prevalent among the study population of patients with ER-positive aromatase inhibitor-treated MBC. Two common ESR1 mutations, D538G and Y537S, may also reduce the effectiveness of aromatase inhabitation therapy, though this relationship has not yet been clinically validated.
