Estrogen receptor α (ESR1) mutations are prevalent in patients with estrogen receptor (ER)-positive metastatic breast cancer treated with aromatase inhibitors, with particular mutations increasing the risk for more aggressive tumor biology, a study published in JAMA Oncology has shown.1

ESR1 mutations harbored by patients with metastatic breast cancer promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in preclinical models; however, the prevalence of these mutations and their effect on clinical outcomes is unclear.

For the study, investigators analyzed cell-free DNA from baseline plasma samples from 541 patients with metastatic breast cancer who participated in the phase 3 BOLERO-2 trial, which evaluated the efficacy and safety of exemestane plus everolimus vs exemestane plus placebo. All patients were postmenopausal women who had previously received an aromatase inhibitor.

Results showed that 21.1% of the 541 evaluable patients had ESR1 mutation D538G and 13.3% harbored the Y537S mutation. Thirty patients had both.

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Researchers found that both mutations were associated with worse overall survival. Patients with wild-type ESR1 had a median overall survival of 32.1 months (95% CI, 28.09-36.40); those with the D538G mutation had a median survival of 25.99 months (95% CI, 19.19-32.36); Y537S conferred a survival of 19.98 months (13.01-29.31); and having both mutations was associated with a median survival of 15.15 months (95% CI, 10.87-27.43).

The study further demonstrated that patients harboring the ESR1 mutation D538G derived a similar progression-free survival from the addition of everolimus to exemestane compared with those with wild-type ESR1.


1. Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer. JAMA Oncol. 2016 Aug 11. doi: 10.1001/jamaoncol.2016.1279. [Epub ahead of print]