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ESR1 mutations associated with reduced survival in metastatic breast cancer

Roshini Claire Anthony
07 Sep 2016

Estrogen receptor α (ESR1) mutations Y537S and D538G are associated with reduced overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, according to findings of a secondary analysis of the BOLERO-2* clinical trial.

Compared with patients with neither mutation (wild-type; OS, 32.1 months, 95 percent confidence interval [CI], 28.09‒36.4 months), those with either ESR1 mutation had poorer OS (25.99 months, 95 percent CI, 19.19‒32.36 months and 19.98 months, 95 percent CI, 13.01‒29.31 months for patients with D538G and Y537S mutations, respectively). Patients with both mutations had an even lower OS (15.15 months, 95 percent CI, 10.87‒27.43 months). [JAMA Oncol 2016;doi:10.1001/jamaoncol.2016.1279]

To determine the prevalence of the ESR1 mutations Y537S and D538G and if these mutations were associated with poorer outcomes in estrogen receptor (ER)-positive metastatic breast cancer, researchers analyzed cell-free DNA from baseline plasma samples of 541 of the 724 patients in the double-blind, randomized, placebo-controlled phase 3 BOLERO-2 trial. Patients were randomized to receive exemestane (25 mg daily) with either everolimus (10 mg daily) or placebo.

One hundred and fifty-six patients (28.8 percent) had an ESR1 mutation, with 21.1 percent (n=114) and 13.3 percent (n=72) having the D538G and Y537S mutations, respectively. Thirty patients had both mutations.

Mutations were three times more common in metastatic breast cancer patients who had failed first-line therapy (prior treatment with aromatase inhibitors [AI]) compared with those who were just initiating AI therapy (adjuvant therapy; 33 percent vs 11 percent).

“We were surprised that the prevalence of mutation was this high,” said study author Dr Sarat Chandarlapaty from the Memorial Sloan Kettering Cancer Center in New York, US.

In patients on exemestane only, patients with D538G mutation had shorter progression-free survival (PFS) compared with wild-type (2.69 vs 3.94 months; hazard ratio [HR], 1.71, 95 percent CI, 1.09‒2.68 months). The addition of everolimus resulted in improvement of PFS for those with wild-type (8.48 months; HR, 0.4, 95 percent CI, 0.31‒0.51 months) and D538G mutation (5.78 months; HR, 0.34, 95 percent CI, 0.02‒0.57 months).

According to the authors, it has been suggested that constitutively active mutations in the ER may reduce the efficacy of hormonal therapies such as AIs, though the impact of these mutations on clinical outcomes is uncertain.

“Now that we know that these mutations are present, [and] that they are impactful, we can say that this is critical to look at with respect to prediction; does presence of mutation impact whether therapy works,” said Chandarlapaty.

“The reported shorter OS for patients harbouring ESR1 mutations suggests that they may represent potential poor prognostic factors in breast cancer,” said Drs Suzanne Fuqua, Yassine Rechoum, and Guowei Gu from the Lester and Sue Smith Breast Center, Dan L. Duncan Cancer Center, Baylor College of Medicine in Houston, Texas, US, in a separate editorial. However, they cautioned against drawing conclusions that the mutations were predictive of everolimus response due to the lack of a no-treatment control arm in the trial. 

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