The Lynx Group

ESR1 Mutations Predict Worse Survival in ER-Positive Advanced Breast Cancer

June 2016, Vol 7, No 5

A “liquid biopsy” was able to detect 2 mutations in the ESR1 gene that predicted worse overall survival (OS) in women with estrogen receptor (ER)-positive metastatic breast cancer who were originally enrolled in the phase 3 BOLERO-2 clinical trial, according to results presented at the 2015 San Antonio Breast Cancer Symposium.

The presence of a D358G and/or Y537S mutation in the ESR1 gene was associated with significantly worse median OS, and approximately 30% of blood samples carried these mutations.

“Even though women with ER-positive metastatic breast cancer are all generally given treatments that target the estrogen receptor, there is a real diversity in how their tumors respond to these drugs, and therefore, a real diversity in patient outcomes. Our goal was to determine if changes in the estrogen receptor itself might explain these differences,” said lead investigator Sarat Chandarlapaty, MD, PhD, Medical Oncologist, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, NY.

“Specifically, we wanted to know whether mutations in the estrogen receptor are common in patients with advanced breast cancer. And do they have an effect on outcomes?” Dr Chandarlapaty added.

“Using a simple blood test [for cell-free DNA], we found that D358G and Y537S mutations are more common in patients with advanced ER-positive breast cancer than previously appreciated, and that patients with these mutations don’t respond as well to currently used therapies and die from their disease sooner than patients who do not have these mutations,” Dr Chandarlapaty said.

The analysis reported by Dr Chandarlapaty and colleagues was based on blood samples from 541 of the 724 patients enrolled in the BOLERO-2 study. The D358G mutation was found in samples from 83 patients, the Y535S mutation was found in samples from 42 patients, and both mutations were found in samples from 30 patients.

The median OS was 32.1 months for patients without these mutations, 26 months for those with only a D538G mutation, 20 months for those with only a Y537S mutation, and 15.2 months for those with both mutations.

Commenting on this study, Lisa A. Carey, MD, Medical Director, University of North Carolina Breast Center, Chapel Hill, said that the study shows the prevalence of ESR1 mutations, and that a blood test can be used to detect them. “At present, these results are not actionable, but I think this is coming within the next year or two,” she said.

ESR1 Mutations Affect Response to Treatment

The data also suggest that these 2 mutations (D538G and Y535S) affect the response to everolimus (Afinitor), but further research is needed to confirm these results. Previously published data from BOLERO-2 showed that the addition of everolimus to standard hormonal therapy with exemestane (Aromasin) improved outcomes for postmenopausal women with ER-positive, locally advanced or metastatic breast cancer that progressed after treatment with an aromatase inhibitor. Everoli­mus was approved by the FDA for this indication.

In an exploratory analysis, adding everolimus to exemestane more than doubled progression-free survival (PFS) in patients without these mutations and for those with theD538G mutation only. However, no PFS benefit was observed for the addition of everolimus in patients with the Y537S mutation only.

Dr Chandarlapaty reported that the number of patients with the Y537S mutation was so small that it is too early to consider not using everolimus in this patient population, and further research is needed.

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