February 2016, Vol. 5, No. 1

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ESR1 Mutations Portend Worse Survival in ER+ Advanced Breast Cancer

Sarat Chandarlapaty, MD, PhD

San Antonio Breast Cancer Symposium

Chandarlapaty,Sarat98pxA “liquid biopsy” was able to detect 2 mutations in the estrogen receptor 1 (ESR1) gene that predicted worse overall survival (OS) in women with estrogen receptor–positive (ER+), metastatic breast cancer who were originally enrolled in the BOLERO-2 clinical trial.

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

“Even though women with ER+, 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. 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?” said lead author Sarat Chandarlapaty, MD, PhD, Memorial Sloan Kettering Cancer Center, New York City.

“Using a simple blood test, we found that D358G and Y537S mutations in the estrogen receptor are more common in patients with advanced ER+ 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,” he said.

The data also suggest that these 2 mutations affect response to everolimus, but further study is needed to establish this with certainty. Previously published data from the phase 3 BOLERO-2 trial showed that the addition of everolimus to standard hormonal therapy with exemestane improved outcomes for postmenopausal women with ER+, locally advanced or metastatic breast cancer that progressed after treatment with an aromatase inhibitor. Everolimus is approved by the FDA for this indication.

The analysis reported by Chandarlapaty and colleagues was based on blood samples from 541 of the 724 patients enrolled in BOLERO-2. The D358G mutation was found in samples from 83 patients, the Y537S mutation in samples from 42 patients, and both mutations in samples from 30 patients.

Median OS was 32.1 months for patients free of 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.

In an exploratory analysis, adding everolimus to exemestane more than doubled progression-free survival (PFS) for patients who did not have either of these mutations and for those with a D538G mutation only. No PFS benefit was observed with the addition of everolimus for patients with a Y537S mutation, however.

Chandarlapaty said the number of patients with the Y537S mutation was so small that it is too early to consider not using everolimus in this population. Further study is needed, he said.

Commenting on this study, Lisa Carey, MD, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, said that the study is interesting and shows the prevalence of ESR1 mutations, and also 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.

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