Abstract
A recent analysis of cell-free DNA from blood samples found that ESR1 mutations are highly prevalent and associated with worse overall survival in women with advanced estrogen receptor–positive breast cancer that progressed on aromatase inhibitor therapy. The data also show that patients' mutation status may affect their response to the mTOR inhibitor everolimus.
Mutations in the estrogen receptor 1 (ESR1) gene are highly prevalent and associated with worse overall survival in women with advanced, metastatic estrogen receptor (ER)–positive breast cancer, according to data presented at the 2015 San Antonio Breast Cancer Symposium in Texas, held December 8–12. The results shed light on why some tumors resist hormonal therapy and may aid in developing more personalized treatments.
Researchers analyzed cell-free DNA in blood samples from 541 of the 724 women enrolled in the phase III BOLERO-2 trial. All of the participants were postmenopausal women with advanced, metastatic ER-positive breast cancer that had progressed after treatment with an aromatase inhibitor. In that trial, adding the mTOR inhibitor everolimus (Afinitor; Novartis) to the standard hormonal therapy exemestane improved overall survival (OS), leading to FDA approval of everolimus for this use in 2012.
In this new study, almost 30% of the blood samples from BOLERO-2 tested positive for the ESR1 mutations D538G (15.3%), Y537S (7.8%), or both (5.5%); these mutations have been observed in animal models of the disease and are known to promote resistance to estrogen-deprivation therapy. In these patients, median OS was highest among those with neither mutation: 32.1 months compared with 26.0 months for those with a D538G mutation, 20 months for those with a Y537S mutation, and 15.2 months for those with both.
During the San Antonio Breast Cancer Symposium, Sarat Chandarlapaty explained how the ESR1 mutations D538G and Y537S may affect responses to everolimus in women with estrogen receptor–positive breast cancer.
During the San Antonio Breast Cancer Symposium, Sarat Chandarlapaty explained how the ESR1 mutations D538G and Y537S may affect responses to everolimus in women with estrogen receptor–positive breast cancer.
Researchers also found that adding everolimus to exemestane more than doubled median progression-free survival (PFS) among patients with D538G mutations (5.8 vs. 2.7 months) or neither mutation (8.5 vs. 3.9 months), but did not extend PFS for those with Y537S mutations (4.2 vs. 4.1 months).
The findings suggest that there are differences in how ESR1 mutations affect patient responses to everolimus, said Sarat Chandarlapaty, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, NY, who presented the findings.
“We cannot say, ‘don't give everolimus to these patients based on this result,’” he said. “But it tells us that we need to look at these mutations and ask how they impact therapies that we're developing going forward.”
In addition, the high frequency of mutations found in the study suggests that analyzing cell-free DNA is a more accurate way of identifying ESR1 mutations than analyzing tissue from the primary tumor, said Chandarlapaty. Sequencing of 302 archival tumor tissue samples from the study participants found D538G and/or Y537S mutations in only 2% of the samples.
“When we use plasma, we're looking at the summation of different metastatic breast cancers, not just one particular lesion,” he said. “If a woman has bone and liver cancer, we often only biopsy one of those, but with plasma, we think we might be capturing the summation of both.” –Janet Colwell
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