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ESR1 mutations may influence treatment, outcomes in metastatic breast cancer
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Women with estrogen receptor–positive metastatic breast cancer who received treatment with aromatase inhibitors frequently harbored ESR1 mutations, according to a secondary analysis from a clinical trial.
These mutations correlated with aggressive disease biology and shortened OS.
Sarat Chandarlapaty
“Activation of the estrogen receptor is a key feature of the 70% to 80% of breast cancers in which estrogen receptor expression is detected,” Sarat Chandarlapaty, MD, PhD, breast medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “Estrogen deprivation therapy in the form of an aromatase inhibitor is an effective, targeted therapy for these tumors, reducing disease morbidity and disease mortality. Outcomes of patients with estrogen receptor–positive metastatic breast cancer who are treated with aromatase inhibitors vary considerably.”
Researchers have speculated that ESR1 mutations — the two most common of which are D538G and Y537S — may reduce the effectiveness of aromatase inhibition therapy; however, this link has not been clinically validated.
Chandarlapaty and colleagues assessed the frequency of these mutations in women with metastatic breast cancer and analyzed whether the presence of the mutations corresponded with substandard outcomes.
The researchers analyzed cell-free DNA from plasma samples collected from the BOLERO-2 trial, a randomized phase 3 study of women with metastatic breast cancer.
The BOLERO-2 trial recruited postmenopausal women previously treated with an aromatase inhibitor. The researchers randomly assigned study participants to daily oral exemestane (Aromasin, Pfizer) plus everolimus (Afinitor, Novartis) or exemestane plus placebo.
Chandarlapaty and colleagues assessed the effect of mutation status on OS in the entire study population, as well as on PFS by treatment arm.
Baseline plasma samples were available from 74.7% (n = 541 of 724) of the BOLERO-2 study population.
In total, ESR1 mutations could be identified in 28.8% (n = 156) of available samples. D538G mutations occurred in 114 patients (21.1%), and Y537S mutations occurred in 72 patients (13.3%). Thirty patients harbored both mutations.
Women with neither mutation had a median OS of 32.1 months (95% CI, 28.09-36.4), compared with 20.73 months (95% CI, 17.71-28.06) for women with a mutation.
Patients who harbored the D538G mutation had a median OS of 25.99 months (95% CI, 19.19-32.36) and patients who harbored the Y537S mutation had a median OS of 19.98 months (95% CI, 13.01-29.31). Patients with both mutations had a median OS of 15.15 months (95% CI, 10.87-27.43).
Among patients assigned to placebo, those who harbored the D538G mutation achieved shorter median PFS than those who did not have either mutation (3.94 months vs. 2.69 months).
In the group assigned everolimus, researchers observed PFS improvements among those without mutations (8.48 months; HR = 0.4; 95% CI, 0.31-0.51) and those with the D538G mutation (5.78 months; HR = 0.34; 95% CI, 0.02-0.57).
The benefit of everolimus for patients with the Y537S mutation or patients with both mutations could not be definitively assessed, due to the small number of patients in these groups.
However, the researchers hypothesized that the benefit of everolimus would not be significant in patients with Y537S alone (HR = 0.98; 95% CI, 0.49-1.94) or patients with both mutations (HR = 0.53; 95% CI, 0.23-1.25).
The researchers highlighted the availability of biomarker testing and encouraged its use in this patient population.
“With this information, clinicians and investigators facing a wide range of outcomes may identify clinically valuable information regarding prognosis and prediction about treatments under consideration,” Chandarlapaty and colleagues wrote. “The ease and affordability of such a test will also enable dynamic testing that will improve our understanding of the evolution of this disease and the design of strategies to improve outcomes.”
The influence of ESR1 mutations represents a major opportunity for research and treatment of metastatic breast cancer, Suzanne A.W. Fuqua, PhD, Yassine Rechoum, PhD, and Guowei Gu, PhD, all of Baylor College of Medicine, wrote in an accompanying editorial.
“These results suggest that knowledge of the resistance escape mechanisms coexisting with ESR1 mutant expression will need to be identified to accurately guide targeted therapy of metastatic breast cancer,” Fuqua, Rechoum and Gu wrote.
The potential targeted agents useful for treating advanced breast cancer in a metastatic setting include histone deacetylase, heat shock protein 90, cyclin-dependent kinases 4 and 6, and phosphoinositide-3-kinase inhibitors.
The efficacy of targeted agents combined with new selective estrogen receptor degraders may be beneficial to patients with metastatic disease, Fuqua, Rechoum and Gu wrote.
“The use of sensitive yet simple mutation monitoring of plasma as described in this study could provide indispensable predictive information for correcting the course of therapy in advanced or perhaps even early breast cancer,” they wrote. “We eagerly await an illumination of what is not just evident on the surface, the ‘tip’ of circulating cell-free DNA, but also what resistance networks lie beneath and drive the bulk of the metastatic ESR1 mutant-positive tumors in unique distant microenvironments.” – by Cameron Kelsall
Disclosure: Novartis funded the BOLERO-2 study. Chandarlapaty reports a consultant role with AstraZeneca. Three study researchers report employment with Novartis. The other researchers report no relevant financial disclosures. Fuqua, Rechoum and Gu report no relevant financial disclosures.
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