Estrogen receptor mutations in estrogen receptor–positive metastatic breast cancer are more prevalent than previous studies and methodologies suggest, investigators found during a secondary analysis of patients enrolled in the BOLERO-2 trial.
Furthermore, two specific estrogen receptor 1 (ESR1) mutations, D538G and Y537S, were associated with reduced overall survival.
Of the 724 patients enrolled in the BOLERO-2, a phase III trial of women with postmenopausal ER-positive, HER2-nonamplified advanced breast cancer refractory to nonsteroidal aromatase inhibitors, 541 had evaluable cell-free DNA from baseline plasma samples and consented to genomic testing. Cell-free DNA (cfDNA) was extracted from patient’s plasma samples and assayed (via BioRad’s QX200 Droplet Digital PCR [polymerase chain reaction] System) for two specific ESR1 mutations, D538G and Y537S.
Dr. Sarat Chandarlapaty
ESR1 mutations were detected in 156 of the 541 patients (28.8%), with D538G mutations occurring in 114 patients (21.1%), Y537S mutations occurring in 72 patients (13.3%), and both mutations occurring in 30 patients (5.55%), according to Sarat Chandarlapaty, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, and his associates.
Frequency of ESR1 mutation did not differ by age, race, or site of metastatic disease. However, mutation prevalence was significantly associated with ECOG status (P = .04). Also, “there was a threefold increase in mutation prevalence in patients who had failed first-line therapy for metastatic disease (33% were mutant) compared with those who were initiating first-line treatment for MBC (11% were mutant), in whom exposure to AI therapy occurred only in the adjuvant setting,” the researchers wrote (JAMA Oncol. 2016 Aug 11. doi: 10.1001/jamaoncol.2016.1279).
Overall, patients with ESR1 mutations had shorter median overall survival times. Among patients with only D538G mutations, median overall survival was 25.99 months (95% CI, 19.19-32.36 months). Patients with only Y537S mutations had a median overall survival of 19.98 months (95% CI,13.01-29.31 months) whereas patients with neither mutation had an overall survival of 32.1 months (95% CI, 28.09-36.4 months). Patients carrying both mutations had an even further reduced median overall survival of 15.15 months (95% CI, 10.87-27.43).
Patients in BOLERO-2 had been randomized in a 2:1 ratio to receive either exemestane plus everolimus or exemestane plus placebo. For this secondary analysis, researchers found that patients who had received exemestane therapy and had the D538G mutation experienced a shorter median progression-free survival time (2.69 months; hazard ratio, 1.71; 95% CI, 1.09-2.68) compared with patients with no mutations who received exemestane therapy (3.94 months). Patients with no mutations who received everolimus had a median progression-free survival of 8.48 months, and patients with D538G mutations who received everolimus had a median progression-free survival of 5.78 months.
“One of the key findings of this work is the high prevalence of ER mutations in this patient population,” the investigators said.
The investigators also noted the ease, feasibility, and affordability with which cfDNA can be analyzed for these genetic mutations, and they believe the digital drop polymerase chain reaction assay used in this study could easily be implemented into regular clinical practice.
This study was funded by Novartis and supported by the Integrated Genomics Operation Core. Four of the investigators reported being employed by Novartis, and Dr. Chandarlapaty reported receiving financial compensation from AstraZeneca.
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