Dr. Chandarlapaty and colleagues detected the D538G mutation in 15.3% of patients, the Y537S mutation in 7.8%, and both in 5.5% patients, for an overall prevalence of 28.8%.
In a subset of cases having both cell-free DNA and archival tumor tissue, the proportion of cases having these mutations was much higher in the former (28.4% vs. 1.3%).
Subgroup analyses showed mutations were more common for patients who had received prior aromatase therapy in the metastatic setting versus only in the adjuvant setting (P for difference less than .001).
In the study sample as a whole, median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both. Compared with patients having neither mutation, patients having either or both had an increased risk of death (hazard ratio, 1.40), as did those having the D538G mutation (1.25), the Y537S mutation (2.31), and both (1.77).
Additionally, exploratory analyses showed that adding everolimus to exemestane more than doubled median progression-free survival for patients with neither mutation (8.5 vs. 3.9 months; hazard ratio, 0.40) and for those with a D538G mutation (5.8 vs. 2.7 months; hazard ratio, 0.34). In contrast and unexpectedly, adding this drug did not improve the outcome for patients with a Y537S mutation.
Numbers of patients in the Y537S group were small, and a clear explanation for lack of benefit in that group is lacking, Dr. Chandarlapaty cautioned. “But it does tell us the biology, and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we are developing going forward,” he said.