SAN ANTONIO — ESR1 mutations occurred frequently in the cell-free DNA of women with ER-positive breast cancer and appeared associated with shorter OS, according to an analysis of data from the BOLERO-2 trial presented at the San Antonio Breast Cancer Symposium.
Further, women who harbored the ESR1 D538G mutation benefited from everolimus (Afinitor, Novartis), whereas women with the ESR1 Y537S mutation did not.
Sarat Chandarlapaty, MD, PhD, a breast medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues have identified mutations in the estrogen receptor in women with advanced breast cancer, especially those who have been exposed to aromatase inhibitors.
“These mutations make the receptor no longer need estrogen — the breast cancer seems to become estrogen independent and cells can grow despite the absence of estrogen,” Chandarlapaty said during a press conference. “That led us to two major questions as we were thinking about this for the clinic: How often do we see these constituently actively estrogen receptor mutations in patients, and how do patients fare who have these mutations present?”
To explore these questions, Chandarlapaty and colleagues evaluated data from 541 women enrolled on the BOLERO-2 trial (74.7% of study population) because women in that trial had ER-positive metastatic disease, were treated with an aromatase inhibitor and had available plasma samples.
Researchers evaluated patients’ plasma, which had been collected at the time of study entry, using QIAamp Circulating DNA kit (Qiagen) or QIAsymphony DSP Virus/Pathogen kit (Qiagen).
Overall, 156 (28.8%) of the women harbored an ESR1 mutation in D538G (21.1%) and/or Y537S (13.3%). Thirty women harbored both types of ESR1 mutations.
Chandarlapaty and colleagues then compared these findings with the presence of ESR1 mutations in 302 archived tumor biopsies — 244 from primary tumors and 57 from metastases — from the cohort. Results showed only four (1.3%) samples had detectable ESR1 D538G and one (0.3%) had ESR1 Y5375.
There are three reasons why ESR1 mutations may be more common in plasma than tumor biopsies, Chandarlapaty said.
“The archival tumor is often the primary breast cancer, and we’ve already observed that with metastases, there is more frequent identification of mutations,” he said. “By virtue of the study, we’re only looking at the time they had metastatic disease when we’re looking at the plasma.”
Further, primary tumors often were collected prior to aromatase inhibitor exposure.
“So, there is a selection over time for these active mutants when you give them a drug,” Chandarlapaty said. “After they’ve been exposed to the drug, there is a higher incidence of the mutation.
“Third, when we evaluate plasma, we are looking at the summation of metastatic breast cancer, not just at one particular lesion that we biopsied, but perhaps many different lesions,” he added.
When researchers evaluated outcomes, median survival appeared shorter among women who harbored the ESR1 D538G mutation (26 months; HR = 1.25; 95% CI, 1.02-1.54), Y537S mutation (20 months; HR = 2.31; 95% CI, 1.34-3.97) or both (15.2 months; HR = 1.77; 95% CI, 1.31-2.39) compared with patients with wild-type ESR1 (32.1 months).
Researchers then assessed how these mutations affected outcomes with the addition of everolimus to exemestane on the BOLERO-2 trial.
Everolimus appeared to prolong median PFS among wild-type patients (8.5 months vs. 3.9 months; HR = 0.4; 95% CI, 0.31-0.51) and patients with the ESR1 D538G mutation (5.8 months vs. 2.7 months; HR = 0.34; 95% CI, 0.2-0.57). However, patients with the ESR1 Y537S mutation did not derive benefit from everolimus (4.2 months vs. 4.1 months; HR = 0.98; 95% CI, 0.49-1.94).
“This was a small group of patients in the Y537S group,” Chandarlapaty said. “We wouldn’t today say, ‘Don’t go out and give [everolimus],’ based on this result. But it does tell us the biology, and what we need to do moving forward in the clinic is look at these mutations, not just as a whole, but individually, and ask how they impact therapies that we are developing.” – by Alexandra Todak
Chandarlapaty S, et al. Abstract S2-07. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.
Disclosure: Chandarlapaty reports grant support from Novartis and consulting fees from Chugai, Foresite and Oncothyreon.