SAN ANTONIO – Women with estrogen receptor–positive advanced breast cancer who have common mutations of the estrogen receptor 1 (ESR1) gene detectable in plasma cell–free DNA have poorer overall survival, according to data presented at the San Antonio Breast Cancer Symposium.
Investigators led by Dr. Sarat Chandarlapaty, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, analyzed archival baseline plasma samples from 541 patients enrolled in the BOLERO-2 trial, which evaluated addition of everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin). They specifically looked for the D538G and Y537S mutations of the ESR1 gene, the two most commonly seen mutations in this setting and ones that lead to activation of the receptor even in the absence of estrogen.
Overall, nearly 29% of the women had either or both mutations, he reported in a session and related press briefing. “We think that is almost certainly an underestimate of the mutation rate, because there will be some other mutations … that we didn’t assay for here,” he commented. Of note, this prevalence using plasma was sharply higher than that found when analysis was instead performed on archival tumor tissue.
Patients with these ESR1 mutations had a 40% higher risk of death than counterparts who did not have them. And those with the D538G mutation (but not those with the Y537S mutation) had better progression-free survival if they were given everolimus.
“Patients with different mutations might end up having different responses to therapies in the future, and I think that’s what we are looking for in future research,” Dr. Chandarlapaty commented.
Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos L. Arteaga, a professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Breast Cancer Program, noted the high rate of discordance in mutation prevalence between the tumor tissue and the plasma. “Can you speculate about the reasons for that discordance?” he asked.
There are three possible explanations, Dr. Chandarlapaty replied. The archival tumor was often the primary tumor, whereas plasma samples were collected in the metastatic setting. Also, the tumor tissue was often obtained before any aromatase inhibitor therapy, which precipitates a low-estrogen environment that may promote emergence of resistance mutations. Finally, mutations detected in plasma likely reflect a summation of all mutations in the body in different sites. “I think for all these reasons, plasma may have certain advantages, especially for this alteration,” he said.
In the session, attendee Dr. Daniel F. Hayes of the University of Michigan Health System in Ann Arbor wondered whether the plasma samples were treated in any special way before the mutational testing.
“This trial started before we recognized the importance of plasma tumor DNA, so I’m pretty certain these samples were not handled in a way that we all believe they should be. The reason I’m asking this question is that if you did something special, the rest of us would love to know what it is because we are all sitting on samples like this that I’ve been told are worthless, but maybe I’m wrong,” he elaborated.
The plasma samples were collected in a routine manner, without any consideration of future genomic analysis and mutational testing, according to Dr. Chandarlapaty. “These were collected as a regular spin … and frozen at –70 [degrees],” he said. And they were stored that way, in some cases for many years, at various global sites. The investigators simply performed an additional hard spin before analyzing the samples. “So I think it does tell us that some of these archival samples that we have in our freezers may be usable for this type of analysis,” he said.
Attendee Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston said, “So on Monday morning, people can’t go home and order circulating tumor DNA in most centers. What studies need to be done and how long do you think it will be before this is something we should consider?”
Efforts are under way to try to rapidly make these assays available in the clinic, according to Dr. Chandarlapaty. “Actually, there are some that are not in the CLIA lab but sort of are available by different vendors,” he said. Additional studies still needed include validation of the observed findings in other cohorts, among others.
BOLERO-2 tested addition of the mTOR inhibitor everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin) in postmenopausal women with metastatic or locally advanced estrogen receptor–positive, HER2-negative breast cancer that had progressed despite treatment with other aromatase inhibitors.