Interest in treatment with novel combinations of targeted agents and hormonal therapies in hormone receptor-positive breast cancer caused the establishment of several unique clinical trials, including BOLERO-2, suggests moderator Adam M. Brufsky, MD, PhD.

Initially, some researchers did not believe the combination of an mTOR inhibitor and hormonal therapy would prove to be effective. This skepticism was partially based on earlier research into the mTOR inhibitor temsirolimus, which did not demonstrate efficacy in this space, Brufsky suggests. However, since this initial setback, the treatment paradigm changed to include more exposure to aromatase inhibitors (AIs) and longer durations of treatment with hormonal therapies, explains Hope S. Rugo, MD. Also, the mTOR inhibitor dose in initial trials may not have been correct, based on levels of stomatitis, a common side effect of mTOR inhibition.

Initially, research into the mTOR inhibitor everolimus was undertaken in the neoadjuvant setting, looking for a potential biomarker, explains Rugo. In this trial, a great deal of information was uncovered about treatment with everolimus, including the occurrence of interstitial pneumonitis and other side effects. Additionally, the trial demonstrated a slight clinical benefit and a significant drop in Ki67.

The rationale to explore mTOR inhibition in the metastatic setting stemmed from information on the PI3K pathway and the increased mutational burden in advanced disease. The phase III BOLERO-2 trial was undertaken to explore this rationale further. In the trial, patients were randomized 2:1 to receive exemestane plus everolimus or exemestane and placebo. Most patients enrolled were chemotherapy naive and a large amount had visceral disease, which generally indicates the need for treatment with chemotherapy, Rugo notes.

In the trial, there was a large difference in progression-free survival favoring treatment with everolimus. Interestingly, Rugo explains, the progression free survival benefit was less pronounced by local assessment than by independent central evaluation, which is not generally the case.

Examining the toxicity profile, the main concern that has been raised was the occurrence of stomatitis. In general, Rugo notes, grade 3 stomatitis occurred in 8% of patients. However, Joyce A. O'Shaughnessy, MD, recommends the utilization of a steroid mouthwash as a preventive option. This approach seems to be largely effective in most patients, Rugo and O'Shaughnessy agree.