Ruth O’Regan, MD
Researchers are merely cracking the surface of therapeutic regimens fit for patients with estrogen receptor (ER)-positive or HER2-positive breast cancers, as great work lies ahead in immunotherapy, biomarker identification, and the optimal use of CDK 4/6 inhibition.
“We have seen a huge, rapid approval of agents in the past few years, so it is kind of interesting,” said Ruth O’Regan, MD, a professor of medicine at University of Wisconsin School of Medicine and Carbone Cancer Center. “Up until about 3 years ago, we just had endocrine therapy, which of course is still very important, but now over the past few years, we have a number of targeted agents that all appear to enhance the efficacy of endocrine therapy.”
While CDK 4/6 inhibitors have taken the arena of ER-positive breast cancers by storm, immunotherapy is under investigation in HER2-positive disease, O’Regan adds, explaining that a subset of these patients may elicit responses to that treatment. However, the tried-and-true regimens with HER2-directed therapy remain solid standards, at least in the first- and second-line settings.
In an interview during the 2017 OncLive®
State of the Science Summit on Metastatic Breast Cancer, O’Regan, who also chaired the event, provided insight on the evolving landscapes of ER-positive and HER2-positive breast cancers, and what regimens remain solid approaches for effective patient outcomes.
OncLive: You had a couple of lectures at tonight’s meeting. What did you highlight in the discussion on ER-positive breast cancer?
Regarding endocrine therapy, 1 of the things that has come out in the last year or so is the data with fulvestrant versus anastrozole in the first-line setting. The data from the phase III randomized FALCON trial did show an improved outcome for patients who got fulvestrant at the 500-mg dosing schedule compared with anastrozole. However, the data results were not as profound as seen in the first randomized phase II study, so we will wait for more data from that study. There were data basically showing that, in patients who did not have visceral metastases, they did have quite a considerable improved outcome [with fulvestrant] versus anastrozole. I am not sure that every patient needs this in the first-line setting but, in the absence of a biomarker telling us whether a patient needs 1 or not, most of us lean toward giving those drugs to patients.
Then, we have the CDK 4/6 inhibitors, which are exciting. We had palbociclib (Ibrance) for several years approved in the frontline setting for hormone-refractory patients. Then, most recently, we got approval of ribociclib (Kisqali) in the first-line setting, as well. As far as those 2 agents go, they appear somewhat similar. There are some slightly different toxicities, but as we start using ribociclib, we will be able to work out how to use it in the real world for patients.
The third CDK 4/6 inhibitor, abemaciclib, has data as a single agent in patients who have heavily pretreated ER-positive metastatic breast cancer. It looks like a very interesting drug with a different toxicity profile, and it can be given continuously. It is clearly different from the other 2 CDK 4/6 inhibitors.
The other area of discussion is inhibiting the PI3K/mTOR pathway in patients with hormone-refractory metastatic breast cancer. Obviously, we have had everolimus (Afinitor) for a number of years. There are recent data of combining everolimus with fulvestrant that looks feasible and encouraging, so we now have an option of giving it with fulvestrant as well with exemestane and tamoxifen. There are some data looking at targeting the PI3K pathway with a pan-PI3K inhibitor in hormone-refractory metastatic breast cancer that showed some signal of activity but, unfortunately, the drug that was used—buparlisib—is quite toxic, so the future development of that drug in this area is probably going to be abandoned.
We are always talking about resistance mechanisms. One that has emerged recently that is very important is ESR1
mutations. They can be detected either in primary tissue or in cell-free DNA. They do appear to be very important because they appear to predict for resistance to aromatase inhibitors, specifically.