Combinations, Proper Sequencing Needed for Optimal HR+ Breast Cancer Treatment

William J. Gradishar, MD

Physicians and researchers should turn their focus to what occurs in patients with hormone receptor (HR)-positive breast cancer before and after they develop resistance to therapies. This will optimize the treatment of these patients, explains William J. Gradishar, MD, and he suggests combining and sequencing anti-hormonal therapies with novel targeted agents—including PI3K inhibitors and CDK 4/6 inhibitors.

Gradishar, deputy director of the Lurie Cancer Center Clinical Network and director of the Lurie Cancer Center’s Maggie Daley Center for Women's Cancer Care in Prentice Women's Hospital, addressed this issue in a presentation during the Lynn Sage Breast Cancer Symposium, which was hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

OncLive: Could you provide a brief preview of your talk?

In an interview with OncLive, Gradishar summarized the need for new strategies to alter the landscape of HR-positive breast cancer for the better, and how these methods can overcome drug resistance and delay disease progression.Gradishar: The talk I'm giving Friday is focusing on HR-positive breast cancer and the strategies that have been employed to enhance the effect of standard anti-hormonal therapy and the strategies to overcome resistance that develops.

This has taken us into the realm of combining endocrine therapies with targeted therapies: mTOR inhibitors, such as everolimus (Afinitor), and CDK 4/6 inhibitors such as palbociclib (Ibrance) and others that are in development.

Additionally, there has been a lot of work and interest in looking at PI3K inhibitors because that pathway is amplified and mutated in patients with estrogen receptor (ER)-positive breast cancer. The strategy would be to look at a combination of anti-hormonal therapy and a PI3K inhibitor and see if that improves response and translates into a better overall outcome. We are also evaluating drugs that affect epigenetic phenomena using HDAC inhibitors, such as entinostat.

What are the challenges associated with treating patients after disease progression?

To date, we know that adding an anti-hormonal therapy adds time to when the disease progresses. We're hopeful that as we go forward some of these other drugs may have the same effect. Some of these drugs are being investigated in early-stage breast cancer to see if similar strategies might translate into a better overall outcome.It's inevitable that patients with metastatic disease will develop progressive disease. All of the therapies we have—even beyond anti-hormonal therapy—despite good responses, the disease figures out a way of working around the treatment. There are a number of reasons why that may occur: the tumor can evolve, mutations can develop, bypass pathways can become more dominant, and subclones of tumor cells may be more responsive to one therapy versus another. This speaks to the issue of having more strategies when progression happens.

Does this mean that you want to have more effective therapies before resistance develops?

The hope would be that by having other agents that can be combined with anti-hormonal therapies, that you may be able to suppress or delay those resistances. The ultimate goal with anti-hormonal therapy is to continue it as long as possible because compared with chemotherapy, it's much better tolerated.Yes. As an example, if you combine palbociclib with an anti-hormonal agent like an aromatase inhibitor, the time until the disease progresses is significantly longer—by about 10 months—compared with those who just get the anti-hormonal therapy. That's before there are these resistance mechanisms are developing.

You mentioned CDK 4/6 inhibitors, PI3K inhibitors, and HDAC inhibitors. Is toxicity a big concern with combining these agents?

We have data that show us when patients have been exposed to other agents, we can still further delay time to progression. We can achieve an initial enhancement or one that happens when a patient has been exposed to more than one other anticancer therapy.Toxicity is a concern because anti-hormonal therapy alone is pretty well-tolerated. I'm not suggesting that by combining an anti-hormonal agent with something else that you'd make it prohibitively toxic, but you do change some expectations. For instance, palbociclib added to an anti-hormonal therapy is going to cause neutropenia, which is not typical of anti-hormonal therapy by itself. Clinically, it won't be a significant, but you have to check them. Everolimus can cause mouth sores. These wouldn't be typical of what we'd see with just anti-hormonal therapy.

What about sequencing these agents?

With this change in toxicity, you want to be sure that the upside is much, much bigger—how responsive the tumor is and how long until the disease progresses—to make those side effects worthwhile.The questions that are still unanswered are: What do you do when a patient who has had a CDK 4/6 inhibitor, will they respond to an alternative CDK 4/6 inhibitor? We don't know the answer to this. Will they benefit if you stay with the CDK 4/6 inhibitor and switch anti-hormonal therapies? We don't know the answer to this either.

We don't have a lot of data regarding changing the class of targeted therapy either. Right now, the only two approved drugs in this setting are palbociclib and everolimus, but there are dozens being evaluated.

A good problem we may have is that if these drugs prove to be effective, how do we optimally use them? That's where the questions about sequencing come in.

Based on what we've talked about today, what do you hope treatment looks like for HR-positive disease in the coming years?

There's an obvious other piece of this. We've talked about efficacy and toxicity, but there's also an increase in the expense that goes with adding targeted therapies to standard anti-hormonal therapies. A combination in this space could cost $10,000 or $20,000 per month. That would be the cost to the system.Though we freely toss around the term “precision medicine,” we're still practicing relatively crude medicine. The promise of precision medicine is that we'll identify specific signatures in an individual patient at a specific point in time to help dictate the therapy we think is best for them. Rather than checking drugs we've tried off of a list, we hope to have an objective reason to choose any drug for a given patient. With new assays, we can order these treatments but we need to show that they’re making a difference in patient outcomes.