William J. Gradishar, MD, spoke with the Journal of Clinical Pathways at the National Comprehensive Cancer Network (NCCN) Annual Conference regarding the latest advancements in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer.

Please introduce yourself by stating your name, title, organization, and relevant professional experience.

I’m Bill Gradishar, Northwestern University professor of medicine and chair of the National Comprehensive Cancer Network (NCCN) Breast Cancer Panel.

Can you outline the most significant recent advancements in the treatment of hormone receptor-postive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer, and how these developments differ from previous standards of care?

The changes that we've made recently are reflective of advances in how we think about both advanced disease as well as early-stage breast cancer. Starting with the last first, in early-stage breast cancer, we've used antihormonal therapy as a monotherapy, meaning alone, for five to 10 years. And those include drugs like tamoxifen and aromatase inhibitors. And more recently, we have seen the effectiveness of what we call CD4/6 inhibitors in the advanced disease setting.

But the question became whether or not adding those drugs to antihormonal therapy in an earlier stage of disease might further decrease the risk of recurrence. There have been a series of trials that have been done over the last five to seven years that explored that question. We have three CD4/6 inhibitors available that we widely use in metastatic disease, but the question is whether or not they are all equally effective. And what the trials have demonstrated—at least to date—is that they are not.

There is an approved drug in the form of abemaciclib that when added to antihormone therapy, it further decreases the risk of recurrence compared to antihormonal therapy alone. Patients are selected for this treatment based on clinical characteristics that suggest they may have a higher risk of recurrence and positive nodes. Biologic features that indicate a higher risk of recurrence would also make them eligible.

The other drug that is showing effectiveness based on the  NATALEE trial is ribociclib. As I mentioned, based on the monarchE trial with the abemaciclib, the US Food and Drug Administration (FDA) has approved abemaciclib in this setting. With respect to ribociclib, the data is still a little bit early, but the presentations to date are showing a similar effectiveness of ribociclib in a comparable population, but also including some patients who are node negative. Unfortunately, the data in the early stage setting with palbociclib has not demonstrated an effect that's favorable. So right now, we are anticipating that, of course we have abemaciclib available, but we probably will have both ribociclib and abemaciclib available at some point.

The second area in early-stage disease that has affected outcome is in young women who had ovarian suppression. We've known for decades that ovarian suppression, or oophorectomy, is an effective therapy to decrease the risk of recurrence. That was demonstrated in large data sets. The questions then becomes is that additive to other therapies that we give to patients in early-stage disease.

With the introduction of molecular tests, we can define patients with ER+ breast cancer who may be able to avoid chemotherapy because the risk is low enough to not need chemotherapy. But there is a gray area where ovarian suppression or oophorectomy may have a similar effect to chemotherapy.

The OFSET trial will compare ovarian suppression along with antihormone therapy to chemotherapy plus ovarian suppression plus antihormone therapy. The purpose is to define whether or not chemotherapy can be avoided in certain subsets of patients and achieve the same outcome.

How do these updates influence the selection of treatment modalities for patients with different stages of HR+, HER2– breast cancer?

In patients with advanced disease—metastatic disease with HR+ or HER2– disease—the starting point is generally antihormone therapy. The antihormone therapy is effective and much better tolerated as a general statement than chemotherapy.

In patients with ER+ disease, we try to continue antihormone therapy for as long as possible before transitioning to chemotherapy. What's changed in the last decade with respect to strategies with antihormone therapy is rather than giving it as a single agent or monotherapy, we now partner it frequently with other targeted therapies.

Earlier I mentioned that CDK4/6 inhibitors are being explored in the adjuvant early-stage setting, but they were demonstrated to be highly effective in the metastatic disease setting. There are three drugs— ribociclib, abemaciclib, and palbociclib—that have all demonstrated significant activity prolonging the time until disease progresses. Two of the drugs, ribociclib in particular and abemaciclib, have shown a survival benefit when they are combined with antihormone therapy. 

Other trials in the last couple of years have pushed aside the notion that chemotherapy is more effective because they have compared chemotherapy to a combination of antihormone therapy with a CD4/6 inhibitor in women with ER+ disease and in particular young women. It has been demonstrated that the combination of antihormone therapy with the targeted therapy is at least as effective as chemotherapy if not more so. The general old school notion that chemotherapy is more effective is probably not valid and there are patients where antihormone therapy could be used.

The other broad area where changes and advances have been made in the last five years (as demonstrated recently by additions to the NCCN guidelines) is how we look for mutational changes in the tumor, either through tissue or circulating tumor DNA, and that may guide our therapy. For instance, we now know that about 40% of patients harbor PI3 kinase mutations, and there are a variety of drugs available that can be partnered with antihormone therapy that improves the effectiveness of antihormone therapy. If a patient doesn’t have a PI3 kinase mutation, these drugs will not add anything, but in that specific subset, there are drugs like alpelisib and more recently capivasertib, and both of those drugs are FDA approved and in the NCCN guidelines. And there was a third that was presented at San Antonio, Texas, in December, which we anticipate at some point will be approved.

All of these drugs, when combined with antihormone therapy, additionally reduce the risk of disease progression. They have unique side effects, oftentimes a rash or elevations of glucose, so patients must be aware of the side effects. But in terms of benefiting patients, they have prolonged the time until disease progression.

If patients are treated with antihormone therapy over time, they are also inclined to develop what we call an estrogen receptor (ESR) mutation, which makes them more resistant to different kinds of antihormone therapy. How to overcome that has been a challenge.

There is an approved drug, elacestrant, that specifically targets tumors that harbor these ESR mutations. The drug is now approved as a monotherapy and will be further developed to be combined with CDK4/6 inhibitors, PI3 kinase inhibitors, etc.

We also have in a whole long list of oral selective estrogen receptor degraders (SERDs), which are oral antihormonal therapies that are in development but not yet approved. In the next couple of years we're going to see additional drugs in the antihormonal therapy armamentarium that will be available for patients.

With the emergence of new therapeutic options, how do you anticipate these updates will impact the overall survival rates and quality of life for patients with HR+, HER2– breast cancer?

Our hope for early-stage disease, particularly in high-risk women, is that using the targeted therapies in combination with antihormone therapy will reduce the number of patients that recur, and then by extension, those patients will be cured and they won't have a problem in the future. Whereas, if those drugs were not available, some of those high-risk patients may recur and develop metastatic disease and ultimately succumb to it.

In the metastatic disease setting, increasing the number of options that we have for patients is important because it may not cure the disease, but it may increase the duration of time a patient is on a particular therapy and by extension, it delays the time until chemotherapy. And with that, you have higher quality of life in many cases. Our hope is to ultimately use these drugs in sequence, meaning we will have more options to offer patients, that we will increase and improve survival. We have not demonstrated that yet, but I think it is a very reachable goal.

CDK4/6 inhibitors drugs in combination with antihormone therapy, at least a couple of the drugs, have demonstrated a survival benefit from data that has been presented over the last five years. So, even if we're not curing patients, extending their survival, improving their quality of life, and avoiding chemotherapy are all important goals.

Are there any promising avenues for further research or potential breakthroughs on the horizon?

In this space, there's a lot of work being done on additional drugs. As I mentioned, there are a variety of drugs in development, including this broad class of oral SERDs. And these are drugs that are successors to fulvestrant—a shot given once a month—but you can take it orally. Some of these drugs appear to have an effect against ESR mutations.

My hope is that these treatments will prove to be effective and perhaps enhance the time until disease progression. We're also looking at a variety of other strategies of antibody drug conjugates for patients who have exhausted their options that can be used effectively in these patients. Drugs like trastuzumab deruxtecan or sacituzumab govitecan as well as others are in development. Even when we're past the stage in ER+ patients where we don't have antihormonal therapy to offer them, we will have novel drugs that hopefully will be better tolerated and more effective than standard chemotherapy.