William Gradishar, MD, Robert H Lurie Comprehensive Cancer Center at Northwestern University, Chicago, Illinois, discusses how to optimize endocrine therapy for patients with hormone receptor-positive, early-stage breast cancer.

Of extended endocrine therapy, Dr Gradishar said, “It has to be a situation where there's shared decision-making, in the absence of clear data about how long you should go.”

Dr Gradishar will be presenting on this topic at the 2025 Miami Breast Cancer Conference.

Transcript:

Hello, I'm Bill Gradishar, professor of Medicine, and the Betsy Branson, professor of breast oncology at Northwestern University in the Robert H Lurie Comprehensive Cancer Center.

What is the current role of endocrine therapy for patients with early-stage breast cancer?

Since about two-thirds of all breast cancer patients have hormone receptor-positive disease, endocrine therapy, or anti-hormone therapy, plays a huge role in reducing the risk of recurrence for the vast majority of patients who are ever diagnosed with breast cancer. It is the general approach to anybody with early-stage disease that they would get a recommendation for anti-hormone therapy typically for a minimum of 5 years. And there may be variants in the drugs that are used, the sequence that is used, the duration beyond 5 years, as well as the incorporation of targeted therapy, all dependent upon risk.

What factors are considered when deciding whether a patient should receive extended endocrine therapy?

One of the features of, or behaviors of hormone-sensitive breast cancer is that it can recur late. And by that, I mean even with patients having small tumors that are node-negative, there's a small subset of them that even at 10 years and 15 and 20 years can develop metastatic disease as the volume of disease increases. In other words, as a patient develops either a bigger tumor when she's diagnosed and or there are positive lymph nodes or more of them, the probability that you can get a recurrence is increased. And with time, the fraction of patients at 10 and 15 and 20 years who will have the development of metastatic disease goes up. We look at the baseline risk at the time of diagnosis as one way of making some estimation about how we'll approach a given patient.

Are there any biomarkers or clinical tools that you can predict which patients are going to benefit from that extended therapy or benefit?

There are some tools that have come into play. There are clinical ones that I've already mentioned. Additionally, there molecular tools like the Breast Cancer Index, which looks at a couple of genes. And you can tease out whether or not a patient might have a delayed risk of recurrence until some later time point. And by extrapolating, those may be the patients where you consider longer durations of therapy because they're at risk seemingly for a late recurrence. And there are other tools that have been looked at in that same vein, biomarkers that may have a role similar to breast cancer index for trying to make that determination.

How is the optimal length of extended treatment determined?

Despite 25 to 30 years of clinical trials asking every permutation of question with sequence of anti-hormone therapy, duration, et cetera, the real answer is we're not sure. All that said, we think of a minimum of 5 years as baseline, what everyone should get if they can tolerate it. We know that there have been trials done all the way out to 15 years, but it doesn't appear that you're necessarily adding a great deal of additional risk reduction when you go much beyond 7 or 8 years based on clinical trial data.

Now with that said, if we had an individual patient who had an extraordinarily high risk, lots of nodes, big tumor, and they were tolerating the therapy well, there may be a situation where you would continue therapy acknowledging that you don't know how much added benefit there is. And the reason that you're doing that is because your concern for recurrence based on their volume of disease, again, is so high. The flip side is if you have that high-risk patient who you're torturing in a sense with side effects, you have to have a discussion about the reality that, you don't know for sure that additional therapy or duration of therapy is going to add benefit, but you already know that you're causing significant side effects. It has to be a situation where there's shared decision-making in the absence of clear data about how long you should go.

What are the potential long-term side effects to consider? Are there ways to manage or mitigate them?

All of the drugs we use, we always tell patients they're generally well tolerated. But the reality is, if you look the side effects up in whatever reference you want to look up, there's a million potential side effects. There's a handful that we make patients aware of. Obviously, with tamoxifen there's a low probability of blood clots, but they happen.

There's a low chance of endometrial cancer. But it happens. Patients can get hot flashes. For most it's a nuisance, but for some it can be very debilitating. With aromatase inhibitors, patients can get achiness in their joints, some can get hot flashes as well. You could also have worsening osteopenia over time, and the consequence of that could be an increased risk of fracture.

How do we mitigate those? The things that we can do as an example for hot flashes, and I should add that in many patients, some of these side effects, particularly hot flashes and so forth, diminish with time, but not in everyone. We have things that we can use, low dose antidepressants, they're not perfect, but they do diminish the frequency in severity. In some patients you can use acupuncture works in some, but not all decreases risk. For arthralgia, we don't have great things we can do other than encouraging, again, patients to be active. It seems to correlate with the reduced risk of developing severe achiness. The more active you are, the more exercise you do, the better you are. And acupuncture in some situations works for that as well.

There isn't a way of really mitigating the small risk of a blood clot or endometrial cancer other than telling a patient it's rare, if you experience abnormal bleeding when you should not be, then you should have it evaluated again, the idea of being active, moderating your weight, et cetera. All things that can hopefully reduce your risk of developing a blood clot are simple things — that sounds simple, but not always easy to do. But those are things that could further help reduce the risk.

What are the latest developments or upcoming research that could change this treatment paradigm for this population?

The most recent addition to our approach for patients at high risk is the addition of targeted therapy to anti-hormone therapy. The drugs I talked about remain foundational, tamoxifen and aromatase inhibitors, but for high-risk patients, there have been trials now that have demonstrated that the addition of CDK4/6 inhibitors, particularly ribociclib and abemaciclib, based on the NATALEE trial and the monarchE trial. Patients who fit the criteria of high risk for eligibility into those trials, we now have pretty long-term follow-up from that experience that suggests you can further reduce the risk of recurrence in appropriate patients who receive those drugs.

And I would also add that the complexity of the treatment goes up too, because now, you're not giving them chemotherapy, but you're adding a drug or a class of drug, CDK4/6 inhibitors, that have their own unique set of side effects, some causing more neutropenia, some more GI symptoms. You have to make patients aware of this, you have to have them on board. You have to tell them what their expectations should be and encourage them to contact you if they start to experience things that are making it difficult for them to continue because there are ways of reducing the dose. Or as an example, if patients were having significant GI symptoms, you could not only reduce the dose, but in some patients, they need antidiarrheals. That may help keep the patient adherent to the plan.

The duration of CDK4/6 inhibitors is not as long as the endocrine therapy. It's often front loaded in the first part of the adjuvant endocrine therapy for a couple of years, 2 years for abemaciclib, 3 years for ribociclib, at least according to the trials. The anti-hormone therapy itself will continue beyond that, but you have to get the patients through that first part so they reap the benefits of the addition of that medication.

Where do you see SERDs or SERMs fitting in?

There’s a whole, in a sense, word salad of drugs that are in development. Some of them are already approved in the metastatic disease setting. One example being elecestrant, that's a drug that seems to work particularly in patients who have ESR mutations. We heard data with another one, imlunestrant recently, again, in the metastatic disease setting, it's shown activity. And we anticipate that these drugs will find their way into the adjuvant setting. And we've heard data with others that look very encouraging.

What I'm expecting in the next few years is not only will we have a variety of options for patients with advanced disease that are above and beyond what we currently have, we'll be using NGS testing or circulating tumor DNA to understand how the disease is evolving over time in the advanced setting. But we may also use those same tools in the adjuvant setting if mutations start arising, it may lead us to change the therapy even in the absence of clear evidence of metastatic disease so that we can, in a sense, address that clone of cells that is developing a mutation and may become resistant to their current treatment. I think what we're going to see in the next handful of years is not only the approval of those drugs in advanced disease, but the introduction and use of them in the earlier stages of disease as well.

How do you personally manage patients in this population, with regards to extended endocrine therapy?

Well, if we're all honest with ourselves, if somebody gives us a 2-week prescription for antibiotics for something, we start feeling better after 7 to 10 days. and then what happens? You sort of, well, maybe I'll take 1 or maybe I won't take the rest of. That's in contrast to people who you're asking to do something the same thing every day for 5 years, 7 years, 10 years. I think one of the things that you have to implore and impact on patients is that you don't get the benefit unless you take the drug. If you are not i adherent to the plan, it's been shown for many, many years that you don't reap the risk reduction in terms of recurrence and survival that comes with optimal durations of therapy. I think it's incumbent upon the physicians, the nurses, whoever interacts with the patient, to spend a moment just reemphasizing that every time we see patients.

And the other thing that happens is as patients get farther out in follow-up, the frequency with which we see patients, it lengthens, or I should say the interval lengthens. We're not seeing patients every month, not every 2 months. It may be 4 to 6 months. And there's a lot of opportunity to become lackadaisical or noncompliant. I think we just have to spend a moment every time we see a patient just to drive home the point that it's really important that you stay on the medication and if they are indeed experiencing side effects, identify the things that we might be able to alter change or adjust so that they will be compliant.