What Advanced Practitioners Need to Know About CDK4/6 Inhibitors in HR+/HER2– Breast Cancer: Optimizing Benefit and Minimizing Toxicity

Chapter 1: Early-Stage Breast Cancer

Last Updated: Friday, March 31, 2023

Mikel Ross, MSN, RN, NP-BC, OCN, CBCN, Deborah L. Toppmeyer, MD, and Sarah Donahue, MPH, NP, AOCNP, discuss how CDK4/6 inhibitors can be best put to their clinical utility in patients with early stage breast cancer. The faculty discuss data from clinical trials, considerations for clinical decision-making, and walk through a case study of a 30-year-old female with multifocal left breast cancer that is ER/PR+ and HER2–negative.



Mikel Ross, MSN, RN, NP-BC, OCN, CBCN

Breast Medicine Service, Memorial Sloan Kettering Cancer Center


Deborah L. Toppmeyer, MD

Stacy Goldstein Breast Cancer Center, Rutgers Cancer Institute of New Jersey

Sarah Donahue, MPH, NP, AOCNP

Carol Franc Buck Breast Cancer Center, University of California, San Francisco


Mikel Ross:

Welcome to this roundtable discussion about the management and utilization of CDK4/6 inhibitors in hormone-sensitive, HER2-negative breast cancer. This is a case-based approach. My name is Mikel Ross. I'm a nurse practitioner at Memorial Sloan Kettering Cancer Center and support the breast medicine service, and I am absolutely thrilled to have with me two colleagues.

First of all, just down the road in New Jersey, Dr. Deborah Toppmeyer. She is a professor of medicine at the Robert Wood Johnson School of Medicine. She's the chief medical officer, chief of the division of medical oncology, director of the Stacy Goldstein Breast Cancer Center at the Rutgers Cancer Institute in New Jersey at Rutgers, the state university of New Jersey. Then skipping all the way across a couple of sets of mountains, Sarah Donahue. She has a master's of public health. She's a nurse practitioner at the Carol Franc Buck Breast Cancer Center, part of the Helen Diller Family Comprehensive Cancer Center at the University of California in San Francisco.

As we go through this first section, we're going to be talking a little bit how about how these agents, CDK4/6 inhibitors, can be utilized and optimized and best put to their clinical utility in the early stage breast cancer patient. Sarah, would you please start us off by walking us through the data that will inform our decision making and clinical recommendations?

Sarah Donahue:

Thank you. Happy to do this. Thank you so much for inviting me. For our early stage breast cancer patients, about 280,000 patients are diagnosed every year with breast cancer. About 200,000 of those, so the larger proportion of those patients will be hormone-positive. Six percent of patients present with de novo metastatic breast cancer and about 180,000 patients are treated with adjuvant endocrine therapy every year.

How do we determine if a patient is at high risk for recurrence of their breast cancer? This is a patient that's gone through treatment for their early stage breast cancer and now you're trying to figure out what the risk of it coming back would be. We use all sorts of things to sort that out. One is their staging, so the size of their tumor, whether or not they have nodes involved. We can look at the grade of the tumor, grade one through 3. We can look at the receptor status. Are they hormone-positive, HER-2 negative? Are they a hormone-positive, HER-2 positive? Things like that. We can also look at the age at which they were diagnosed. Are they young or are they postmenopausal? Then finally we can look at things like Oncotype or PAM50 or MammaPrint and we can determine based on that whether or not the patient will be more likely to recur.

Now more recently we have something called the BCI, which can also tell you even more information about whether or not a patient... what their likelihood recurrence would be after the first 5 years. What we know, just looking at one of those factors that I just discussed, that the number of nodes positive can determine a patient's risk for recurrence. If you look at this graph here, these patients with 4 to 9 nodes positive have a higher rate of recurrence than a patient that has no nodes positive.

There've been several trials to look at medications to add to endocrine therapy for patients with hormone positive breast cancer. These trials are looking at CDK4/6 inhibitors and they're highlighted here in this table. They all enrolled patients that were at higher risk of recurrence, but there was a little difference in the different studies and the amount of risk that the patients had. In the PALLAS trial that looked at palbociclib with endocrine therapy, patients were allowed on trial if they were stage 2 or 3. They could have T2 tumors, meaning 2 to 5 centimeters or more than 5 centimeters, and they could be node negative. They did not have to be node positive. In that trial patients were given palbociclib for 2 years.

In the monarchE trial that looked at abemaciclib with endocrine therapy, they enrolled patients that had to have at least 1 node positive. Then they had 2 groups. They had a group with high clinical features, so patients with more than 4 nodes positive or patients with 1 to 3 nodes positive but then they also had to have tumors that were larger than 5 centimeters or have a grade 3 tumor. Then they had another group, another cohort that was enrolled, and those patients could have 1 to 3 nodes positive as well, but they couldn't be grade 3 or have a tumor greater than 5 centimeters, but they did have to have a Ki-67 of greater than 20%. In general, a very high-risk population enrolled in monarchE. They were given abemaciclib for 2 years.

In the NATALEE trial, which looked at ribociclib, a little bit less high risk than monarchE, but more high risk than PALLAS. Those patients, they could be node negative, but if they were node negative, they had to have a grade 2 or 3 tumor and they had to have a Ki-67 of greater than or equal to 20%. Same if they had 1 to 3 nodes positive. However, if they had 4 or more nodes positive, they did not have to have any other risk factors like Ki-67 or grade that was above 2. Those patients were given ribociclib for 3 years.

The NATALEE trial, the last one that I spoke to with ribociclib, it's still gathering data and we don't have results from that quite yet. The PALLAS trial has resulted. We have 48 months of data represented here in this graph, and it shows that those patients that received palbociclib for 2 years did not do better than those patients that did not. Everybody got endocrine therapy, but adding the palbociclib did not help. In the monarchE trial shown here, we see that those patients that received abemaciclib for 2 years did do better as far as invasive disease-free survival went. They also did better with distant relapse-free survival.

Now we have 1 medication, one CDK4/6 inhibitor that is approved in the adjuvant setting for hormone-positive, HER-2 negative breast cancer patients, and that is the abemaciclib. That approval did come out last year and there were some caveats to it, but now it is approved for anybody that had similar features as was enrolled in that trial, the monarchE.

Mikel Ross:

That's great. Sarah, thank you for walking us through the trial, and as you walked us through that, the thing that always strikes me in terms of the recurrence data that shows us regardless of nodal status that for our hormone-sensitive, HER-2 negative breast cancer patients, that risk of recurrence really truly never goes away. It's so exciting that a CDK4/6 inhibitor, so far abemaciclib being the only one that's approved, gives us the opportunity to do better, to change those curves and actually decrease recurrence. Dr. Toppmeyer, we've not had this indication very long. We often think things are into the clinic within a week, but we don't know that that's the case. From where you sit and also consults that you receive within the area, to what extent do you find this indication adopted in practice?

Dr. Deborah Toppmeyer:

I think as we become more comfortable with the agent, we're using it more frequently. I think those centers that participated in the clinical trials were more comfortable with some of the unique side effects of abemaciclib, which were primarily GI side effects. There was about an 81% incidence of diarrhea and less neutropenia than the other agents. I think that dosing patients appropriately, really working with your nurse practitioner to guide them in terms of side effects, being very, very proactive about the use of Imodium, calling, stopping the drug if they're having significant side effects, really allows us to manage this.

Frequently for patients that I'm a bit more worried about, I may start at a slightly lower dose and then escalate that dose, but I think as we've all become more comfortable with the agent when it is indicated, and as Sarah mentioned, that the Ki-67 requirement greater than 20% was recently removed by the FDA. I think that it's an important agent. I think we need to see what's going to happen long term in terms of overall survival advantage, but I think that it is appropriate to use this agent in those patients that meet the criteria.

Mikel Ross:

Absolutely. On one hand we want to make sure that everyone that's eligible and that we think is at high risk gets the opportunity to benefit from these agents, but at the same time, there are some that don't meet that criteria. Have either of you had someone who doesn't quite meet that criteria or who may be well into their endocrine therapy, ask about, hey, what about me? What does that sound like?

Sarah Donahue:

I have that question often. I think when this medication was first approved, there were patients that were coming to me saying, okay, I've been on my endocrine therapy for 6  months. Can I go on this now? Yes, absolutely. I think that in the monarchE trial they allowed patients to go on that were within 16 months. I could be wrong.

Mikel Ross:

16 months from surgery, I believe it was.

Sarah Donahue:

... from surgery. In that case I would say, yes, you could absolutely go on it. Let me just get the drug to you, but then the patients that are worried, they're worried that their breast cancer's going to come back, they don't know the amount of risk that they carry. They just are really worried, so a lot of the times I'll be sitting down with them and saying, let's look at your pathology. Let's look and see did you have any nodes positive? Did you have a tumor that was greater than 5 centimeters? Was there a high grade? Was there something about your tumor that makes me feel like taking this medication that does have side effects, that that would actually bring down your risk? Because we can give you treatments, we can give you all sorts of treatments and say whatever to the insurance companies, you can pay out of pocket for it, but if it's not going to do anything for you, then what's the benefit?

Mikel Ross:

Have you guys seen the financial toxicity of these therapies playing a role and how does that enter into your decision making? Dr. Toppmeyer, maybe you'd want to handle that one first.

Dr. Deborah Toppmeyer:

We see that both in the metastatic setting and also the adjuvant setting. I have patients who are on Medicare that don't qualify for patient assistance and some of them are actually paying out of pocket with a very, very, very high copay, and other patients choose that, they say that they just can't afford it despite not quite meeting that threshold for patient assistance. It's a problem, and these are very, very expensive agents. That is an issue and it's very difficult as a provider to say, I can't give you this because you fall right between the cracks here and don't meet eligibility for patient assistance and yet your insurance doesn't cover enough.

Mikel Ross:

Yeah. As we were preparing for this discussion, I just wanted to reground myself in the cost of these agents. When they first came out in 2015, it was around $7,000 a month. We have now gotten to where almost all of them are approximately $15,000 a month. Again, when we make those decisions in early stage breast cancer to start someone on this, we're making a $300,000 decision. I think we just have to couch it in that perspective. Great discussion, really appreciate that. It always comes down though to the person you have in clinic. I'd like to tee up a case study for you guys, and this is actually a patient that I've seen in clinic, so I get to know the backstory, but I want to know if what I did or what I did in combination with my collaborating attending, because I always say attendings set strategy, nurse practitioners are great at execution, and between the two of us, we always get where we need to go.

We had an early stage patient, 30 year old female. She was diagnosed in August of 21. She had a multifocal left breast cancer, clinically quite large, T3, and a lymph node that we could feel, and in fact, did biopsy and it was positive, hormone-sensitive, HER-2 negative. She was given neoadjuvant treatment and she got through dose-dense AC, only got 3 dose-dense taxols, and then had what we presumed to be a Taxol pneumonitis. She went off to surgery one Taxol short, had a mastectomy and had some residual disease, T1A, so a small, less than a centimeter, less than a half a centimeter residual disease in the tumor bed, but she did have micromets all the way to just a few isolated tumor cells in 6  out of 17 lymph nodes. She's currently started off with ovarian suppression and aromatase inhibitor and she came to us to discuss adjuvant CDK4/6. Eligible? Not eligible? Recommended? Since we talk about MDs with strategy, Dr Toppmeyer, what do you think?

Dr. Deborah Toppmeyer:

Based on her original tumor, you know she is eligible. She had a large tumor, she had involved lymph nodes, so one could truly make an argument for treating her. Plus, she's 30 years old, and in a young patient with breast cancer, you want to give them every drug possible to reduce their risk of recurrence. This was a lobular and ductile. Was it a lobular and ductile or ductal with lobular features? Not that it makes a huge difference, but I certainly would have considered abemaciclib in this patient.

I think the issue of the pneumonitis is a very good one. I just had a patient also with paclitaxel pneumonitis and quite significant. The risk of pneumonitis is relatively low with these agents, but it happens. It's not like many other agents that we have, in HER-2 for example, but I think that I would be willing to treat her with very close observation of follow-up and really a significant amount of patient education. This is where our collaborating nurse practitioners can be very helpful in terms of education, follow up, et cetera, really driving the point home about any shortness of breath that's new that the patient notify us, but I think that in a 30-year old such as this patient, I would be very aggressive about treating her.

Mikel Ross:

Sarah, what's your vote?

Sarah Donahue:

She definitely qualifies for abemaciclib adjuvantly just based on the tumor size and node positivity. I don't know if there's data that says that if somebody has paclitaxel pneumonitis they're more likely to get pneumonitis from abemaciclib, but I also don't think that it's something that I would want to risk. Absolutely I'd be telling the patient to let me know if she has any shortness of breath or cough and even if it doesn't seem like it's more likely not a real thing, I'll just get a CT of her chest. You don't even have to use contrast, just to take a look and make sure that she's tolerating it well.

I think that this, in question of whether or not you would dose reduce for toxicities more likely in a patient like this, like if she had evidence of pneumonitis, of course you would stop the medication, but just more broadly thinking if somebody had toxicities like diarrhea, what's our threshold for dose reducing? I think that it does depend on the patient's risk. This patient is very high risk, so I'd be really tempted to ramp up the loperamide prevention and really try to keep her on full dose and on this medication. It's incredibly important to reduce her risk, so I think if I had a patient that was borderline qualifying for something, like not this patient, somebody with a smaller tumor, I might be a little bit more open to reducing dose, but it all depends.

Mikel Ross:

Great, thank you for that discussion. Both of you bring out an excellent point, which is we don't start and forget about it. We watch these patients closely. We have risk, we have benefit, we have close monitoring, and your threshold to do something about it can be really quite different based on the patient, based on their history and also based on the setting. Fast-forward with this patient, has not had any issues with pneumonitis. She did have an upper respiratory infection that we did have to hand hold through to say yes, common things continue to happen commonly, and this is something that's not a diffuse process, and we had a very low threshold to image when there was an upper respiratory. It was focal. It was consolidated at one spot. It was not diffused. Talked her through that, but she did struggle very much with GI toxicity, and in fact after optimizing pretty much anything we could think of to stop the diarrhea, still just had a real decrement to quality of life. We did dose-reduce to 100 twice a day and she has done quite well and is now 6  months into it.

Thank you both for this discussion. I think near and dear to all of us is that early stage patient that we want to add on as much protection and make sure that we prevent the recurrence that becomes a treatable but not curable breast cancer, and appreciate the conversation on how CDK4/6 inhibitors have given us new tools to really optimize that early stage therapy and change those curves that we saw historically. Thank you very much and I hope that everyone took away a few nuggets as I did.

Thank you again for joining us. I’d like to thank both Dr. Toppmeyer, as well as Sarah, for their time, their insights, and their thoughts, taking time out of their busy days. For more information, please always visit JADPRO online at advancedpractitioner.com. And thank you so much for tuning in and taking the time to learn a little bit more about how we can give the very best for our patients.