High-Risk HR-Positive, HER2-Negative Early-Stage Breast Cancer: Bridging Evidence, Risk Identification, and Real-World Practice

Dr. Sara Tolaney:

Welcome to High-Risk HR-Positive, HER2-Negative Early-Stage Breast Cancer: Bridging Evidence, Risk Identification, and Real-World Practice, a JADPRO Virtual Roundtable. My name is Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute. And I'm very lucky to be joined by my very esteemed colleagues, Dr. Erica Mayer, who runs our clinical research program at Dana-Farber Cancer Institute, and Dr. Elahe Salehi, a nurse practitioner who has a wealth of experience in managing breast oncology patients. So, thank you both for joining us today.

Dr. Erica Mayer:

Thanks for having us.

Dr. Elahe Salehi:

Thanks, Sara.

Dr. Sara Tolaney:

We're going to start with our first case where we're really going to dive in to think about our patients who present with hormone receptor–positive breast cancer, and really focus in on how to think about risks for this particular patient population. So, starting off with this patient, L.R., she's a 62-year-old postmenopausal woman who had a routine screening mammogram and was found to have a 3-cm mass on imaging. She underwent a core biopsy that came back with a low-grade invasive lobular carcinoma that was hormone receptor–positive and HER2-negative with a low Ki-67 at 5%. She went to upfront surgery and had a lumpectomy and sentinel node evaluation, where she was found to have a 4.5-cm invasive lobular cancer that was grade 1. She had a sentinel node evaluation where two out of four sentinel nodes were positive. The breast tumor was sent for a 21-gene recurrence score and came back with a score of 8. She also underwent staging scans, given that she had nodal positivity, and did not have any evidence of metastatic disease.

So just to summarize, she has a 4.5-cm grade 1 lobular carcinoma that has two positive lymph nodes with a low genomic assay score. And so, maybe I'll start off with you, Erica. When thinking about this particular patient, how are you determining risk for this patient? How do you figure out if this is someone with low risk or high risk? What are the features that you're keeping in mind?

Dr. Erica Mayer:

Yes, so there's a variety of features that we incorporate when we try to generate a sense of risk for an individual patient's presentation. Primarily, we are thinking about features inherent in the cancer. One of them is stage, so the anatomic burden of disease. What is the size of the tumor? Is there lymph node involvement? If so, how much lymph node involvement is present?

We also want to think about tumor biology, and this is an area that's evolved a lot over the past several years in terms of our ability to interrogate and understand the tumor biology. One thing we might look at is tumor grade. We also increasingly look at genomic risk score as a component of understanding tumor biology, both in a prognostic capacity to think about risk, but also increasingly in a predictive capacity to help us with treatment selection. Ki-67 is a test that perhaps goes into the category of tumor biology. This is performed at some oncology practices, not uniformly, mostly as this is a somewhat difficult test to do very consistently in all pathology offices globally, but sometimes this is available as well and does get incorporated into our consideration of risk. And then there's additional features you might consider. For example, age can be a risk feature, as some of our youngest patients may have somewhat more risk associated with their cancer compared to patients who are somewhat older. Although in my mind, the anatomic stage and the biologic risk of the cancer trump age, and we've learned that from several recent studies.

This case is really interesting because there is a dichotomy between the anatomic risk and the biologic risk. This patient has presented with a T2-size cancer that's node-positive with two involved nodes. Just based on that presentation being node-positive, having at least a T2-size cancer, we know there is risk here. That's anatomic risk. But this is a grade 1 cancer and it is low Ki-67. It is low Oncotype. These are all highly favorable features, and suggest a very favorable tumor biology. And so, there's a little discord there, discordance between the two, that we have to consider when we want to think about how best to take care of the cancer.

And I would say the X factor here that we're adding is that this is a lobular cancer, which represents about 15% of all the breast cancer we see, typically hormone receptor–positive, HER2-negative. And lobular cancer can be a bit sneaky, and it's not unusual when a patient presents that when they go to surgery, we might see a larger burden of disease than we had originally anticipated, even with what is often a very favorable tumor biology. So, it creates a somewhat complex situation with the anatomic vs biologic risk, and how that might have impact on our treatment selection.

Dr. Sara Tolaney:

Well, I think it's super helpful to think about this sort of dichotomy between anatomic risk and sort of biologic risk here. And so, if you were thinking about the treatment approach, Erica, what are you recommending in all likelihood to this patient with a 4.5-cm cancer, two positive nodes, but low grade, low Oncotype?

Dr. Erica Mayer:

The most important therapy for any patient with hormone receptor–positive disease is adjuvant endocrine therapy. And so, I think we would all agree that is the most important. That's the bedrock of therapy. That's what will give the greatest benefit. And we also can understand that for a lobular cancer, low grade, low Oncotype, these are often our most endocrine-sensitive cancers, so not only do we want to offer endocrine therapy, but we offer it because we think we're going to get our greatest benefit. Here's also a situation where extended duration adjuvant endocrine therapy is very important, so I would be thinking about a duration of at least 7 to 10 years for this patient. And that's something that I will share with a patient on day 1 so people have a good understanding that this is not kind of a short course therapy, but this is going to be something folded into their life over the next several years.

The next type of therapy I would be thinking about for this patient would be a CDK4/6 inhibitor. And over the past several years, we have had a growing body of data looking at the two lead agents, abemaciclib and ribociclib, which have demonstrated through the monarchE and NATALEE studies respectively, substantial benefits in reducing the risk of cancer recurrence, and even improving overall survival for abemaciclib in higher-risk disease. Now, what's interesting is that when we think about which agent to use, we not only want to think about the details of administration, the duration, the side effect profile, but we have to think about the eligibility for the respective trials. This patient having node-positive disease is eligible for ribociclib. Although she's node-positive, I don't actually think she meets criteria for abemaciclib, as one needed to have a cancer that was 5 cm or more, or high grade or high Oncotype, or high Ki-67, or have four or more nodes. And although she has high-risk features, she doesn't actually meet any of the monarchE high-risk features, but I would be thinking about offering this patient adjuvant ribociclib.

Finally, when we think about chemotherapy, which for many years was a kind of expectation for node-positive disease, we are now in an era with data from studies such as RxPONDER that for a patient with a very low Oncotype score who is postmenopausal, we would say that this patient would be unlikely to receive benefit from adjuvant chemotherapy. So, I would not be offering chemotherapy to this patient. I would be focusing much more on the endocrine-based therapy and the introduction of a CDK4/6 inhibitor.

Dr. Sara Tolaney:

That's super helpful. Elahe, you obviously have a ton of experience administering CDK4/6 inhibitors. As Erica brought up, technically this patient wouldn't meet monarchE eligibility, but it's pretty darn close, being 4.5 cm instead of 5. So, let's just say you were picking between the two different agents of abemaciclib and ribociclib. From your experience when counseling a patient about these agents in particular, what are some key things that you think about with each of them that are important for patients to be aware of?

Dr. Elahe Salehi:

Absolutely. Both of them have different side effect profile, so in this setting for ribociclib, we do a great level of teaching about the side effect profile, including the abnormal LFTs and possible increased QTc intervals. So, we tend to bring them back and make sure that during the education we follow them every 2 weeks for the first 2 cycles. We complete blood count, including CBC with differential, as well as complete metabolic panel. In ribociclib, we do add EKGs in this regard to make sure we monitor their QTc, and we'll initiate that prior to initiation of treatment, and we'll do every 2 weeks until cycle 2 day 1. And after that, if their QTc is absolutely normal, no further EKG is required. As for follow-up with them after the 2 cycles of the treatment, we tend to bring them back on a monthly basis with blood work, and eventually can move on to every 2 to 3 months if they're tolerating it well and if their blood work is stable.

Dr. Sara Tolaney:

Oh, that's super helpful. Just from a practical standpoint, so if I see someone postsurgery, and these patients often have very high-risk cancers, many of them need radiation if they've had a lumpectomy, or some of them even need postmastectomy radiation, how are you just thinking about timing of things? So, if I see them post-op, I start them, let's say, on their aromatase inhibitor, when are you starting the CDK4/6 inhibitor? Are you doing it after radiation? How do you think about that?

Dr. Elahe Salehi:

I think with our patients, when we see them, we give them all the bad news, and then we try to give all of these treatment one after another. I think it's important to try to do one agent at a time so we can understand the side effect profile, so we tend to start aromatase inhibitor about 2 weeks after radiation therapy, so we know that they have tolerated radiation well. And after 4 weeks, we do recommend starting a CDK4/6 inhibition if they are tolerating the endocrine therapy well.

Dr. Sara Tolaney:

Yes. I think that's a good point. And I will just say, just for people in the audience, we don't like to give concurrent CDK4/6 inhibition with radiation. There's some theoretical concern that you're putting the cell into cell cycle arrest, and that could potentially diminish the efficacy of radiation. It's not really proven, but I think in general, we would like to avoid any concurrent CDK4/6 inhibition with radiation in this particular setting. So as Elahe mentioned, we would do it sequentially, postradiation, with the initiation of CDK4/6. And again, usually we like to get them settled on their endocrine therapy and then introduce the CDK4/6. In this case, this may be a patient you may also offer bisphosphonate to, for example. And so, I think as Elahe pointed out, sequencing all these therapies one after the other, just so you understand what side effects you're also bringing up with each agent, letting the patient accommodate to each one, is, I think, what most of us tend to do in clinic.

Well, maybe just to throw a twist into this case, so if this patient actually had a 3-cm high-grade hormone receptor–positive node-negative cancer, and it came back with a high recurrence score, Erica, would you give this patient a CDK4/6 inhibitor? Again, we've tried to change the nodal status here, but increase the grade and the recurrence score. How do you think about risk for this patient, and do you think a CDK4/6 is warranted?

Dr. Erica Mayer:

Yes, so it's an interesting twist on the case. So, our patient is no longer node-positive. Now she's node-negative, which we always think of as being quite favorable from a prognostic point of view, but now we have high-risk features biologically. She's grade 3 and she has a high Oncotype. And so this is a, I'll say, pretty classic picture of what we might call high-risk node-negative disease, and it actually fits very well into what the NATALEE trial defined as high-risk node-negative disease, where patients needed to have high grade or high Oncotype, these biologic features. And it's interesting that if you look at all node-negative disease and you separate by the higher risk based on these features vs lower risk with lower grade or lower Oncotype, it's quite different how patients do. There's quite a substantial difference in terms of prognosis and risk of recurrence.

So, when I see this type of presentation, I want to think about being more, or I want to think about choosing my appropriate tools to meet the risk that I see here. First of all, we give this patient adjuvant endocrine therapy, like we did for our prior patient. This patient also would get chemotherapy, in my mind, with a recurrence score of 28. So, if that wasn't used before, I would be using it here. And then regarding CDK4/6 inhibitor, as I mentioned, this patient really fits the picture of the NATALEE high-risk node-negative.

Now, that node-negative group, when the NATALEE trial was first presented, showed what appeared to be a benefit from the use of adjuvant ribociclib, but there weren't that many events in that category, and I think we wanted to see a little more data maturity. At ESMO 2025, there was an updated presentation from NATALEE that showed with longer follow-up, there is a significant improvement in preventing disease recurrence for patients with high-risk node-negative disease who receive adjuvant ribociclib. And so, I think for many of us, that has really cemented our interest and enthusiasm to offer adjuvant ribociclib for these patients. So for me, I would also want to offer ribociclib to this patient.

Dr. Sara Tolaney:

I think you brought up a really important point, which is, while maybe traditionally we think of node-negative patients as being lower risk, as you pointed out, this patient has very high biologic risk with being high grade, high recurrent score. And in fact, these are patients that can have higher risk of recurrence than a node-positive patient who has lower biologic risk. So, if you compared it to an N1 patient who was grade 1, for example, with low Oncotype, the node-negative patient with high genomic risk may have a higher risk. So, I think as you, again, very nicely discussed, we do really have to factor in both anatomic and biologic risk when making these decisions, which is really important, but it's great that we have very effective therapies for these patients.

So, I think just the key takeaways from this particular case are that adjuvant CDK4/6 inhibitor therapy should be considered as standard of care for patients who have high-risk hormone receptor–positive breast cancer, that both adjuvant ribociclib and abemaciclib have been shown to significantly reduce risk of recurrence. And in fact, we do have data from monarchE that adjuvant abemaciclib actually improves overall survival, which is quite remarkable, so really, these agents should be considered in our high-risk patients.

Thanks so much for this great discussion. This brings us to the end of this case. Please do see our two other videos for further discussion about the latest research in breast cancer at JADPRO.com.