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Navigating Between Endocrine Therapy, Chemotherapy, and CDK 4/6 Inhibitors for High-Risk HR+/HER2- Early Breast Cancer: The Great Debate

  • Authors: Nadia Harbeck, MD; William J. Gradishar, MD; Sarah Donahue, MPH, NP, AOCNP
  • CME / ABIM MOC / CE Released: 11/17/2023
  • Valid for credit through: 11/17/2024, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for hematologists/oncologists, obstetrician/gynecologists, surgeons, pharmacists, and nurses.

The goal of this activity is for learners to be better able to appreciate the nuances of selecting therapy and maintaining persistence to therapy through an in-depth discussion that will expand upon expert insights and best practices.

Upon completion of this activity, participants will be able to:

  • Explain the clinical data associated with therapies for patients with high-risk, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC)
  • Select the most optimal adjuvant therapy for a patient with high-risk, HR-positive/HER2-negative EBC
  • Employ strategies to improve persistence to adjuvant therapy in patients with high-risk, HR-positive/HER2-negative EBC
  • Utilize an interprofessional approach to select and manage adjuvant treatment in patients with high-risk, HR-positive/HER2-negative EBC


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  • Nadia Harbeck, MD

    Director, Breast Center
    Full Professor
    Department of Obstetrics and Gynecology
    LMU University Hospital
    Munich, Germany


    Nadia Harbeck, MD, has the following relevant financial relationships:
    Consultant or advisor for: Gilead Sciences, Inc.; Novartis; Roche; Sandoz; Sanofi; Seagen, Inc.
    Speaker or member of speakers bureau for: AstraZeneca Pharmaceuticals LP; Daiichi Sankyo, Inc.; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme, Corp.; Novartis; Pierre Fabre; Pfizer, Inc.; Roche; Sandoz; Sanofi; Seagen, Inc.; Viatris
    Research funding from: AstraZeneca Pharmaceuticals LP; Bristol Myers Squibb Company; Daiichi Sankyo, Inc.; Merck Sharp & Dohme, Corp.; Pfizer, Inc.; Roche


  • William J. Gradishar, MD

    Professor of Oncology
    Betsy Bramsen Professor of Breast Oncology
    Chief of Hematology and Oncology
    Robert H. Lurie Comprehensive Cancer Center
    Feinberg School of Medicine
    Northwestern University
    Chicago, Illinois, United States


    William J. Gradishar, MD, has the following relevant financial relationships:
    Consultant or advisor for: AstraZeneca; Merck; Stemline
    Other: IDMC: Gilead Sciences, Inc.; Lilly; Novartis

  • Sarah Donahue, MPH, NP, AOCNP

    Carol Franc Buck Breast Cancer Center
    Helen Diller Family Comprehensive Cancer Center
    University of California, San Francisco
    San Francisco, California, United States


    Sarah Donahue, MPH, NP, AOCNP, has no relevant financial relationships.


  • Victoria Phoenix, BS

    Medical Education Director, Medscape, LLC


    Victoria Phoenix, BS, has no relevant financial relationships.

Compliance Reviewer/Nurse Planner

  • Maria Morales, MSN, RN, CLNC

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Maria Morales, MSN, RN, CLNC, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Navigating Between Endocrine Therapy, Chemotherapy, and CDK 4/6 Inhibitors for High-Risk HR+/HER2- Early Breast Cancer: The Great Debate

Authors: Nadia Harbeck, MD; William J. Gradishar, MD; Sarah Donahue, MPH, NP, AOCNPFaculty and Disclosures

CME / ABIM MOC / CE Released: 11/17/2023

Valid for credit through: 11/17/2024, 11:59 PM EST


Activity Transcript

Nadia Harbeck, MD: Hello, my name is Nadia Harbeck. I'm the Director of the Breast Center and Professor at the Department of Obstetrics and Gynecology at the Ludwig Maximilians University Hospital in Munich, Germany. Welcome to this program titled "Navigating Between Endocrine Therapy, Chemotherapy, and CDK4/6 Inhibitors for High-Risk HR-Positive/HER2-Negative Early Breast Cancer: The Great Debate."

Joining me today are William Gradisher, who is Chief of Oncology and Hematology and Professor of Oncology at the Northwestern University Feinberg School of Medicine, and Sarah Donahue, an Advanced Oncology Nurse Practitioner at the Carol Franc Buck Breast Care Center at the University of California, San Francisco. Welcome, Sarah. Welcome, Bill.

William J. Gradishar, MD: Thank you.

Sarah Donahue, MPH, NP, AOCNP: Yeah.

Dr Harbeck: So today we're going to spend some time talking about the clinical data associated with therapies for patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer and choosing the optimal adjuvant therapy for these patients. Strategies to improve persistence to adjuvant therapy, and how we use an interprofessional approach to select and manage adjuvant treatment in patients with high-risk HR-positive/HER2-negative early breast cancer. So, I think we should get started. I don't know whether this is going to be much of a debate or whether we basically agree, but we'll see on the management of our patients.

I brought you 2 cases. One case is a 52-year-old perimenopausal school teacher. She has 2 children, no family history, and at her initial diagnosis, she had a 3.5 cm tumor, clinically node-positive disease.

We did a core biopsy and verified 1 lymph node metastasis histologically and G3 tumor, ductal carcinoma, no specific type, estrogen receptor (ER) 100%, progesterone receptor (PR) 75%, HER2 1+, Ki-67 of 20%. We did an oncotype, in this case, because we had the ADAPT program running at the time, and recurrence score came back as 24.

And we decided on neoadjuvant chemotherapy with 4× EC, 12× paclitaxel, then breast conservation surgery, and a targeted axillary dissection because she really had a good clinical response. At the end, it was an ypT1a with 3 mm, ypN0 in the surgical specimen. So, if you put this all together, it was, ypT1 because we had this 1 histologically verified lymph node metastasis out of 4 nodes removed.

Bill, maybe we start with the indication for chemo, for adjuvant endocrine therapy -- adjuvant cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). How do you see a case like this? A non-pathological complete response (non-pCR), clinically a high-risk situation. Would you consider continuing chemo like capecitabine based on the CREATE-X trial; would you give a CDK4/6i? What are your thoughts for this case?

William J. Gradishar, MD: Sure. Thanks, Nadia. I think the first thing is she didn't get a pCR, but she came pretty darn close to getting a pCR. She just has a bit of tumor left and she had a particularly sensitive tumor to the chemotherapy that was given. But as you pointed out still has a substantial risk of recurrence just based on what her status was at the outset.

I'm not an enthusiast of giving capecitabine in this kind of setting, and I'm referring specifically to a tumor that's ER-positive. If you look at the CREATE-X trial, the overall population did gain benefit from capecitabine, but where the really compelling piece of that trial is really within the group that was triple-negative, which was about a third of the patients. And although there is some evidence of benefit, even in luminal breast cancers, I would be not enthusiastic about giving any further chemotherapy.

Now the other point would be that obviously she needs endocrine therapy. I would certainly support that. I think more likely than not she's probably going to become postmenopausal as a result of the chemotherapy. I don't think I would be thinking about ovarian suppression or anything like that.

However, I think you could make the case based on her presurgical status, before we even started with the chemotherapy, that her risk profile was such that she would have met criteria for the monarchE trial and as such, I would give some consideration to adding abemaciclib in this patient.

And then the final point is, I think we always, in the back of our minds, have to keep in mind, just looking at BRCA status, with respect to the use of poly(ADP-ribose) polymerase (PARP) inhibitors.

I think that... That's my side of the ocean view of how we would do things. How about you, Nadia?

Dr Harbeck: Yeah, simply, I can't agree more. This is a case where I think the chemo indication right from the beginning was very clear, and she did benefit, which also points at a more aggressive tumor biology. I mean her nodes were gone at the time. But I would not use capecitabine in a luminal breast cancer case. I think we've used it once in a case where the non-pCR specimen, then turned out to be very low in ER, like 5%, more like a triple-negative biology, then I suggested capecitabine to this patient, but in a patient with highly hormone receptor-positive disease, I think we now have CDK4/6i, and this is, certainly a much better way of trying to help them increase their chances for cure.

So, I would not give her any further chemo. I think she's a clear candidate for abemaciclib. She has 1 positive node, and she does have a Ki-67 of 20%, but she also has G3. So, there's these 2 indications why she would have fit in the monarchE study.

Sometimes people ask me, how do you make the decision about abemaciclib in the case of neoadjuvant chemotherapy? Do you take into consideration the pCR, and I think the answer is no.

The study recruited node-positive patients. We needed to verify node positivity like we do these days anyways because we want to have the option of targeted axillary dissection later on, and then you had to fulfill 1 of the other criteria, like large tumor or G3 or high Ki-67, so our patient did that, and then we don't have to count any nodes or look at anything after neoadjuvant chemo.

So pCR is not a decisive marker for giving abemaciclib after neoadjuvant chemo. I think that's a very important point. Have you had colleagues ask you that?

Dr Gradishar: Oh, it's I think, it's a common question because -- and this is a perfect case for illustrating the points you just made -- because one might think we've rendered this patient into a low-risk patient by the near-pCR. But I think really what highlights her risk profile is where she was right at the beginning before we did anything. So it's great that she has almost a pCR, but I think she remains at a significant risk based on her initial clinical status. So I would give abemaciclib.

Dr Harbeck: There's this wonderful paper from the monarchE study by Miguel Martin who looked at the neoadjuvant chemotherapy patients in particular and found that their benefit was even higher than that reported for the overall population, which is exactly the point you're making.

They have a very high risk right from the beginning, and I think that is very clear in this case. pCR is not a decision point for abemaciclib. We decide abemaciclib on the initial tumor biology, and there's also a very nice paper from the German Breast Group looking at what are the risk factors in patients with pCR for getting a relapse and the high tumor burden at the beginning of diagnosis, like you said, Bill, is the decisive factor. So these patients, even if they have a very good response, like our patient, they still need to protect themselves further.

And that brings me to Sarah. How do you talk to patients about this treatment? Do you feel that patients after chemotherapy already know about their risk and so they're more likely to accept? And do you have any tricks what to tell them and keep them on therapy?

Sarah Donahue, MPH, NP, AOCNP: Often, these patients have been told that they might be getting abemaciclib, prior to even getting their chemotherapy. So they've already been primed for this. They've gone through all this chemotherapy and now they're tired, then they've gone through a surgery, and so often they're saying, "I have to get more treatment? I don't know if I can do that." And it's for 2 years, that's a long time. So often when I'm talking to them about abemaciclib, I have to review with them the rationale, the importance, that they do get the medication to reduce their risk of recurrence. I think the more that you explain it, you have your physician that's explained it, and then I come in and I can explain it again. It really helps for them to understand it. And then if they understand the rationale, then they're more likely to adhere to the treatment.

They often will tell me, as far as symptoms go, that they're most concerned about the diarrhea that could happen with the medication. Some of them have said, "Oh I've heard that you can't even leave your house. How am I going to go to work? How am I going to take care of my family?" And so I explain to them that it's often not so bad, very easily controlled with medications like loperamide, they can take it as needed. And if we can't get it under control with loperamide, we can reduce the dose, and it can really reduce their diarrhea, and sometimes even stop the diarrhea altogether, but still be as effective for them, hopefully, in reducing their risk.

These patients have gotten chemo before, and they're used to being concerned about having neutropenia. I explain to them that it can increase your risk of mild infections, but generally patients aren't getting hospitalized. It's very manageable.

And then finally, the fatigue, which sort of, again, they're worried about whether or not they'll be able to work and take care of their families and do the things that they had planned to do. And so we discuss exercise, having a healthy diet, and ways of preventing or treating that fatigue.

Dr Harbeck: And how do you feel that patients need more advice in the beginning or do you schedule visits with them all throughout the therapy and try to identify risk of them discontinuing?

Ms Donahue: We see them every 4 weeks in my clinic. Once they start the therapy, we can, after a while, we can spread that out a little bit, but we want to get labs every 4 weeks anyways.

I also give them the phone number for our triage nurses that we have so that they can call if they have side effects. I remind them that it's better that they call or write a message in through the medical records with how they're feeling so that we can address their symptoms because often it's easy for us to fix it and then they can have limited time of being uncomfortable.

Dr Harbeck: We've seen data earlier this year that actually was quite practical from the monarchE study that there is the same quality of life in the abemaciclib arm vs the control arm during the treatment period. And Dr Hamilton showed at American Society of Clinical Oncology (ASCO®), a point that you made earlier, that if you dose reduce that doesn't affect efficacy.

Do you discuss these new data with patients? Do you feel that is helpful to have all this information available for the drug?

Ms Donahue: I do. I do. I definitely find that patients, even if the data is confusing to them, knowing that if I can explain it to it in a simple way, knowing that the drug will still be as effective if we have to reduce it, and knowing that there is some even data out there from prior, from not new data, but older data, showing that the diarrhea can get better after the first 3 months, that really does help them.

And to know that when I explained to them also what my experience with other patients has been, that helps as well.

Dr Harbeck: I think it's very important to have this interprofessional approach and with the physicians and the nurses because these long adjuvant therapies, I think we need to take proper care of the patients.

Otherwise we lose a lot of them because like you said they want to go back to work. They want to be with their family, and they don't want to be bothered by more treatment because they don't really feel sick. Yeah. I think it's an important point.

Let's look at another patient and maybe look at this a little bit from a different angle. Bill, are you ready?

Dr Gradishar: I think so. What are you going to throw at me?

Dr Harbeck: Okay, we have a slightly older patient, 58 years old. She's a lawyer, postmenopausal, no children. She has a maternal grandmother with breast cancer at the age of 70. And her initial diagnosis was quite a large tumor, 5.3 cm on ultrasound.

Clinically node-negative G2, NST (no special type), ER 80%, PR 20%, HER2 2+, but on chromogenic in situ hybridization (CISH) negative, and Ki-67 of 15%.

You know that we routinely give this endocrine therapy before surgery to our patients to see what the endocrine response is in the tumor. And so we gave her preoperative endocrine therapy. In postmenopausal patients, 2 weeks of an aromatase inhibitor (AI) is enough to see the desired effect in the tumor. And we ordered, because she was node negative, we ordered the Oncotype DX from the core biopsy, which turned out to be a recurrent score of 12. You have to do this from the core biopsy because if you give this preoperative endocrine therapy, obviously the tumor will be altered once you take it out at surgery.

So she had a nipple-sparing mastectomy and immediate reconstruction and a sentinel node procedure and indeed had a large tumor, 5.8 cm. She did have 1 sentinel lymph node involved, 1 out of 2. And interestingly, her Ki-67 dropped to 5%. So we have this large tumor, which has a very good endocrine response and a low-risk oncotype, but still it's a T3 tumor.

So, Bill, looking at this from all angles, how would you proceed with her?

Dr Gradishar: In the States, I guess there's what would clinicians be struggling with? They'd first face the fact this is a big tumor with node positivity. Do we need to give chemotherapy? The flip side is we have some insights into the biology of the disease.

So the fact that she had a decrease in Ki-67 with a very short exposure to endocrine therapy would suggest to me that she's going to be particularly endocrine sensitive to therapy and perhaps with the recurrence score, perhaps, less chemo sensitive.

So, this is somebody that I would still make an argument that endocrine therapy in lieu of chemotherapy could be justified based on those features alone. I think that, quite frankly, there are many oncologists in the US that would probably still be inclined to give chemotherapy, but I think the data that you presented regarding the case would support the idea of avoiding chemotherapy giving endocrine therapy alone.

Dr Harbeck: Yeah, I couldn't agree more. Again, I think we see this quite in the same way, and that's why we like to do this endocrine response because it gives it additional certainty that we can rely on an endocrine-based therapy later on. And with the recurrence score is one thing, but you could say maybe it's a heterogeneous tumor, but then you have another factor.

I take it you will not give her chemo. Would you go for a CDK4/6 inhibitor in this case, or would you feel that endocrine therapy is enough for her?

Dr Gradishar: I think I would consider and discuss a CDK4/6 inhibitor with her. Everything we know about this tumor now is that it's chemosensitive. But again, with the mindset that there may be an attraction to chemotherapy just because of the clinical volume of disease, if we're not giving chemo, I'd try to optimize her endocrine therapy. And I, at least, have a discussion about adding abemaciclib to endocrine therapy. I'm curious, when you see this size tumor, and I realize you had a change in the Ki-67 that's supportive of endocrine therapy, and the recurrence score is low, do you see any of your colleagues giving chemotherapy to this kind of patient?

Dr Harbeck: Once you have all this on the table, I think people would be reluctant to order chemo, but some people may not do the endocrine response assessment and just give chemo right away. There's also colleagues who say, if it's a large tumor, we'll shrink it and take her to breast conservation.

But she had a rather small breast, so even if the tumor had shrunk by like a centimeter or so, a breast conservation would probably not have been the best option. So I think we should, in nowadays, take all the biological information into account and see this differently, whether we have a chemo indication, yes or no, and whether we have an indication to enhance the efficacy of endocrine therapy.

So I would also think that she is a candidate for abemaciclib. I would not give her chemo based on the things that we just discussed. With regard to abemaciclib, she does fulfill the criteria because she has this large tumor and 1 positive node. So I feel good with that decision that we're not just doing endocrine therapy but adding something to protect her.

Dr Gradishar: Exactly.

Dr Harbeck: So, maybe, she had this maternal grandmother, which doesn't make her a high-risk candidate for a BRCA mutation. But how do you go about if she did have a germline mutation, let's say that she wanted the testing done and it turned out to be a BRCA2 mutation, do you still give her just abemaciclib, or do you think about a PARP inhibitor, do you sequence that, what do you do?

Dr Gradishar: Yeah, so that complicates it, and the answer is probably yes and yes. But to be elaborate a bit more, I think that if you look at the OlympiA trial, we clearly have with longer follow-up, an advantage in such patients for getting olaparib to reduce the risk of recurrence and survival improvement.

Dr Gradishar: The question is, would you give them concurrently, meaning abemaciclib and olaparib? The answer would be no, at least from my way of thinking. We do know that with longer follow-up in monarchE, the hazard rates are actually improving with time. If one were to consider doing it, I would do it in sequence. And I might consider giving the olaparib first, endocrine therapy could be started, and then once the olaparib is done, the PARP inhibitors completed, then adding abemaciclib. But I think this is an individualized thing. It's a lot to expect of a patient, and you just have to talk about, what they can expect with side effects and how it's going to affect their day-to-day life.

I'm curious, how would you deal with that circumstance where you have a candidate for both kinds of therapies?

Dr Harbeck: We would probably do it the same way. I feel strong about giving the olaparib first because, first of all, that would be according to how it was done, the OlympiA study; and second, it's a change in the therapeutic principle. So we have a non-cross-resistant agent. I think to sequence is based on the data also from the monarchE, we had patients, and that is written actually in the first JCO publication, that we had patients more than a year out from primary diagnosis because in some countries the radiotherapy took such a long time to be delivered. So there were actually patients a year after primary diagnosis in monarchE. So I think, we could say that sort of falls into the how the study was conducted. And I also agree that we should not combine these agents. And when we had the discussion at St. Gallen, 30% of the experts said olaparib, and the others, I think almost 40%, both in sequence.

So I think we have this feeling if we have a high risk of recurrence, then it would be advisable to give both agents.

That brings me to Sarah. Let me just ask you before we talk maybe about the different management of olaparib and then abemaciclib, whether you see differences there. This patient didn't have chemotherapy, so usually her peers go out of the breast center and just get an AI, and now we have to tell her that she needs 2 years of more intensified therapy. Do you feel it's more difficult in patients who didn't get chemo because they're not so aware that there is an underlying risk, or do you think it's about the same?

Ms Donahue: So these patients, I do feel like they know that they have some risk though; they have a larger tumor, and so they want to reduce that risk as much as possible. They do seem to worry a little bit more about the potential side effects of these added targeting therapies over the aromatase inhibitor, hormone, basic therapies because they've never had any treatment at all. So far they've just had surgery, plus or minus radiation. And the side effects from that are short term. It's after surgery for a few weeks; during radiation, maybe after for a little bit of time. And now we're recommending that they go on 2 years of maybe a CDK4/6i inhibitor or a year of olaparib and then going on to the abemaciclib. It's a lot longer period of time that they're going to be experiencing potential side effects. And they worry about the side effects may be more than if they had chemotherapy prior because chemo can cause so many side effects that when you say, oh, now you're going to go on to these targeted therapies that have less side effects, those patients might feel like more open to that. Whereas a patient that's never had any side effects from chemotherapy, might be more worried. But I do feel like, just like with that first case, just explaining to the patient the rationale again and repeating it over and over again with a physician and then the nurse really helps promote adherence because then they understand that it's needed and can reduce their risk of recurrence.

I already discussed sort of the potential side effects of abemaciclib and how I address that with patients. For the olaparib, the patients seem to be most worried about nausea, anemia, and fatigue. I tell them that for nausea, that we can use anti-nausea medications, oral pills that they can take at home. I tell them to have small, frequent meals; avoid certain foods that might aggravate nausea like acidic foods or spicy foods. I also tell them that if they're vomiting that is just totally unacceptable. My goal is minimal to no nausea. We have a very low threshold for intervening. I don't, I really don't want them to be experiencing any if minimal nausea; no vomiting at all.

And then for the anemia and the fatigue, because they come together, we monitor their labs, frequently, at least every month. If we're seeing that the anemia is becoming so much that they're becoming very fatigued or very symptomatic, we can always decrease the dose and it could potentially really help them feel better.

It's just a lot of education about potential side effects and that reassuring them that we can manage those side effects and that they just need to keep in close contact.

Dr Harbeck: I assume that maybe because she didn't have chemo before that some of the side effects, she just waits and see how this pans out, whether patients who've had severe side effects during chemo may also be more difficult to manage because they already have seen that and they're afraid that they may experience that again.

Ms Donahue: Yeah, I do. I mean I think it's just the different perspectives, and each individual patient's concern, and their prior experiences are always going to affect how they approach these adjuvant therapies. So I think part of my assessment with patients when they're first starting these is to figure out where they're coming from.

Of course, whether or not they got chemo, but really ask them about what their worries are, what things make them most anxious about going on the treatment and addressing each of those items to help them understand that we can help them and know when to reach out to us to ask questions.

Dr Harbeck: Definitely. And I think a patient with a BRCA mutation, where we even thinking about sequencing these targeted agents for 3 years total, they may have some moments where they think they can't go on with that particularly after the first year when they go on then to abemaciclib as the second agent. Do you have any tips for that or just continued availability on your side for any questions?

Ms Donahue: Yeah, just being present for them and easy to reach and responsive and fairly quick amount of time is helpful. I think that people say like chemotherapy is like running a marathon, but like all of this is a marathon for many of my patients.

It's not a quick treatment. And even for my patients that don't go on these adjuvant therapies that have smaller tumors and tiny surgeries and little radiation, it's a marathon for them too. They're dealing with the emotions of the whole process, worrying about side effects from whatever treatments they're getting, and it's just every patient's individual and being there to support them is, and giving them the time is, really important.

Dr Harbeck: I just have 1 point. Maybe, Bill, can I get back to you? In my opinion, now that we've discussed these 2 very different cases, for the time being, we have to make the indications for chemo, for endocrine therapy, obviously, but also for abemaciclib, independent of each other, and we cannot replace chemo with abemaciclib because 90% of the patients in monarchE did have chemotherapy.

So would you agree with that?

Dr Gradishar: I would, and I think the things you just said really highlight the fact that each patient’s decision has got to be nuanced. They're not all the same. It's not cookie cutter. And we have a variety of therapies that we can utilize but using them in the smartest way possible for a given patient situation is really how we get into this notion of precision medicine.

Dr Harbeck: And there will be more data coming. We have the ADAPTcycle study just fully recruited where we randomized chemo vs CDK4/6 in the early breast cancer setting to see whether we can actually replace chemotherapy a little bit more.

And we have ADAPTlate open where we randomized patients up to 6 years out from their primary therapy and to get abemaciclib or not. So to see whether later initiation will also help. And we just amended the trial to also include patients with node-negative disease and, all those patients that were not eligible for monarchE.

So I think there will be more data coming, which will help us, like you said, to refine our decision-making even further.

Thank you, Bill. Thank you, Sarah. That was a great discussion. I hope our colleagues found it interesting and, to our audience, thank you so much for participating in this activity.

Please continue on to answer the questions that follow and complete the evaluation. Thank you very much.

This transcript has not been copyedited.

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