Activity Transcript

Chapter 1: Current Recommendations for Risk Assessment in Patients With HR-Positive, HER2-Negative EBC

Sara M. Tolaney, MD, MPH: Hi, my name is Sara Tolaney. I'm chief of the Division of Breast Oncology at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School. Welcome to this activity titled, "Assessing Risk in Hormone Receptor Positive HER2-Negative Early Breast Cancer, How to Approach Challenging Cases in Clinic."

This activity consists of 5 chapters, including a discussion with Dr Elizabeth Mittendorf about the necessity of axillary dissection for risk assessment and discussions between Dr Hope Rugo and Dr Javier Cortés about the management of borderline high-risk patients and how genomic assays and circulating tumor DNA (ctDNA) reports are used in the clinical setting to assess risk of recurrence.

I'd like to start with an overview on current recommendations for risk assessment in patients with hormone receptor-positive, HER2-negative early breast cancer (HR+/HER2- EBC). What we do know is that patients who have significant nodal involvement are at high risk of recurrence from their estrogen receptor (ER)-positive disease. Patients who have 4 or more lymph nodes involved have a risk over 10 years, that's ≥ 30%. Patients who have 1 to 3 positive nodes have a risk in the range of approximately 20%.

While we're very fortunate to have endocrine therapies (ETs) to help us mitigate this risk, such as things like tamoxifen, aromatase, and ovarian suppression, it is really critical to specifically identify those patients who may be at the highest risk of recurrence and those patients who may present with endocrine refractory disease. So, it’s those patients who have high risk for early events, with those events occurring usually within the first 2 to 3 years of their adjuvant therapy.

One study that specifically looked to address this population was the monarchE study because it really looked at those very high-risk patients who tend to have very early events. The way they tried to capture that risk was by looking at clinical pathologic features, taking those patients who had 4 or more positive lymph nodes involved, or had 1 to 3 positive nodes and had a large tumor over 5 cm, or was high grade, or could also have had a high Ki-67.

We do know that Ki-67 in itself is prognostic and associated with higher rates of recurrence. Those rates of recurrence do tend to happen within an earlier timeframe. This study, as we'll get into more details during this activity, did result in a significant improvement from the addition of abemaciclib with a risk reduction of about 30%. The absolute difference between those 2 arms was a little over 5%. In general, abemaciclib's benefit was seen similarly in the Ki-67-low group as well as the high groups

Toxicities included things like diarrhea, which was predominantly low grade, as well as mild neutropenia. There was a low risk of venous thromboembolic events as well as interstitial lung disease.

Based on this data, the FDA approved abemaciclib for patients who met the monarchE eligibility based on tumor size, grade, and lymph node status, and also added in the eligibility criteria patients who have a high Ki-67. Their rationale for this indication was they wanted to see a trend towards survival benefit, and a trend was only seen in the high Ki-67 patients. I think it’s important to consider this was only with 27 months of follow-up and this survival analysis was purely exploratory and not pre-planned, with insufficient events for any statistical trends to be noted.

So, the American Society of Clinical Oncology (ASCO®) and National Comprehensive Cancer Network (NCCN) did take a stance that was a little bit more flexible with their guidelines for use of abemaciclib, which was you just had to meet monarchE eligibility: having 4 or more positive nodes or 1 to 3 positive nodes involved with the tumor over 5 cm or be high grade. This has led us to have the availability of abemaciclib for these particularly high-risk patients, which I think is really critical because these are the patients who do tend to have early events and have higher risk of relapse.

While we have abemaciclib for our high-risk ER-positive patients, we also have olaparib that is available for high-risk germline BRCA-mutant patients. This data comes from the adjuvant OlympiA study, which took patients who had high-risk early-stage breast cancer with a germline BRCA mutation and randomized them to get 1 year of olaparib or 1 year of a placebo. The study demonstrated that giving a year of olaparib resulted in about a 40% reduction in invasive disease-free survival (iDFS) events as well as a statistically significant improvement in overall survival (OS). Because of this, olaparib has an FDA indication for patients who do have high-risk germline BRCA-mutant breast cancers.

It is very important to have these options for our high-risk patients, and so important to remember that for high-risk ER-positive disease, abemaciclib for 2 years can be considered, given the data from monarchE. And for someone with a germline BRCA-mutant tumor, ie, high risk, think about 1 year of olaparib.

Please continue on to the next segment of this activity.

Chapter 2: Is Axillary Dissection a Necessity for Risk Assessment?

Sara M. Tolaney, MD, MPH: Hi, my name is Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute, and I'm joined today by my colleague, Elizabeth Mittendorf, who is a professor of surgery at Harvard Medical School and the Robert and Karen Hale Distinguished Chair in Surgical Oncology at Dana-Farber Cancer Institute. Thank you so much, Beth, for joining us today.

Elizabeth A. Mittendorf, MD, PhD: Thank you.

Dr Tolaney: I thought maybe we could start off with the first case, which was a 58-year-old post-menopausal woman who had undergone a lumpectomy and sentinel node evaluation and was found to have a 3.5 cm invasive ductal carcinoma that was intermediate grade, and on sentinel evaluation, had 2 out of 3 lymph nodes that were involved.

The tumor was strongly ER- and progesterone receptor (PR)-positive and HER2-negative, and the medical oncologist had sent an Oncotype DX Recurrence Score (RS) with regards to making a decision about whether or not chemotherapy would be of benefit, which came back high at 28. So, the physician elected to move forward with adjuvant systemic chemotherapy. The patient received anthracycline-based treatment followed by taxane, and the decision was also whether or not they needed abemaciclib.

So, just to circle back to the time point post-surgery, Dr Mittendorf, if you had seen this patient and she had 2 out of 3 lymph nodes involved, is this someone that you would then take to axillary dissection after seeing the sentinel node results?

Dr Mittendorf: So, Sara, based on the randomized controlled trials that inform the surgical management of patients, the answer to the question would be no. We would think about the ACOSOG Z0011 data that suggests for patients who start off as clinically node negative (which is where I'm presuming this patient did) and found to have only 1 or 2 positive sentinel nodes, we in fact do not routinely dissect those patients. The thought is the radiation that's going to follow will treat the low axilla, and the long term +10-year follow-up for Z0011 shows that there's no difference in survival for patients who have that lymph node dissection or not. From a surgical standpoint, I would've suggested the patient does not need a lymph node dissection.

Dr Tolaney: I would say from a medical oncology perspective, with the decision-making regarding chemotherapy, we had sufficient information, given that she had a high RS; she was going to get chemotherapy anyway. Even if you had taken her to dissection and you found maybe another couple of lymph nodes, once someone has 4 or more positive nodes, we're usually giving chemotherapy anyway, irrespective of score. The question comes after chemotherapy when we're giving ET. In this case we would've started an aromatase inhibitor. But the question would've then come up, would we add abemaciclib?

I think the challenge that we face now is what if the case was a little bit less straightforward? Let's say it's the same situation in terms of a 58-year-old post-menopausal woman who had a clinically negative axilla at presentation and came back after surgery with the lumpectomy and sentinel node with the same 3.5 cm tumor, but now say it's grade 1, and she had 2 out of 3 nodes involved.

So, we'll take it back to you, Beth. In this particular case, let's say the Recurrence Score came back low and the oncologist felt, assuming she only had 2 nodes, she would've met RxPONDER criteria, and they would've said, "No need for chemotherapy in a postmenopausal woman with the low [RS]." But in truth, it could have changed the decision if there were 4 positive nodes. It also could impact decisions for abemaciclib because currently the patient wouldn't meet eligibility, but if they ended up with 4 positive nodes, they would've met eligibility for monarchE and could have gotten abemaciclib. Understanding nodal involvement could change systemic therapy recommendations. How do you then think of these situations in terms of what to do with further axillary surgery?

Dr Mittendorf: That's a great question that, as you know, we're addressing on a fairly frequent basis in our tumor board. Again, the surgical literature I could quote goes back to Z0011, and you would suggest maybe we don't need it. But it's more complicated than that because now my multidisciplinary colleagues, both you as a medical oncologist as well as our radiation oncologist colleagues might really want to know the total extent of nodal burden to help inform their decisions.

We've looked at our data at Dana-Farber, specifically at women who are in the 50- to 75-year-old age range with 1 to 3 positive sentinel nodes after having been clinically T 1-3, N0, HR-positive and RS >26. So, the scenario you just described. It turns out only about 1.5% had 3 or more positive nodes.

A little bit older data from Memorial Sloan Kettering, they just looked at a broad population of HR-positive, HER2-negative patients and found that less than 10% have 4 or more positive nodes. So, the high likelihood is a patient will not, but I do acknowledge the benefit of knowing the extent of nodal burden. This is a patient where, since monarchE was published, I would be interested in a multidisciplinary discussion as to how that total extent of nodal burden would impact your decisions as well as well as that of the radiation oncologist. I would be more willing to consider doing a lymph node dissection for that reason if it's going to inform treatment.

Dr Tolaney: That's so tricky because I think the numbers that you quoted are a bit on the low side in terms of the probability of finding additional nodal burden. How do you weigh risk/benefit here in terms of what's the risk of taking that patient back to surgery and doing a dissection to get that information for systemic treatment decision making?

Dr Mittendorf: I think the risk that most people are going to be concerned about is the risk of lymphedema, which is not insignificant. We anticipate that these patients will do well in the long term, so it becomes a survivorship issue. Their risk of lymphedema with sentinel node dissection alone is going to be 5% or less. If we do an axillary lymph node dissection, it's probably closer to 20%. The patients that are getting the axillary dissection are likely going to require regional nodal radiation as well, and now we're bumping up against 35%. So, it's not insignificant to consider lymphedema. It's an important conversation to have first with your multidisciplinary colleagues to make sure that the information is needed and then with the patient.

Dr Tolaney: I find this one to be a tough decision because with such a low probability of finding additional axillary nodes, it makes you wonder if it's worth that potential risk, especially in someone with a low RS who likely is going to do well with ET. It's hard to know if it's truly needed. So, I agree, these are the discussions we struggle with in tumor board about knowing what to do here.

Dr Mittendorf: If that patient, now low grade, didn't meet monarchE but had a high RS, is that good enough, in your opinion, to define her as high risk to inform an abemaciclib decision without having that additional nodal burden information?

Dr Tolaney: It's an excellent question. In monarchE, there was a separate cohort for people who had 1 to 3 positive nodes but didn't meet eligibility based on having the big tumor over 5 cm or being high grade. Exactly like this patient. It was cohort 2 and while that cohort was included in the intention to treat (ITT) analysis, the truth is it only had 500 patients and it was enrolled much later during the course of monarchE. So, the data from that 500-patient cohort is very immature. We actually don't have the data for someone who is out of that high-grade tumor over 5 cm range, but instead was high Ki-67 as cohort 2 was. I would assume a high RS patient probably also had a high Ki-67.

Should we get a Ki-67 in this patient to make that determination? Again, you could. I think with the higher RS, I would feel comfortable. It would be unusual for a grade 1 tumor to have a high Ki-67 and high RS, but anything is possible. I probably would think about abemaciclib there. But in truth, it isn't 100% data-driven because there isn't mature follow up yet from cohort 2. That is the caution with making that decision. But an excellent question.

Dr Mittendorf: But to your point, I think we have to realize too that the axillary management, specifically the surgical management in these trials, was not mandated. If you look at the monarchE publication, it doesn't even tell us the extent of axillary surgery that was performed. So, there's a lack of data there, too. And now you just brought in our pathologist to the multidisciplinary team.

Dr Tolaney: That's a good point. As you know, our group has had quite a lot of discussions about Ki-67 as well, and whether or not we should be routinely getting it on these ER-positive patients to make these systemic therapy decisions. We haven't routinely been getting it at our institution, given the poor reproducibility and challenges, particularly in this range of Ki-67 where monarchE had to be over 20%, and by the International Ki67 in Breast Cancer Working Group guidelines, that's where there was quite a bit of variability in testing. But in the case with the low-grade tumor, where it's a little bit of a tricky decision, maybe Ki-67 could potentially be helpful there.

So, so many pieces of the puzzle to think about, axillary decisions, radiation decisions, pathology decisions: not such a straightforward case.

But thank you so much for your input here. Again, it's such a critical thing to have these multidisciplinary discussions, particularly in these challenging situations.

Well, thank you so much again for this great discussion, and please continue to the next segment of this activity.

Chapter 3: Borderline High Risk: Now What?

Hope Rugo, MD: Hello, I'm Hope Rugo from the University of California San Francisco's Comprehensive Cancer Center and joining me today is Dr Javier Cortés from the International Breast Cancer Center of Oncology and MEDSIR in Barcelona, Spain. Welcome Javier.

Javier Cortés, MD, PhD: Hi, Hope. Very nice to be with you today.

Dr Rugo: It's great to talk to you and we have so many exciting areas to talk about in breast cancer right now. It's been really an amazing few years and one of the areas that's shown a huge advance is options for treating our patients who have early stage, HR-positive, HER2-negative breast cancer.

One of the big questions, of course, when we have new treatments that seem to have a big impact on outcome is who do we give these treatments to? And often we get frustrated by trying to follow narrow guidelines. One of the areas that comes up a lot in clinical practices are these patients who still have a risk of recurrence (of course, all of our patients do) but don't fit into that high-risk niche that we see and that's been defined by our early stage clinical trials.

So how do you approach a treatment for a patient who's borderline for risk of recurrence?

Dr Cortés: It's difficult to know the risk a patient might have and how to decide the optimal treatments. In the premenopausal women, for example, when to decide on goserelin or triptorelin or just going to tamoxifen. Sometimes it's tricky because it is not only about the risk, it is also about adverse events.

And in the general population in both post- and premenopausal, when we look at, for example, in monarchE study with the activity of abemaciclib in the adjuvant setting for 2 years, we look at the risk based on the clinical aspects: the tumor size, the node involvement, and maybe grade, Ki-67, etc. But we know today that, for example, the Oncotype DX or MammaPrint can also help us to select who will have more or less risk for relapse.

So, in my opinion in clinical practice it's not complex if just looking at the clinical trials. The clinical trials are quite simple. If you fulfill the criteria, you go for the drug. If not, you will not. But what about the clinical practice? Imagine that you have a patient, for example, with 1 node, grade 2, Ki-67 20% or even 15%, but you have a Oncotype DX [RS] of 35, 40 for example. For me this a patient with highest risk. That other patient with 2 nodes or 3 nodes, if the RS for example is 10 or 12. So then, in my opinion, we have to integrate all the tools available in our hands to try to decide if we go for goserelin/triptorelin in the adjuvant setting for premenopausal with also abemaciclib. Abemaciclib in premenopausal EBC, I feel have to integrate both. It's difficult we find who will benefit and who will not get a benefit. I don't know your thoughts about that?

Dr Rugo: I agree. It can be really difficult. I think practically certainly I use the criteria that were in the monarchE trial in order to decide about using, for example, abemaciclib. And then I think the other big choice we make is using ovarian function suppression in young women with an aromatase inhibitor (AI) or tamoxifen. And in that situation, I will use really just the clinical risk as put forth in the SOFT and TEXT trial analyses. Most of my young patients under the age of 40, I use ovarian function suppression and sometimes as a way to avoid chemotherapy as well, I try using AIs, but my general approach is that some therapy is better than none.

For me, you have to take the individual patient and reach into our storage of information about outcome in these patients to try to decide which patients we're going to offer more vs less. And then along the way, I think we have to be incredibly conscious of issues with adherence and trying to really support patients with the importance of taking treatment, but also not freak them out because that young woman with the Ki-67 at 5 to 10%, she's so anxious about her recurrence risk

It can be difficult. Are there situations where you would give a patient, for example, the CDK 4/6 Inhibitor as a lower risk who doesn't fit into the monarchE criteria?

Dr Cortés: If they do not fulfill the criteria of the monarchE, I think that, first, this is an in-depth discussion with our patients. Second, maybe if there are patients that do not fulfill the criteria completely, but they have a very high risk, according to the platforms, is something that after discussion I would consider. But certainly, again, I know that we do not have enough data to support the drugs, but in the end, our patient is there, our patient can understand pro and cons. So, the risk is important, that's something at least to consider.

Dr Rugo: That's a really important point. In the United States, we are limited by insurance approvals, but I think in a patient who has particularly high-risk disease and just fits outside of the criteria of monarchE, I would consider use of abemaciclib and try and get over the authorization issues with a so-called peer-to-peer review.

But I think that the other area, for example, that I've actually had 2 patients recently where they had mastectomies and then they had a local recurrence while taking tamoxifen in 1 patient and not on any therapy in the other. These are tiny little local recurrences, not in the skin but in the subcutaneous tissue. And 1 patient had a little ductal carcinoma in situ (DCIS) in there, so you know it's residual breast tissue and these are half a centimeter, some millimeters. The recommendations from a couple of very esteemed breast oncologists were that they consider taking a CDK 4/6 inhibitor in that situation. What would you do there?

Dr Cortés: I think this is a patient with important risk and we do not have so many trials for this group of patients, but certainly in my opinion, this a patient that should be treated with all the best drugs we may have at that time. And for sure, abemaciclib for 2 years is something that I would go for.

Dr Rugo: I've taken the approach that it really depends on the disease. If somebody has disease infiltrating skin, CDK 4/6 inhibitor. If they have 2 mm of disease in the subcutaneous tissue and they were taking either no ET or minimal ET, I think in that case we might be able to say they really fall on the very low risk side and we could use ovarian function suppression and an AI. So, this just highlights how we have to individualize everything that we do so carefully in terms of understanding risk.

With that we have really highlighted the way we approach our patients in the clinic and I think it's an ever-changing landscape as we learn more and more.

I really appreciate discussing that with you, Javier, and recommend that everyone go on and continue to the next segment of this activity.

Chapter 4: Genomic Assays and ctDNA: What to Do With the Results?

Hope Rugo, MD: Hello, I'm Hope Rugo from the University of California San Francisco's Comprehensive Cancer Center. Joining me today is Dr Javier Cortés from the International Breast Cancer Center of Oncology and MEDSIR in Barcelona, Spain. Welcome, Javier.

Javier Cortés, MD, PhD: Hello, Hope. Nice to be with you today.

Dr Rugo: Our topic today is to talk about genomic assays and ctDNA testing and really what we've seen is increasing use of genomic assays following guidelines in patients with HR-positive, HER2-negative EBC. But we also know that it's hard to decide the tests and the results can sometimes be contradictory or confusing.

And now we know that there has been some interest in looking at cell-free DNA (cfDNA). Certainly, in the metastatic setting we use this quite frequently to look for mutations and it's been enormously helpful and helped us to avoid trying to find somewhere to biopsy when there's only bone-only disease, for example, or there's pain and trauma. But in the early-stage setting it still remains quite controversial.

Let's deal with the first question, which is genomic assays. We have quite a number of assays, Oncotype, MammaPrint, for example, Prosigna in Spain. Then you could choose getting additional data on intrinsic subtyping with BluePrint.

What do you use in your clinical practice and how do you use this to determine treatment?

Dr Cortés: Thanks, Hope. In my opinion, I use them when I do not know, I have some doubts about the pros and cons about using or not using chemotherapy. Just as an example, imagine you have a patient with a tumor of 3 cm. It's a postmenopausal woman with 1 node, Ki-67 in the range of 20%. I think that [a genomic assay] here might help us a lot to decide if we go for chemotherapy plus ET or we can go directly to ET.

I think that the more we use these platforms, the less chemotherapy are going to use without compromising the outcome. So, I think this is something that we have to incorporate, in my opinion, in the clinical practice. I don't know, being in the United States, if you agree or not.

Dr Rugo: I agree completely, and I think where that controversy exists it's important. Now there are 2 areas of particular interest for me. One is in the neoadjuvant setting for higher-risk HR-positive disease where we use MammaPrint in our I-SPY2 phase 2 adaptively-designed trials.

Further analysis of the data from this study has shown us that if you have the highest score on MammaPrint, we call it High2, the upper half of the high end, that those patients with HR-positive disease have a much higher chance of having a pathologic complete response (pCR) to neoadjuvant chemotherapy. They may also have a higher response to immunotherapy, something that's being worked on with additional gene signatures. New immune gene signatures, I think, will potentially be incorporated into understanding benefit of immunotherapy in HR-positive disease, so I think that's exciting.

I also use the Oncotype in the adjuvant setting for patients who don't receive neoadjuvant therapy. One area of interest is in the premenopausal patients who have node-positive disease. I'm still using it in patients where I really feel like chemotherapy is unlikely to benefit the patients if I use ovarian function suppression. Because in RxPONDER, less than 20% of women received ovarian function suppression, which we know improves outcomes.

Dr Cortés: I think that you nicely incorporated MammaPrint in the I-SPY2 trial. I think this is very like a model. Do you think that in the future we should incorporate these platforms to escalate or to deescalate future treatments in the adjuvant or in the neoadjuvant setting? Do we have to integrate this also in clinical research?

Dr Rugo: I actually think that we have now quite a bit of data to show that there are subsets of patients with higher scores who benefit more from chemotherapy and [those] who benefit more potentially from targeted agents. I think we need a little bit more data before this becomes routine practice. But I feel like incorporation of these kinds of data would've helped us understand RxPONDER better. We just need to go one step past the assays themselves. Now you could say that that corresponds to high Oncotype scores > 25. I think that we are already using this to some degree.

I think that you bring up an important point, which is that we don't really know how to best use these assays in patients where we are concerned about response to treatment. Then, once patients have had treatment and they had a high score, we know they're still at high risk for recurrence. So, there's been interest in cfDNA to try and understand which patients are at the highest risk of recurrence.

Do you think this is ready for prime time or should this only be used in the setting of clinical trials?

Dr Cortés: In my opinion, I think that this could be great for the clinical practice in the metastatic disease to try to optimize different mutations.

But, in my opinion, in the early breast cancer setting, this should be not used outside clinical studies for 2 key reasons. The first one is that we are not sure if we have to change the treatment based on the results of this ctDNA analysis. The second one is the patients that maybe if they have an increase in this DNA could be very difficult to live knowing that the possibility of recurrence is higher than expected without doing anything about that.

So, I think that for these 2 reasons, we have to be very cautious about using this analysis in the clinical practice in the early breast cancer setting. I don't know if you agree or not, Hope.

Dr Rugo: I agree completely. We have some fascinating data from I-SPY showing that a small number of patients who have cfDNA at the time of surgery after neoadjuvant therapy did not have recurrence right afterwards or even for our length of follow-up. We know that it increases risk to have cfDNA related to your tumor after you receive your treatment. But we also know that there are many ways to modify this risk that we've already incorporated into clinical practice. So, I do think we need the clinical trials to tell us that changing treatment and modifying risk solely based on cfDNA changes outcome. We don't have that yet so we shouldn't be using this test in standard clinical practice at the moment.

With that, I think that we've had a great discussion and we seem to be agreeing on all points, as usual. I think we've made some great advances, but we also need to really evaluate our technology carefully.

I really appreciate you joining me today, Javier, and to our audience, please continue to the next segment of this activity.

Chapter 5: Summary

Sara M. Tolaney, MD, MPH: Thank you so much for participating in this activity; I hope you found it educational and useful. It's really nice to see how much improvement we've made for patients particularly with high-risk HR-positive breast cancer, with agents now available such as abemaciclib and olaparib.

It’s really important to think about multidisciplinary care when making decisions for these high-risk patients and incorporating information not just from the medical oncologist, but also from her surgical oncologist, radiation oncologist, and pathologist. It’s also important to incorporate the use of genomic assays when making decisions about systemic chemotherapy.

Thank you again for your participation, and please continue on to answer questions that follow and complete the evaluation.

This transcript has not been copyedited.