Listen to Manali Bhave, MD, and Erin F. Cobain, MD, discuss their management of patients with HR-positive/HER2-negative early breast cancer including insights on identifying high-risk disease considering clinical/pathological factors and gene expression assays and answering healthcare professional questions on how to personalize adjuvant therapy for these patients.
In this podcast episode, breast cancer experts Manali Bhave, MD, and Erin F. Cobain, MD, discuss their management of patients with HR-positive/HER2-negative early breast cancer including insights on identifying high-risk disease considering clinical/pathological factors and gene expression assays and answering healthcare professional questions on how to personalize adjuvant therapy for these patients. Supported by an educational grant from Lilly.
Faculty:
Manali Bhave, MD
Medical Director, Phase I Clinical Trials Unit
Assistant Professor
Department of Hematology and Oncology
Winship Cancer Institute
Emory University
Atlanta, Georgia
Erin F. Cobain, MD
Associate Professor of Internal Medicine
Division of Hematology/Oncology
Breast Oncology Program
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan
Link to obtain CME/CE credit:
https://bit.ly/46RvtgH
Link to Oncology Breast Cancers with additional educational activities:
https://bit.ly/4h7R3AO
Dr. Cobain: Today we are going to be talking a bit about how we define patients with high risk, early stage HR+/HER2‑ breast cancer. Then after we define that population, we are going to spend quite a bit of time actually talking about the systemic therapy that is relevant for those patients in order to decrease risk of breast cancer recurrence.
With this first question of really, how do we define patients that have high risk HR+/HER2‑ early stage breast cancer, I think the traditional way that we are very used to thinking about this is by really anatomic risk. What we mean by that is measuring things like tumor size, number of lymph nodes involved by the cancer, and also some histopathologic features that are seen by our pathology colleagues when they are looking at these tumors under the microscope. Things like grade 3 disease or even a high Ki‑67 index. I think these are the types of parameters that have long been associated with prognosis in early stage HR+/HER2‑ breast cancer. Generally, the larger the tumor, the greater the number of lymph nodes that are involved by the disease, the higher the grade of the tumor or the higher the Ki‑67, and the more proliferative the cancer, generally, the greater the risk of breast cancer recurrence. Obviously, there has been a lot of interest in utilizing systemic therapy in order to decrease risk of recurrence for these patients.
However, in the more modern times, we have been able to really layer on additional tools beyond these anatomic features and basic features of histopathology in order to define risk. One of these is the use of assays such as gene expression profiling assays like the Oncotype DX recurrence score or the MammaPrint test, which are, in general, again, gene expression analyses that help us really in both prognosis and prediction of chemotherapy benefit.
We often think of these gene expression profiling assays as being along a continuum. They can be both prognostic, in the sense that when there is a low risk Oncotype or MammaPrint score that returns, we generally know that these patients have lower risk of breast cancer recurrence over the subsequent 10 years. Also, lower scores tend to correlate with less benefit from chemotherapy treatment and generally greater sensitivity to anti‑estrogen therapies.
In contrast to that, gene expression profiling results that are on the high end of risk generally correlate with greater likelihood of breast cancer recurrence over the subsequent 10 years. Specifically, greater likelihood of distant recurrence, and also these patients having greater benefit from chemotherapy. I think if we think of these tumors as highly chemotherapy sensitive, we know that administration of either neoadjuvant or adjuvant chemotherapy generally decreases risk of breast cancer recurrence for these patients.
Use of CDK4/6 inhibitors
Beyond Chemotherapy, I think one of the things that we like to think about now, utilizing for these patients that really has just come into the mainstream within the last few years, has been the use of CDK4/6 inhibitor therapy to further decrease risk of breast cancer recurrence. There have been two CDK4/6 inhibitors that have been demonstrated to have clinical benefit in terms of decreasing risk of breast cancer recurrence. They are ribociclib and abemaciclib, and they were studied respectively in the NATALEE and the monarchE clinical trials.
A couple of things I wish to highlight about these clinical trials before we delve into some questions about how we utilize these drugs in our in our patients that we see in clinic every day. One of the things that I wish to highlight is that the patient populations that were included in these two clinical trials are slightly different.
monarchE clinical trial
In the monarchE clinical trial, it was a requirement that patients had lymph node involvement by their breast cancer. They were eligible for enrollment if they had four or more axillary lymph nodes involved, or they could have between one and three axillary lymph nodes involved, and some other high risk feature of the tumor, such as a tumor that measured greater than five centimeters or a grade 3 tumor. The monarchE patient population is really what we would consider to be a very high risk patient population in terms of risk of recurrence.
NATALEE clinical trial
The NATALEE clinical trial population differs in that there were patients with slightly lower‑risk disease that were included. For example, there were even some patients that had no axillary lymph node involvement that were included in the NATALEE clinical trial. They could be lymph node negative and have a high genomic risk based upon, for instance, a high Oncotype DX recurrence score or a grade 3 tumor. Also really important to note that patients with macro metastatic disease in any number of lymph nodes were eligible to receive ribociclib within the context of the NATALEE clinical trial.
Durations of therapy
One thing we should note is that these two clinical trials used different durations of CDK4/6 inhibitor therapy. The NATALEE clinical trial, which studied ribociclib, utilized this drug for three years in combination with adjuvant endocrine therapy. In contrast, the monarchE clinical trial, which studied abemaciclib, used this drug for two years in combination with adjuvant endocrine therapy. We do not know for certain what is the optimal duration of adjuvant CDK4/6 inhibitor therapy. Again, there has not been a head‑to‑head comparison but these two trials chose different durations of CDK4/6 inhibitor use within the context of these studies.
Again, I started with this point, but I will just mention that both the NATALEE clinical trial and the monarchE clinical trial have demonstrated significant improvement in invasive disease‑free survival, favoring the use of CDK4/6 inhibitor in combination with endocrine therapy over endocrine therapy alone, and that has resulted in an FDA approval for ribociclib and abemaciclib for patients with HR+/HER2‑ early stage breast cancer that have high risk of recurrence as defined by the clinical trial eligibility criteria.
In a few moments, we are going to talk about some common questions we all have with use of these agents and really how we are using these drugs in practice.
Use of neoadjuvant or preoperative chemotherapy
Before we get to our questions, I just want to touch very briefly on one other topic, which is the subject actually of use of neoadjuvant or preoperative chemotherapy in patients that have high risk HR+/HER2‑ early stage breast cancer. I think that for those of us that treat breast cancer and are very used to treating patients with triple negative breast cancer and HER2 positive breast cancer that is clinical stage II or stage III, it has really become the standard of care that we are utilizing systemic therapy in advance of surgery in order to better understand that patient's prognosis and also to better personalize the treatment that they may receive in the adjuvant setting.
For example, patients with triple negative or HER2 positive breast cancer that have residual disease after neoadjuvant systemic therapy, we know have greater risk of recurrence, and we are often able to utilize agents like T‑DM1 in HER2 positive disease or additional chemotherapy like capecitabine in triple negative disease, to further improve outcomes for those patients that do not have optimal response to upfront systemic therapy. I think in HR+/HER2‑ breast cancer, this has been a bit of a conundrum because we are not yet at the point where we are personalizing or changing the adjuvant systemic therapy that we recommend on the basis of response to neoadjuvant systemic therapy.
Important things to keep in mind
But I do think there are some important things to keep in mind as we consider this option for our patients that we see in clinic. One of them is that if we are certain based on risk of recurrence, either based on anatomic risk or based on risk as assessed by a gene expression profiling assay, that chemotherapy is indicated, really the impact it has in terms of risk of recurrence is equivalent, whether we administer it prior to surgery or whether we administer it after surgery.
One of the things that may be impacted by administering it in advance of surgery is that we may be able to actually de‑escalate the surgical treatment that that patient requires. For example, if we know a patient requires chemotherapy and we administer it in advance of surgery, a patient who may have only been a candidate for a mastectomy at the time of diagnosis, may be rendered a candidate for breast conservation or breast conserving surgery if they are able to have substantial shrinkage of the cancer during the neoadjuvant chemotherapy treatment. It is also possible some patients actually are able to clear the axillary lymph nodes of disease and after neoadjuvant chemotherapy may actually be able to have a sentinel lymph node biopsy alone and may not require a completion axillary lymph node dissection.
I think from a research perspective, we are all really hopeful that administering neoadjuvant systemic therapy in some form in these patients may at some point actually personalize the care that they receive in the adjuvant setting. I do not think we are there yet, but I think that is something that there is a lot of research going into, and just wanted to highlight that administration of neoadjuvant systemic therapy is sometimes a very important consideration for these patients, who, understandably, are highly interested in making sure that the surgical treatment may not need to be as extensive and we may be able to decrease surgical morbidity.
Discussion
So, those are the introductory comments that we wanted to make, and I wanted to just pose a few questions to my colleague here, Dr. Manali Bhave for us to discuss. So Dr. Bhave, can you talk to the audience a little bit about how you use tests like Oncotype or MammaPrint, alongside clinical features, when you are trying to make decisions about systemic therapy for patients with early stage HR+ breast cancer?
Dr. Bhave: Yes. Thank you, Dr. Cobain. You brought up some really excellent points as you were going through topics for patients with intermediate to high risk, early stage, HR+/HER2‑ breast cancer.
When I think about the genomic assays, I mostly utilize them in the adjuvant setting to help predict benefit from adjuvant chemotherapy as well as to provide prognostic information. However, we are seeing now clinical trials that are utilizing these assays in the preoperative setting to better identify patients that are at higher risk, that would benefit from preoperative chemotherapy and maybe even variations of the type of chemotherapy and potentially immunotherapy, depending on level of risk and what those genomic assays show in the neoadjuvant setting.
I think that in the last several years, we have seen more data on the predictive value of these genomic assays in the neoadjuvant setting. However, again, mostly utilized in the adjuvant setting to help better predict benefit from chemotherapy and provide prognostic information. We also, as you mentioned, now have two adjuvant CDK4/6 inhibitors. The genomic assays are helpful to stratify patients at intermediate to high risk: high risk for abemaciclib, intermediate to high risk for the use of ribociclib in the adjuvant setting. Those are the scenarios in which I utilize genomic assays.
Dr. Cobain: Excellent. Then a follow up to that. What do you do when you have a patient where you are contemplating whether or not the clinical risk and the genomic risk maybe do not match? Are there scenarios where you maybe would not use genomic profiling assay because you think the clinical risk is just too high and you think that that patient probably merits chemotherapy regardless of genomic profiling score? Or maybe the converse of that; are there situations where the clinical risk is high, but you think the genomic profiling really would add additional value to the clinical decision making?
Dr. Bhave: Right. I think that is an excellent question. I think one where we are lacking data, but occasionally we do see that patient where there is discordance between clinical pathologic risk and then genomic risk. I would say that I have more patients where they have low clinical pathologic risk where I omit the use of genomic assays, as opposed to patients that are intermediate to high risk where I would omit a genomic assay. There are patients that have grade 1 smaller, luminal A HR+/HER2‑ breast cancers, where I feel that their genomic assay is likely to reflect a low risk disease. In those patients, I might omit sending off an Oncotype or MammaPrint score and directly discuss the use of adjuvant endocrine therapy. Again, just based off of those clinical pathologic features.
I think if there was a patient that had a low clinical risk but high genomic risk, that is a challenging conversation to have with that patient. I think I would be inclined to favor the use of the genomic testing to guide therapy, because, as most of my conversations go, I think most patients would rather have more than less treatment. But again I have a very challenging discussion with them about what discordancy actually means, anecdotally what have we seen in patients that have their level of clinical pathologic risk, but also review the data on why we utilize these genomic assays to help predict chemotherapy benefit.
I think if there was a patient that had high clinical pathologic features but low genomic risk, I am more likely to utilize the clinical pathologic features. Again favoring, escalation of treatment rather than de‑escalation with discordancy, because we, I think, always fear that risk of recurrence for these patients, although you have to look at the patient in front of you. If this is a patient that has a functional status that may not allow for chemotherapy, or comorbidities that would make it very challenging for us to get through chemotherapy, that that might be a patient where I would more favor use of adjuvant endocrine therapy and use of adjuvant CDK4/6 inhibitors as opposed to chemotherapy.
I think it is a case‑by‑case basis. I would be interested in hearing your thoughts too on this as well.
Dr. Cobain: Yeah. I agree with everything that you have said. I think one of the discussion points that comes up often at some of the tumor boards I have attended is that at least with regards to the data for Oncotype, there were not many patients, if any, in the TAILORx or the RESPONDER trial that had large primary tumors greater than five centimeters. Sometimes, for instance, we will see a patient with a 5.3 cm HR+/HER2‑ breast cancer that actually might be lymph node negative. Then the question is, is it appropriate, given the very large tumor size, to consider something like gene expression profiling to potentially make a decision about adjuvant systemic therapy? I think in those circumstances, particularly if there is no lymph node involvement, these are cases where we often might say it is actually very reasonable to consider gene expression profiling. Again, taking it on a case‑by‑case basis, but acknowledging that there is limited data in that scenario.
I would also say that I think while there is great research interest in understanding whether or not the patient population that has four or more involved axillary lymph nodes, we may be able to at some point understand that those patients may not benefit substantially from chemotherapy if they are low genomic risk. It is very important that we acknowledge that that data is not there at present. We do not have data that supports that. I think in general, when the degree of axillary lymph node involvement is four or more involved lymph nodes in a postmenopausal population, as long as my patient in front of me can safely receive chemotherapy, that is generally what I am recommending.
Then, of course, I think important to note the ongoing OFSET clinical trial in the premenopausal population, because right now, the standard of care for all of our premenopausal patients is that if they have any axillary lymph node involvement, the RESPONDER trial demonstrated that there was benefit to adjuvant chemotherapy. However, we all have this question about whether or not all the chemotherapy was doing in those with low genomic risk may have been causing ovarian suppression and thereby giving them optimal adjuvant endocrine therapy. The OFSET clinical trial is an incredibly important study that is really helping us to understand whether or not individuals who are premenopausal with limited axillary lymph node involvement, who we may normally give chemotherapy to, if they received optimal adjuvant endocrine therapy that includes ovarian suppression, would they have equivalent outcomes? With all of my patients who are premenopausal in that setting, I am really encouraging them to consider participation in the OFSET trial to answer that critical question.
Dr. Bhave: Absolutely.
CDK4/6 inhibitors: abemaciclib and ribociclib
Dr. Cobain: Great. Let us actually switch gears then to talking a little bit more in detail about the CDK4/6 inhibitors, so abemaciclib and ribociclib. When you are having the conversation with your patients about which CDK4/6 inhibitor we are going to select, acknowledging the differences that we have already stated between these two studies, how are you approaching that conversation, particularly in patients who would actually qualify to receive both agents?
Dr. Bhave: I think it is a good situation to be in, to have two adjuvant CDK4/6 inhibitors to select between. However, it does make it a more challenging conversation if a patient is potentially eligible for both. I will say that based off of the approval of abemaciclib for the node positive population first, as well as the two years of abemaciclib as opposed to three years of ribociclib, I am more likely to recommend the use of abemaciclib in adjuvant setting for my lymph node positive patients.
However, that comes with some caveats. The primary one being that abemaciclib can be challenging to tolerate. It can cause, as we all are aware, diarrhea, which can have a profound impact on quality of life. It can also cause myelosuppression as well as LFT abnormalities, not as much as ribociclib in terms of LFTs, but lab monitoring that we have to do with use of these agents. I think diarrhea is really the predominant one in which I have had to reduce dose or potentially terminate the use of abemaciclib early because of the impact on quality of life.
Again, for node positive patients, based off of the seven year landmark analysis, survival benefit, iDFS benefit, with the two years of abemaciclib, I am more likely to recommend abemaciclib over ribociclib in that lymph node positive population, unless there is tolerability issues.
For those patients that are intermediate risk, so those patients that are node negative but T2 and have another additional high risk feature, grade 3 or grade 2 disease but have high Ki‑67 or high genomic score, those are the patients that I have been having a discussion on adjuvant ribociclib based off of the iDFS benefit of about 5% with three years of ribociclib in the adjuvant setting.
I think sometimes the challenge really with ribociclib is the three years. I think we are all hoping we can have some additional data in the years to come on whether we can shorten that interval of time, but as of now we have data for three years. I think the other part with ribociclib, again, this is in that intermediate to high risk population where I am recommending ribociclib, you also have to be a little bit careful with QTc monitoring. On patients that are on cardiac medications or other medications that could prolong QTc, it is a challenging drug. You have to follow those patients carefully, ensure that they are maintaining the requirements for QTc.
So I do utilize both agents. Again, lymph node positive lean towards abemaciclib, in my node negative intermediate risk, those are patients that I am recommending ribociclib for.
Dr. Cobain: Yeah. Actually I agree with all that you have stated. I think one of the practical challenges just in clinic that I will add is that for patients that have the option for both of these therapies, obviously we want to discuss with them all options that are available and the side effect profiles of these drugs. This is adding actually a significant amount of time to the clinic visit to walk through all of this. It is complex data. The side effect profiles of the two adjuvant CDK4/6 inhibitors that are FDA approved really are quite different. For the patient in front of you, there may be reasons that one is a better option depending upon their other comorbid health conditions or just their general feelings about the two drugs and the side effect profile once they hear both of those options. We also just wish to acknowledge this is a visit that really you have to set aside a fair amount of time for to really talk through.
I think the other thing that I will emphasize is that the patients with HR+/HER2‑ early stage breast cancer really have now so many treatment options that are a part of the algorithm for them. It is often just they are feeling, I think, a lot of times understandably very overwhelmed by the number of therapies that we are talking about and the duration of all of these therapies.
I have really started to try and make an effort at that initial consultation where if I am clear that my patient is going to be recommended for chemotherapy, endocrine therapy, a CDK4/6 inhibitor, and potentially also bone‑modifying agent therapy, that I am trying to at least mention all four of those things at the initial consultation. I think a lot of times when we do not mention it initially and then patients get through surgery and they are coming back for a subsequent discussion, and we are layering on all of these additional things, it can just feel like a lot and very overwhelming, so the other thing is to start these conversations early, because at least if these drugs are mentioned as a potential part of the therapeutic plan, patients have the opportunity to actually do some of their own reading and gain a little bit better understanding so that when you are ready to implement these drugs, they feel like they've had the opportunity to have a little bit more information in advance of that conversation.
Dr. Bhave: Yeah, Erin, I think that is a fantastic point. I am so glad that you highlighted that. I as well go through the entire treatment plan with patients on my first consultation. Then we will say, now that I have gone through the general plan, let us take it step by step. Let us get through this step first. Chemotherapy if we are going to do that, surgery, radiation therapy, adjuvant endocrine therapy and potentially the CDK4/6 inhibitor. I think that is very helpful for the patient to go step by step, but also have an understanding of what the next five years are going to look like as well.
Dr. Cobain: Absolutely, absolutely. With that, we will conclude our conversation about management of high risk HR+/HER2‑ early stage breast cancer.