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Dr. Hurvitz: Welcome to The ASCO Post Roundtable Series on Updates in Breast Cancer. I'm Dr. Sara Hurvitz, professor of medicine and director of the medical oncology program at the University of California, Los Angeles Jonsson Comprehensive Cancer Center. Joining me today are two of my colleagues, Sara Tolaney and Bill Gradishar. I will allow each of them to introduce themselves. Sara?
Dr. Tolaney: I'm Sara Tolaney. I'm a breast medical oncologist at Dana-Farber in Boston. Thanks for having me.
Dr. Hurvitz: Glad to have you here. Bill?
Dr. Gradishar: Hi, I'm Bill Gradishar, chief of Hem/Onc at Northwestern in Chicago and a breast medical oncologist as well.
Dr. Hurvitz: Thanks for being here today. Today we'll be discussing recent updates in breast cancer, including data presented at the 2021 ASCO Annual Meeting, and we'll be interpreting these new developments into four patient case studies. Our second installment will focus on treatment options for hormone receptor–positive HER2-negative early breast cancer, including adjuvant CDK4/6 inhibitor therapy. So let's move on to a patient case. We have a 54-year-old perimenopausal black teacher who's been diagnosed with a T3N1 left breast cancer that's ER strongly positive, PR-negative, and HER2 negative. It is high grade with a Ki-67 of 35%. Staging scans are completed and are negative, and the surgeon has referred her to a medical oncologist for consideration of neoadjuvant chemotherapy. Sara, I'd like you to take us through how you think about a patient like this, hormone receptor positive, HER2 negative. How do you choose between neoadjuvant chemotherapy or neoadjuvant endocrine-based therapy?
Dr. Tolaney: It's a good question. Prior to utilization of genomic assays, I think most of us tended to use neoadjuvant chemotherapy, it was mostly our standard. But I think we've since learned that there are many tumors that are not going to be very sensitive to chemotherapy, and sometimes neoadjuvant endocrine therapy actually can be quite effective for many patients. So my approach generally has been to be getting genomic assays off the core biopsy upfront in a patient where I think neoadjuvant therapy could be beneficial, to really help guide me to select between endocrine therapy versus chemotherapy. So I honestly usually get an Oncotype off the core to help make that decision if there – this is a perimenopausal patient, but generally if it were on the high side, so above 20 to 25, I'd probably lean towards chemotherapy in a young woman.
Looking at her tumor though, this is a high-grade cancer with a high Ki-67. It sort of feels like a high Oncotype kind of cancer. And I think it would not be wrong to potentially omit a genomic assay in this case, knowing the clinical characteristics, and use chemotherapy here.
Dr. Hurvitz: Thank you. And Bill, do you agree with that approach? What would you recommend for her?
Dr. Gradishar: In this particular case, I agree entirely with Sara. The grade is high, Ki-67 is high, it's a big tumor, positive node in a younger patient. So I would tend to give chemotherapy. The typical setting where we would give endocrine therapy is usually stereotypically the way older patient, the patient who you don't think can tolerate chemotherapy or who has other comorbidities. But I think we're starting to revisit that issue. There's been a lot of work with biomarkers. Nadia Harbeck has done a lot of work defining groups of patients that may not require chemotherapy. And I think we're going to probably come to a situation where there are more patients who are getting endocrine therapy in the preoperative setting rather than less.
Dr. Hurvitz: Yeah, I completely agree. And it's actually interesting when you look at the randomized trials comparing neoadjuvant chemo versus neoadjuvant endocrine therapy, you really don't see much of a budge in path CR rates, or objective response rates, or breast-conserving surgery rates with the use of chemo, but I completely agree with you both. This patient is likely going to benefit from the use of chemotherapy at some point, so why not utilize it prior to surgery? In this particular patient, she does go on to receive neoadjuvant AC-T. She has a 2.5-cm residual tumor at the time of surgery and four lymph nodes out of 10 are involved. It remains ER-positive, PR-negative. Now the Ki-67's 10%. She will receive radiation and agrees to have radiation post-mastectomy; however, she declines capecitabine. She's gone through the data with her oncologist and feels that she'd prefer not to do this given much of the benefit seems to be in triple-negative, at least from CREATE-X.
I want to focus now on the endocrine therapy treatment options, and I'm interested in hearing from you not only which endocrine therapy you would have utilized in this woman who's not yet in menopause and also what your thoughts are on the use of adjuvant CDK4/6 inhibitors. I'll start with you, Bill. Can you weigh in here a bit?
Dr. Gradishar: Yeah. So this is a patient who remains at high risk for a recurrence because of that tumor burden found at the time of surgery. There is some sense that she did have a response. Obviously the tumor seems to have gotten smaller, Ki-67 is lower. So I would certainly not give her more chemotherapy. And the one thing we might've considered, she declined, although as you pointed out, it may not have been that likely to help being ER-positive. So the standard would be tamoxifen, but in this high-risk patient who is perimenopausal, I would probably suppress her ovaries or make the case for removing them, rendering her postmenopausal, in which case you could give an AI. And that lends itself to the question of considering a CDK4/6 inhibitor. And there is data that supports that.
We have a couple of data sets with palbociclib, the PALLAS study, which was an adjuvant trial, which did not show that there was an advantage to giving palbociclib in combination with endocrine therapy. And again, these trials are somewhat different in terms of the characteristics of the patients who were involved, but bottom line, at least in the design of PALLAS and the characteristics of the patient, the addition of palbo made no additional risk reduction.
And in PENELOPE, in patients who had residual disease or ER-positive, then the question was following surgery, whether adding a CDK4/6 inhibitor, again, palbociclib, would add any further risk reduction to endocrine therapy. There was initially some hint, maybe there'd be an upside to doing that, but with longer follow-up, the lines are not suggesting any difference between the two groups.
Finally, we come to abemaciclib in the monarchE trial. Here with a high-risk patient population, and I think this patient would probably fit, that there was an advantage to adding abemaciclib in terms of risk reduction. So I think that although we don't have an approval yet for abemaciclib, it would be a consideration for this patient to consider it.
Dr. Hurvitz: Yeah, these are tough cases. It's not yet approved in the adjuvant setting, but I think we all have patients in our practice where we'd be tempted to add abemaciclib. Sara, can you give us your impression of the monarchE data? And there was also an interesting analysis done, I don't know if you want to touch on it, from PENELOPE-B, looking at the intrinsic subtyping and based on outcomes. Maybe you want to touch a little bit on that as well?
Dr. Tolaney: Yeah, I think the adjuvant CDK4/6 inhibitor data was pretty surprising to us because we had seen such uniform benefit from the CDK4/6 inhibitors in the metastatic setting. I really just thought all these studies were going to be clearly positive. So I got very confused when I saw these data emerge because, as Bill noted, we saw no benefit in PALLAS, which again, was shocking to me. And then when we saw PENELOPE-B, it did seem like there was early separation of the curves, but then out to four years of follow-up, no benefit, whereas monarchE does have a 30% reduction in invasive disease-free survival events. That being said, the follow-up is a median of 19 months, so it is on the shorter side. But it really is a dramatic difference, and these are mostly distant events that are being prevented, so I think a very important thing.
I think the challenge here is these trials are all designed pretty differently, where monarchE was a little different because it really picked very high-risk patients. You had to have four or more positive nodes, or if you're a one to three positive nodes, you had to have big cancers of over 5 cm, or a high-grade tumor, or have a high Ki-67. So it was really designed to pick these high-risk people who are likely to have early events. And so, in essence, they did that because you look at the outcomes in the control arm, and just at 19 months, 11% of people have recurred, so in the end, just with endocrine therapy. So these are endocrine-refractory patients that are recurring early.
The interesting analysis you pointed out that occurred at ASCO was they specifically looked at those patients who had neoadjuvant therapy and looked at their outcomes. And in fact, when you look at that subgroup of patients, you see that the hazard ratio is actually a little bit better even than we saw in the overall population. It's around 0.61, suggesting even greater benefit in these particularly, again, high-risk patients. So I think that was reassuring that, again, the high-risk patients are deriving benefit.
But then you kind of put that in light of this interesting analysis that we saw from PENELOPE-B at ASCO, which looked at intrinsic subtype of the tumors and then looked at their outcomes. The analysis is challenging because the subgroups get to be kind of small. The luminal B cell group is small in this study, but you do see this interesting exploratory analysis where the benefit from palbociclib in PENELOPE-B was actually seen in these luminal B patients, where you can see that their iDFS in the control arm is actually very poor, it was around 44%. But then you look at the outcome with the palbo being added, it's over 70%. And so clearly, a difference.
I think a lot of people had brought up the fact, well, was this a patient population difference? Was it that monarchE is full of a ton of luminal B patients who tend to be deriving a lot of benefit from CDK4/6 inhibition, whereas maybe the other trials weren't quite as packed with luminal B cancer. So yeah, I think we have a lot to learn. We need longer follow-up from monarchE. It'll be interesting to see what we see in the intrinsic subtype data for monarchE and see what that looks like. But again, I think in this particular case, she had four positive nodes despite having had pre-op chemo, a very high-risk cancer. And so I think, just as Bill alluded to, thinking about ovarian suppression with an AI and potentially adding abemaciclib here would probably be what I would consider.
Dr. Hurvitz: Yeah. That PENELOPE-B analysis for intrinsic subtyping using the HTG EdgeSeq panel was interesting to me. At first sight I thought, the luminal Bs are the ones getting all the benefit. That makes sense. But then if you look at the numbers, it was only 10% of the patients. They're only like 64 patients. The analysis only included about half the patients enrolled in the overall trial, so we do have to be really careful with drawing conclusions here. And I, too, am really excited to see the monarchE data, updated with this sort of biomarker analysis. Bill, before we close out this section, you want to mention the other study that we haven't yet heard reported, NATALEE for ribociclib?
Dr. Gradishar: Sure. We have three drugs, so we have to have three trials in every single setting. And the one that still is outstanding with respect to reporting is the NATALEE trial, which includes ribociclib for... I always forget, two or three years. We don't have data from it yet. So we'll have to see if monarchE is the lone one standing with a positive result or the NATALEE trial shows something similar.
Dr. Hurvitz: Thank you both for your excellent comments here in this particular situation. And just to summarize some key takeaways, we have three trials now for two drugs that have reported out data in the early-stage setting with the use of CDK4/6 inhibitors. Two studies with palbociclib failed to meet the endpoint. However, one study with abemaciclib, the monarchE trial, did show an improved invasive disease-free survival, but longer-term data is needed. We do need to consider toxicity, ILD, venous thromboembolic events that can be seen. And this is not yet FDA approved, though as my colleagues have indicated, in the very, very high-risk patients is something that I think clinicians are beginning to consider. Ribociclib data is not yet available. We're awaiting the NATALEE trial to be reported out of three years of ribociclib in medium or very high-risk patients.
This brings us to the end of this case. Please see the other segments for further discussion about the latest data in breast cancer or visit ASCOpost.com. Thank you.