Introduction

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice and welcome to What Clinicians Want to Know Part 2. Last night, we talked about HER2-positive breast cancer. Tonight, we’re talking about hormone receptor-positive breast cancer. We have an awesome faculty tonight, Dr Aditya Bardia from Mass General Hospital in Boston and Harvard Medical School, Dr Matt Goetz from the Mayo Clinic in Rochester, Dr Virginia Kaklamani from the UT Health San Antonio Center here, Dr Kevin Kalinsky from the Winship Cancer Institute of Emory University, and Dr Hope Rugo from the University of California, San Francisco.

For the clinicians here in the meeting room, you have iPads that have all the slides for the faculty. There’s also a survey that you can take that’ll really help you get more out of the meeting. If you have any cases or questions for the faculty, you can submit them through the iPad as well as doing the evaluation.

For our many attendees online tonight, and there was a whole bunch of — hundreds of people in there last night, the same features are present in the Zoom chat room. We’re going to do a video off of this meeting as well as the one last night for your colleagues who weren’t able to attend. We’ll let you know when that’s ready to go.

We’re heading over to New Orleans as we always do after San Antonio. So tomorrow, believe it or not, we’re actually doing 3 symposia there starting at 11:30 in the morning. We’ll magically appear there talking about CLL first with a great faculty. Same format as what we’re doing here tonight. Then, lymphoma in the afternoon at 3:15. And then, we’ll finish out with multiple myeloma.

We’re really excited to do these 5 meetings because actually, the last time I personally was at San Antonio and ASH was in 2019. And in 2019, we could not put on a meeting like we’re putting on tonight. Because what we’re going to do today is bring to you — we’ve always had as our mission to try to meet the needs of community-based medical oncologists, particularly general medical oncologists. And now, with the widespread acceptance of Zoom technology, we’ve been able to work with these docs. I’ve done hundreds of sessions, closed recordings with docs in practice the last 2 and a half years. Picked up cases, questions and then brought them to investigators. And that’s what we’re going to do here tonight, really to directly allow these physicians to chat or to really ask questions. You’ve heard about TikTok, well this is TikTonc. We’re going to show 9 videos tonight and the average length is going to be about a minute. But I think hopefully, you’ll get more of a flare for the real-world of how hormone receptor-positive breast cancer plays out in the actual patient care setting.

So here’s where we’re heading tonight. We’re going — this is — we have 5 presentations. They’re going to cover some important issues in management of hormone receptor, that’s one meeting. But then, the meeting within the meeting will be, if we can just go back to that last slide, the real cases that we’re going to be presenting. We’re going to start out — yeah, so real-world cases. We’ll sort of go back and forth between 2 meetings tonight. I’m really interested to see what your thoughts are about it.

So we’re going to start out talking about genomic assays in the management of hormone receptor-positive disease, specifically HER2-negative disease. And Matt, in a minute, is going to review some of the data. We want to start out with some cases and questions.

Case: A premenopausal woman in her early 40s with 9-mm, Grade III, ER/PR-positive, HER2-negative, node-negative infiltrating ductal carcinoma (IDC) – 21-gene Recurrence Score^® 22 — Alan B Astrow, MD

DR LOVE: And actually, Matt, I’m going to ask you to respond to this situation of a premenopausal woman, 42 years old, with a 9 mm Grade 3 ER/PR-positive, HER2-negative, node-negative tumor. And here are the questions.

DR ASTROW: Grade 3 IDC, but it’s only 9 mm. So it’s really pretty small. On the other hand, the Oncotype is a little higher, it’s 22. Does that patient need chemotherapy? My understanding of a patient like this is that while you could offer this woman chemotherapy based upon her score of 22 in a pre-menopausal woman, that, in fact, she would do just as well with ovarian ablation + tamoxifen, that chemotherapy, in fact, is not required in a patient such as this. Although then I would ask the panel, what is their experience with ovarian ablation in younger women? Because it is hard for women. It’s very serious hot flashes, quality-of-life concerns can play a big role. And, in fact, is the chemotherapy easier for women?

The other issue that comes up sometimes is if you’re going to treat the patient with ovarian ablation, how long do they treat the patients for? And which patients do they recommend bilateral oophorectomies on?

DR LOVE: So, Matt, any thoughts about this case? You have a small node-negative tumor, Recurrence Score of 22 in a premenopausal woman. How do you think that one through?

DR GOETZ: Neil, this is a really — this case brings up a number of faceting issues. I think one of them is, of course, that we see 2 dichotomous issues here. One of them is that this is a small tumor, 9 mm. But at the same time, we obviously have a high grade. And then, sort of we get the 21-gene Recurrence Score and it’s sort of right in the middle. So what do you do in this situation? I think there is — one thing that I would say is that we have to remember that tumor size is still highly prognostic. And so even though this has some biological characteristics that are higher-risk such as Grade 3, we would think of it in this situation that just the size of this tumor makes me pause before moving on to, let’s say, chemotherapy. The 21-gene Recurrence Score, that fact that it’s sort of in the low 20’s, really suggests to me that one could optimize endocrine therapy. I don’t know necessarily that this patient needs an AI + OFS, but I certainly would be thinking about giving ovarian function suppression to this patient. And my view on this would be to treat her for 5 years.

And the other thing, the question that was brought up by this physician is bilateral salpingo-oophorectomy. I’m not doing that on my patients, especially in this situation where, you know, I’m not quite sure what the tolerability is going to be of the ovarian function suppression. And that’s the beauty of ovarian function suppression, is if you don’t tolerate it, don’t give the next shot. If the ovaries are out, you don’t have a chance to go back. So my view on this would be to optimize endocrine approach, probably tamoxifen + OFS. I wouldn’t be remiss at giving an AI + OFS, but my guess is this patient would do well with tamoxifen + OFS.

DR LOVE: So, Virginia, any thoughts? He brings up the provocative question, is 4 cycles, if you’re going to really choose if you want to that maybe 4 cycles of TC would be easier than 5 years of ovarian suppression. Any thoughts about that? And in what situations do you use ovarian suppression ablation as opposed to just tamoxifen alone?

DR KAKLAMANI: And I think he may be very right, very correct, right? It’s 3 months of chemotherapy versus 5 years of other therapy. So in this case, I actually would run the RSClin score. And that would help me determine the first question, does this patient need chemotherapy or not? And typically, you have to present the data to the patient, give them the absolute benefit and then let them make that decision. And then, a lot of times, I do look at the STEP analysis which is an analysis based on the TEXT and SOFT that, again, gives us the potential benefit of ovarian suppression. Because when you look at the absolute benefits from TEXT and SOFT of OFS, they’re not very big numbers. And most of these patients that benefited were the ones that received chemotherapy. And so you want the higher-risk patient that will benefit from that OFS.

DR LOVE: So you know the art of oncology, last night, we were talking, we talk all the time now about involving patients in decisions when we really don’t know, have a clearcut answer. Kevin, I’m curious about your thoughts about this general scenario, but also in terms of node positivity in not only the premenopausal patient, but I wonder with all the attention talking about premenopausal, people are missing the fact that, you know, in the postmenopausal patients, we have some very clear data in the node-positive situation.

DR KALINSKY: Yeah. I think just to reiterate, I also think that this would be a patient it’s important to mention it’s not just the score by itself, but it’s the clinical and pathologic features. And that’s where RSClin really is extraordinarily helpful with how individualized what the risk is. I want to mention that we did see updates here from TAILORx that have about a median follow-up of 11.5 years or so. And they showed, and these were exploratory analyses, that if you look at the patients who were low clinical risk or high clinical risk with this Recurrence Score of 21 to 25, that was the population who did seem to benefit from chemotherapy. So this would be part of the conversation. In terms of node positivity, a patient who has a Recurrence Score, is premenopausal, she had a node involved, her Recurrence Score is 22, I would have this conversation about chemotherapy. Somebody who was postmenopausal, however, clearly from RxPONDER, no chemotherapy is needed.

Case: A premenopausal woman in her mid 30s with 3.6-cm, ER/PR-positive, HER2-low (IHC 1+), sentinel node-positive (4/4) multifocal IDC after bilateral mastectomies, adjuvant AC-T and ovarian function suppression (OFS)/aromatase inhibitor, Ki-67 50% — Laila Agrawal, MD

DR LOVE: All right. Well let’s go on to another case. And it starts to get into another issue we’re going to get into tonight. Some of these major issues, there are so many questions about, we’re kind of bringing in early even before we start talking about the data, so we have time to really explore this throughout the meeting. And this case of a young patient, another young patient, 35-year-old premenopausal woman with very high-risk disease brings up the always interesting issue of the use of adjuvant CDK, specifically abemaciclib. Here’s Dr Agrawal.

DR AGRAWAL: She was diagnosed with a Stage IIIA/IIB pT2pN2 left breast multifocal invasive ductal carcinoma. And on upfront bilateral mastectomies and sentinel lymph biopsy, she had 4 of her lymph nodes positive. She underwent adjuvant chemotherapy and proceeded with endocrine therapy with ovarian suppression and an aromatase inhibitor.

Which patients would you consider an adjuvant CDK4/6 inhibitor in addition to their standard endocrine therapy? There’s a bit of a difference between the clinical trial inclusion criteria, the results that were published, the FDA approval, and the ASCO and NCCN recommendations. How do you interpret those differences? How do you interpret the benefit to the patient?

In my experience, the adjuvant abemaciclib has generally gone pretty well. I do have to make dose reductions for side effects including diarrhea and fatigue. If this patient had a BRCA mutation, how would you decide between adding adjuvant olaparib, abemaciclib? Would you select one? Would you use them in combination or in sequence?

As we start to use more PARP inhibitors in the treatment of breast cancer, what are some toxicities to look out for and what are some ways that you’ve been able to manage those toxicities?

DR LOVE: So, Aditya, again, this is a gigantic topic. We’re going to look at the data in a little bit, but just to sort of start to get into it. One thing I’m just kind of curious about is she mentions the issue of tolerability of adding in abemaciclib on top of other agents, how you find it. And, for example, how would you compare it to tamoxifen, better, worse or around the same by adding in? And how much quality-of-life issues come up with 2 years of abema?

DR BARDIA: Yeah. Good question. So this is about abemaciclib in this patient with high-risk. So the first thing is, I would consider abemaciclib for this patient. This is a patient who would have met criteria for monarchE. There were 4 positive lymph nodes, so that meets criteria for monarchE. So I would consider abemaciclib for this patient. The other group would be if this patient had 1 to 3 positive nodes with Grade 3 or Ki-67 of more than 20%. That would be the other group.

In terms of tolerability of abema, the #1 side effect is diarrhea, but it’s usually an early side effect. And if patients are given antidiarrheal medications and they do well for the first 3 months or so, in general, they do well for the rest of the duration of the CDK4/6 inhibitor. And if you look at monarchE, the majority of discontinuations of abemaciclib were within the first few months. So the key is to ensure that you provide good supportive therapy in the initial few cycles with abemaciclib.

Now abemaciclib does have a small, but known risk of increasing venous thromboembolism. So, in general, we don’t combine it with tamoxifen. If I were to use abemaciclib, I would use it with an aromatase inhibitor +/- ovarian suppression if a patient is premenopausal. From a quality-of-life perspective, it’s predominantly the diarrhea. We’re able to control the diarrhea. Because it’s a CK4/6 inhibitor, it does not cause the menopausal symptoms that endocrine therapy can cause, but it can impair quality-of-life because of diarrhea. So supportive therapy is critical.

DR LOVE: So, Hope, Dr Agrawal shared with me that she actually has had 2 patients who were BRCA positive, high-risk in this situation. And the question that she brought out, do you give them sequentially? Do you give one versus the other? She chose in those situations to use olaparib because of the survival benefit. How do you deal with that situation?

DR RUGO: I would deal with it fairly similarly. I will say for a patient like this who has high Ki-67, Grade 3 disease, node-positive, that we strongly recommend neoadjuvant therapy and an evaluation of the tumor by whatever you need to evaluate it by to determine chemotherapy because it’s nice to give the chemotherapy first if you can. You get a better idea about response. And then, you can tailor your treatment a little bit which actually helps with the quality-of-life for the patients. They feel very committed to the abemaciclib if they have residual disease. But then, you wouldn’t not give it if all the cancer melted away. And some of these cancers are basal-like and they do really melt away with the chemotherapy and they have a pCR. So in this case where the patient was treated in the adjuvant setting, you’re kind of stuck. And we do — in general, I don’t know anyone who doesn’t recommend a PARP inhibitor in this setting first. So if she has a BRCA2 mutation, we would give the PARP inhibitor first. I think the question then comes up about what do you do after the first year? And in somebody who has Stage III disease who is young, I think some of us would even consider giving abemaciclib after the first year with no data at all. Because also, at this meeting, we saw this amazing carryover effect from the abemaciclib.

And then in terms of tolerability that she was wondering about, the side effects of olaparib, they certainly add to the toxicity you have. But, in general, patients manage it pretty well. You’ve got to watch out for the anemia, a little bit of nausea/headache, but dose reduction works really well for olaparib. And mostly, people tolerate it pretty well.

I will say one last thing. My experience with the diarrhea is the reason why it gets better after the first few months is because you’ve dose reduced. And if you don’t dose reduce or if people are still getting diarrhea at 200, they have diarrhea up until the day they stop. And the reason why it’s better is because they’re taking a half of loperamide every day. And I’ve found that really negotiating with people about taking little bits here and there works really well, but they have diarrhea.

DR LOVE: So general medical oncologists have spent a lot of time with PARP inhibitors the last couple of years in ovarian cancer. Really, a lot of experience on the granularity of issues there. Virginia, Hope brings up the interesting idea o neoadjuvant therapy in ER-positive, HER2-negative situation. I hear so many cases of people where they try it and the patient doesn’t respond. But what about the use of genomic assays in the neoadjuvant setting? We did a survey, we actually had a poster at the 2019 meeting, on the practices of investigators. We found like about 1/3 of them were using genomic — mainly Oncotype in the neoadjuvant situation. Is that something you ever do? And what are your thoughts about that strategy?

DR KAKLAMANI: And I do that. And I think we’ve started doing that a little more in the beginning of the COVID pandemic when we had patients and the ORs were closed and we had to make decisions on what to do with these patients with ER-positive breast cancer. And so the decision was, do you give them chemotherapy or not? And what do you do in the adjuvant setting? You do a genomic assay to decide. And so I did that. And I’ve continued doing that in the patients that the surgeon sends to me and says I think they will benefit from a neoadjuvant approach. Because at that point, I need to make a decision, is that neoadjuvant approach chemotherapy or endocrine therapy?

DR LOVE: Have you, incidentally, seen tumors melt away as Hope alluded to, ER-positive, HER2-negative?

DR KAKLAMANI: I wouldn’t call them melt away. And I’ve been a little disappointed with the activity of CDK4/6 inhibitors in that neoadjuvant setting. And we’ve had now a few trials that haven’t really blown us away with the results which is something that I wouldn’t expect given the amazing response rate we see in the metastatic setting.

DR LOVE: Okay. Hope?

DR RUGO: So the tumor is just to qualify. We are the first center of I-SPY2, a multicenter trial of which others here participate in. And we do a MammaPrint for a 70-gene assay. And what happens with the ER-positive tumors that really melt away is they’re on the very high end, so close to -1, and those tumors also, there’s a much higher risk that they’re basal-like and those really do respond. It’s just not the standard ER-positive. Even if they’re right around 0 and on the high-risk side, they don’t respond as well.

DR LOVE: So I’m looking forward to hear what Aditya has to say about maybe the future of T-DXd in HER2-low hormone receptor-positive. Maybe that’s going to fit in the mix. Matt, you had a comment?

DR GOETZ: Just one additional comment. Not too long ago, I had a clinician call me up and we had a patient, a similar patient such as this, perhaps maybe not quite as high-risk Grade 2, but higher Ki-67. And the clinician said to me, I would like to give neoadjuvant chemotherapy because I’d like to downstage the axilla. And I said I’m not sure about the data for that. And so I’m going to share shortly the data, but the bottom line is that we all know about total pCR for neoadjuvant. It’s low, 5, 7%. We’re not all impressed. But what I was really impressed about when we looked at the NCDB and we looked at our own data, we actually downstaged the axilla in about 14% of patients, 15% of patients and actually variability based on age, premenopausal status, Ki-67. So I think there are advantages. I really agree with Hope that giving neoadjuvant chemotherapy, that there is — obviously, we know the response rates are lower, but if we only look at total pCR, we actually may miss the boat a bit.

DR LOVE: That’s really interesting.

Dr Goetz presentation

DR LOVE: Okay, Matt. We asked you to review some of the relevant data.

DR GOETZ: Thanks, Neil. So I’m going to just talk a little bit about the current role of genomic assays. The focus today is going to be on the Recurrence Score. We’re going to talk about the Phase III TxPONDER trial. I’ll look over every once in a while at Kevin to see if he thinks I’m on the right page with that. There was some updated findings including the 12-year event rates from the TAILORx study, a very important study, of course, and Joe Sparano presented those data earlier. And then we just mentioned it, what about the 21-gene Recurrence Score and neoadjuvant chemotherapy decision making? Should you do that? And then I think I’m going to end with just some insights with regard to this poor correlation between the Recurrence Score and chemotherapy response in premenopausal patients. Why is there — why don’t we see it perhaps maybe as robustly in the postmenopausal setting?

So many of you are familiar with, this came out earlier this year, an update on the biomarkers for adjuvant endocrine and chemotherapy in early-stage breast cancer. And one of the things that the panel said was, well we know all about the role of Oncotype and MammaPrint and some of these other biomarkers. You can use those, especially in node-negative and node-positive postmenopausal patients. But gee, based on the data from RxPONDER, there’s now insufficient evidence to recommend a biomarker for use. And the NCCN probably disagrees a little bit with this. And I think when I look at this, I see it as 2 things. #1 is we always think about a biomarker as obviously the predictive nature, but we have to remember that the Recurrence Score actually gives us prognostic information as well. And so that’s actually quite important when you’re talking about hazard ratio, the benefit of chemotherapy, understanding where that patient is. And the hazard ratio actually, the benefit of chemotherapy, or the hazard ratio might be, it’s the same, of course, but the absolute difference is going to vary based on your underlying risk. And so I think that from my perspective, clinicians are still using the Recurrence Score in certain situations for premenopausal patients or node-positive. I’ll tough upon the node-negative data in just a moment.

So here’s the RxPONDER, again, originally published in 2021 and then updated data from Kevin last year. Here’s the RxPONDER trial schema. You’re familiar with that. Patients with a Recurrence Score of 0 to 25 randomized to chemo followed by endocrine versus endocrine therapy alone stratified by Recurrence Score, menopausal status and axillary surgery. And so the updated analysis that was presented last year really focused on, again, the — we continue to see with further updates that there is no benefit of chemotherapy in the postmenopausal setting. But, again, there is this small benefit in the premenopausal setting. This, again, is just looking at DRFS, again, stratified by menopausal status. And you’re seeing that there clearly still is a difference here, postmenopausal versus premenopausal.

So I’m going to switch on — or switch and go to the TAILORx. Again, these are the data that was just presented by Joe earlier this week. As you recall, the TAILORx trial took patients node-negative, either pre or postmenopausal, ER-positive, HER2-negative, T1c patients. And if they were a Recurrence Score of 0 to 10, they received endocrine therapy alone. If they were a Recurrence Score of 11 to 25, of course, they were randomized. And greater than 25, they received endocrine therapy plus chemotherapy. So the updated data from this study were presented. Essentially, the updated data really do indeed hold for the overall trial, the intent to treat trial. There’s no benefit of chemotherapy that’s obviously seen. You’re looking at IDFS, DRFI, relapse free interval and overall survival. And I think one of the things that really struck me is if you look at the 12-year event rates, we really don’t see so much difference anymore between the 0 to 10 and 11 to 25. The curves are sort of on top of each other. But clearly, this biomarker is still prognostic. You can see that for patients that are greater than 25, you can see the clear differences in all these endpoints here.

So if we look at the — what continues to be a question, this was the case that was raised earlier. Well what about those patients who are less than 50? Interestingly, if you look, and I’m going to skip through this and move more right to this slide right here, you can see in those patients looking at 12-year distant relapse free interval that in the Recurrence Score of 16 to 20, we didn’t really see much of a benefit. But yet, if you stratify based on clinical risk, now you’re beginning to see a little bit of difference. And then, of course, Recurrence Score 21 to 25, you see this larger magnitude when you stratify by clinical risk.

So I think our conclusions here, we continue to say that adjuvant chemotherapy provides no benefit in postmenopausal ER-positive, node-negative patients and in postmenopausal ER-positive, HER2-negative with 1 to 3 positive lymph nodes, Recurrence Score 0 to 25. So, again, this question continues to arise, why did chemotherapy provide benefit in these premenopausal patients, really both in TAILORx and RxPONDER? So there’s 2 hypotheses and I think both of them have merit. Of course, the endocrine hypothesis is that within these trials, they actually delivered inadequate endocrine therapy. And if you’d deliver proper endocrine therapy, we wouldn’t have seen this such a conundrum. We would have seen findings in the premenopausal that would have mirrored the postmenopausal.

But then, there’s this other hypothesis. And that is that the chemotherapy that’s being delivered in these younger patients is actually related to the fact that these young women are enriched in homologous recombination deficiency. They’re more likely to get chemotherapy benefit. The tumors actually melt away in younger women versus older women not because their menopausal status per se, but because of changes in perhaps mutations that might confer response to chemotherapy. This totally is a hypothesis.

I just show you here the SOFT and TEXT. We have recent updated data by Meredith Regan. This is in press. And, again, you can see that when you add — when you give proper endocrine therapy, you gain. Looking at distant recurrence free interval, less so right now in terms of overall survival.

And I just like to show this figure here. This is an oldie, but goodie, but boy, is this important. This is the Oxford Overview from 2005 where you’re looking at the benefit of chemotherapy by entry age, less than 50 or 50 to 69. All these women received tamoxifen. And one of the hypotheses is that in these younger women, and you can see on the righthand side, maybe they’re getting a direct cytotoxic effect of chemotherapy perhaps because they’re more likely to have tumors that respond to chemotherapy. And you can see in the postmenopausal patients on the below righthand side, you get benefit, but it’s much smaller. So the proportional risk reductions are a bit smaller.

So this is really going to be sorted out by this trial. This is a really important trial, the BR009. This has now been approved by the Breast Cancer Steering Committee. And it’s taking premenopausal patients who really have — we have this conundrum right now, so node-negative, higher Recurrence Score or node-positive 0 to 25 Recurrence Score, stratifying it by those factors here. And they’re either going to get chemotherapy followed by ovarian function suppression and an AI or ovarian function suppression and an AI. And once and for all, we’ll answer this question hopefully.

Just a few things, I’ve just got a few minutes left. 21-gene Recurrence Score and neoadjuvant chemotherapy. This is a meta-analysis that was published actually about a year ago in the British Journal of Surgery. And the bottom line is that 21-gene Recurrence Score is associated with pCR. Interestingly, on this, if you look at Recurrence Score greater than 25 versus greater than 30, it’s hard to know exactly what the cutoff is.

I’m just going to leave you with this slide. I just mentioned it earlier. This is an analysis we did in the NCDB. And I questioned this because a clinician asked me this question. And I was surprised when we looked at our own data in our own institution as well as NCDB is that if you give neoadjuvant chemotherapy for ER-positive HER2-negative breast cancer, you actually achieve nodal responses overall about 14%. But take a look there in those women that have a high Ki-67 and are aged less than 50. You’re seeing nodal responses, that is nodal complete response, that approach 30%. Does that mean anything? Absolutely. In the NCDB, it’s highly prognostic for survival. If you clear your lymph nodes, it’s highly prognostic. Is this really anything that’s earthshattering? It’s basically RCB. I’m accounting for not just the breast, but the lymph nodes. And this is what obviously I-SPY does as well. So I think that we have this question and the question — oh, I have one more slide.

Just a reminder, this is a nice publication by Mitch Dowsett looking at these individual modules by the Recurrence Score. The Recurrence Score is actually mainly driven by the estrogen module. And we may be missing some of the issues with regard to proliferation. And that may be why proliferation is still an important thing to look at in addition to the Recurrence Score.

So here’s my conclusion. And I’m not going to repeat everything I’m going to say. But I think the bottom line is that the NRG BR009 is going to be a really important study to help us sort things out as we go forward.

DR LOVE: So thank you so much. And when you mentioned the TransATAC, I was just kind of flashing, particularly for the people who are online today. We’re actually at the Marriott Rivercenter which, incidentally, since 2019 had a really nice Starbuck’s in there. So new carpet and looking pretty cool elevators. But I think we’re standing in the room where the ATAC trial was actually presented like about 20 years ago by Mike Baum. I think it was maybe a little bit larger and incorporated the whole thing. But interesting to think about how far we’ve come when all we had to talk about was do you get anything by adding the 2 or how much do you get? It certainly did change practice. But wow, we’re getting to a lot more different science. So, Virginia, I guess the talk about neoadjuvant genomic assays, someone on the Zoom wants to know how reliable biopsy is in terms of genomic assays. And I’m going to ask you also what role, if any, do you see of other genomic assays in breast cancer? In what situations do you use MammaPrint or another assay, Virginia?

DR KAKLAMANI: So I think and the data on Oncotype has shown that doing the biopsy and Oncotype on the biopsy specimen is reliable and you get very similar results to the actual excision — excisional tumor. So I do do that and especially if I have to make a neoadjuvant therapy decision. I typically just use Oncotype because my question typically is, do I need to give chemotherapy or not? And I feel that the data with Oncotype is more solid than other assays. But then when the questions are, should I give extended endocrine therapy to patients? Then, I might use the Breast Cancer Index. I’ll present some data from this year’s SABCS potentially suggesting that the Breast Cancer Index might tell us who needs ovarian suppression or not. So I think all of these assays are helping answer different questions.

DR LOVE: So a question from the audience. Again, Kevin, 32-year-old woman 19 weeks pregnant wants to continue the pregnancy status post modified radical mastectomy 1.6 cm ER-positive, HER2-negative, Oncotype 23. What chemo would you offer? What hormonal therapy post-pregnancy?

DR KALINSKY: Got it. So I think that for a patient who is nearing the 20-week point, and let’s just say in this particular context, this patient even if she is node-negative, I do have some concerns about, 1, pregnancy associated cancers, right? There’s some data that maybe these patients may be at higher risk. And I also want to reiterate, there are safety data about giving anthracyclines after 20 weeks. And when I do that, I often give that every 3 weeks. I don’t do that with growth factor. I think that that is one consideration for this patient. If the patient was node-positive, for sure I would think about giving chemotherapy.

Case: A woman in her early 40s with 5.5-cm, ER/PR-positive, HER2-negative, node-positive (20/21) IDC after bilateral mastectomies, bilateral salpingo-oophorectomy, adjuvant AC-T and initiation of letrozole/abemaciclib, Ki-67 3% — Susmitha Apuri, MD

DR LOVE: Okay. Well let’s move on and talk about some more cases. We were starting to get into the adjuvant CDK scene. So we have another young patient, 40-year-old woman with a big tumor, 5.5 cm, node-positive. You’ll hear the story. Interestingly, her Ki-67 is 3%. Here’s Dr Apuri.

DR APURI: She’s a 40-year-old woman. She was actually in the middle of IVF treatments, invasive mammary carcinoma, which was a low proliferation rate, Ki-67 of 3%, ER and PR positive, HER2/neu negative. And subsequently, left axilla lymph node dissection revealing 20 of 21 lymph nodes with metastatic carcinoma. And the final stage was pT3N3a. She did decide to undergo hysterectomy and bilateral salpingo-oophorectomy, and then she was started on abemaciclib at 150 mg dose along with the letrozole.

DR LOVE: Any questions?

DR APURI: Yes. I would love to hear them discuss the Ki-67 because clearly in her case it’s not a direct reflection of the stage of her cancer, Ki-67 of 3% versus 20 lymph nodes being positive, there is a huge discrepancy. So I would love to know if they still use the Ki-67 as an index, as a marker of aggressive nature of breast cancer.

DR LOVE: So, Aditya, would you like to comment on this case and her question about the Ki-67? Also, a very provocative editorial in the JCO about axillary dissection and the fact that we don’t do it. So how are we going to count number of nodes? Again, we could spend all day long talking about it, but let’s just get started. Any thoughts?

DR BARDIA: Yeah. I think part of this confusion is the discrepancy between the FDA label and how monarchE was designed and the ASCO and NCCN guidelines. I think the FDA label mentioned that you need to have high-risk disease, lymph node positive plus a Ki-67 of more than 20%. But monarchE enrolled patients who had lymph node positive that was 4 or more positive nodes or 1 to 3 with either more than 5 cm Grade 3 or Ki-67 of more than 20%. And I think the ASCO and NCCN guidelines have endorsed monarchE ITD population. And personally, I think that’s a good decision because for a patient like this who is young who has 20 positive nodes, I would want to use abemaciclib. And monarchE enrolled a patient like this in the clinical trial. And the benefit of abemaciclib is seen both in patients who have Ki-67 of more than 20% as well as less than 20%. It’s only prognostic, but it’s not predictive. The absolute improvement in disease free survival, obviously, would be lower in Ki-67 less than 20% because it's prognostic, but the relative benefit is similar. So I would consider abemaciclib for this patient who has 20 positive nodes.

DR LOVE: So, Matt, I’m just going to — I’m a simple person. Sometimes, I like to take a macro view of things. So let me ask you a simple question. Do you think that adjuvant CDK, abema, would benefit a patient who has node-negative disease?

DR GOETZ: That’s a great question. And the reality is that as we look at the data with the monarchE, what we’re seeing is a fairly consistent hazard ratio that’s independent, as Aditya said, of Ki-67. And so if you had a patient that was high enough risk, and by the way, I had one of these patients recently, that really had a number of high-risk features, and we discussed this. We obviously discussed the fact that there are no data. So one thing we will have, which I’m really excited about, is we’re going to have data from NATALEE that starts to bring in some of the node-negative because they allowed that. So we’ll be able to see, again, hopefully if NATALEE is a positive trial, we’ll be able to really examine the potential benefit in that subgroup of patients.

DR LOVE: Of course, that’s with ribo. So just to pursue this a little bit more, Hope. Coming out of sort of the classic teachings from the meta-analysis, you establish a hazard rate for tamoxifen, chemotherapy and then you estimate the absolute benefit by applying the hazard rate to the absolute risk. And so if you — even for very low absolute risk, people could consider something like tamoxifen because relatively, you know, compared to chemotherapy. So my question is why would that not apply to abema? And is somebody like the FDA or JCO — I mean, ASCO or whatever, really trying to make a judgement about the risk/benefit? So not a question of whether there’s a benefit. But in their judgement, you can’t justify based on the risk to use the drug. Am I reading that correctly? And do you agree with that?

DR RUGO: Yeah. I think it’s kind of a mixed bag. So we have PALLAS that enrolled a slightly lower-risk group of patients, different CDK4/6 inhibitor. It didn’t show a benefit. We know that women who have a lower-risk cancer although they benefit from tamoxifen, their recurrence risk is low and it continues, you know, whatever you have, 50% of them in the first 5 years and 50% from year 5 to 20. So if you wanted to see you’re going to have an impact giving 2 years of therapy that makes you tired, your hair is thin and you have diarrhea, so every time you eat, you have to carry loperamide in your — and if you go out for a spicy Chinese food, you’re going to have diarrhea. So the — or go for a hike, for example. And so this is a big issue. It’s a good drug, but you’re not going to see any benefit in someone who has a 4% risk of recurrence in the first 5 years. That’s where it doesn’t fall into that low-risk tumor group.

DR LOVE: So, Virginia, do you agree with Hope’s assessment? And I guess my question is, should the patient be involved in the decision? If this is a judgement about whether it’s worth it to go through what you just described if you think that’s a typical patient, should we, should the FDA, should ASCO be deciding this or should the patient be deciding it? There are financial issues as well. Super complicated. Again, we could spend all day on it. But any thoughts?

DR KAKLAMANI: I think that the patient should be involved in the decision. But we should also look for guidance from the clinical trials that we have. And so I, for example, follow strict monarchE criteria to decide whether somebody should be offered abemaciclib. I don’t look at the FDA approval for all of the reasons that Aditya mentioned. And my slides actually go over this too. But ultimately, it is a patient that’s going to be taking that drug for 2 years and they need to feel comfortable taking this drug.

DR LOVE: Yeah, both ways, in high-risk or not-so-high-risk.

DR RUGO: But you’re not going to give it, Virginia, to somebody who has a 1 cm ER-positive, low-grade, node-negative tumor.

DR KAKLAMANI: I will not.

DR RUGO: And the reason for that, besides the clinical trial, is also that the relative benefit, just like that patient that we don’t want to give chemotherapy to who has a 0.9 cm tumor, the relative benefit is small. So it’s hard to — even, you know, we have to help patients and give them our opinion too, we want it to be a shared decision making, but where you have zero data. And actually, you have one trial which suggests no benefit in lower-risk patients. I think you’re hard pressed. We expand the use. We give our ADCs earlier. We do all of this. But this is a situation where I think we really need to use the trial for guidance.

DR LOVE: So let’s introduce another issue. Kevin?

DR KALINSKY: Yeah, I was just going to say one more thing about that case. And the treatment discussion would be the same, but other questions about that particular patient. Does she have an unattended breast cancer? Was she getting mammography? I was a little surprised that this was a ductal. I would have been a little less surprised if this was an invasive lobular or pleomorphic lobular as well even though those are generally more proliferative. There’s something interesting about the biology of that cancer.

DR LOVE: And, you know, when you present a case in a minute, obviously, you’re just kind of using it for teaching purposes. For individual decision making, much more complex.

Case: A woman in her mid 50s with de novo ER-positive, PR-negative, HER2-negative ulcerated breast cancer with pulmonary and extensive spinal metastases — Jennifer L Dallas, MD

DR LOVE: And introducing another very complex decision, Aditya, I’d like you to comment on for this next case, choice of CDK in the first line metastatic setting. It’s a simple question, but not such a simple answer. Here’s Dr Dallas.

DR DALLAS: She had not ever had a screening mammogram because of a lack of health insurance.

On imaging, you could see the breast mass and it was noted to have skin thickening. But on physical exam, she actually had some ulceration through the skin. So it was a neglected breast cancer that was sort of coming through the skin at that point.

I started her on abemaciclib and letrozole as well as denosumab for the osseous metastases. She’s actually done very well with that.

And the most recent imaging shows improvement in her disease. And clinically, the breast lesion has improved significantly.

I would like to hear the faculty discuss how they go about choosing one of the CDK4/6 inhibitors. I chose abemaciclib in this situation based on the side effect profile because she had a lot of problems with constipation. And then the other thing was I was a little bit worried with the palbo that it might drop her white count and then the open lesion would be more of a concern. I think a lot of us don’t like the ribociclib as much just because of some of the monitoring aspects of it that can be a little problematic. But I do consider the survival data with the ribociclib.

For this patient, I would consider potentially sending her for resection of the primary just to mitigate the infectious risk. It’s definitely looking better. So it’s possible that maybe she doesn’t need any sort of resection. If it entirely heals up, maybe that won’t be a problem going forward.

DR LOVE: And you can see there was a mediastinal node there that went away. Aditya, any thoughts?

DR BARDIA: Yeah. And good questions. At 56, I would imagine this patient is premenopausal because — postmenopausal. If the patient was premenopausal, I tend to use ribociclib because we have level 1 evidence from the MONALEESA-7 trial. But for a patient that was postmenopausal, we have options of ribo, palbo or abemaciclib. Ultimately, I think there are 3 factors that need to be taken into account for decision making. The first is efficacy. The PFS is very similar with all these drugs, but there’s improvement in overall survival with the ribo and abema, but we’ve not seen it with palbo. This could either be purely trial and follow-up issues, what happened after the patient discontinued the treatment after the PFS event happened up until overall survival what happened in terms of posttreatment follow-up period in terms of their additional treatment or this could be that ribo does something or abema does something to the immune microenvironment which then results in a longer survival. And this was discussed today at the SABCS meeting. And maybe there’s some difference between palbo and abema and ribo in terms of modulating the immune microenvironment which contributes to the overall survival. It’s impossible to know outside of a head-to-head comparison, but the data are data. And right now, we have data of improvement in overall survival with 2 out of the 3 drugs. So that’s one factor.

The second factor is the toxicity profile. Abema tends to cause more diarrhea. Palbo tends to cause neutropenia. Ribo similar, but also small risk of QTc monitoring and LFT abnormalities.

The third is patient preference. And I think we cannot decide for the patient. We can present the data to the patient in terms of the side effect profile. And there are some patients who would actually prefer to take a drug daily rather than to remember taking it 3 weeks on, 1 week off. I had a discussion with an oncologist today who mentioned that she gives abemaciclib because the patients she sees, many of them get confused with this 3 weeks on, 1 week off, so they just take the medication every day. So I think all of these 3 factors need to be taken into account.

DR LOVE: The art of medical oncology. Kevin?

DR KALINSKY: Yeah, the other thing I just want to add, just pertinent to the data that was presented here was we saw results of the RIGHT Choice study which was a study that compared hormonal therapy and ribociclib compared to chemotherapy in patients who were symptomatic or had symptomatic visceral disease. When I was a fellow a hundred million years ago, we would have thought about giving these patients chemotherapy. But now, we see, and this patient is a good example of this where you can start out with hormonal therapy and a CDK4/6 inhibitor. We saw in this study that patients had this same sort of response rate, patients did better. And also, it’s worth noting, this is with doublet chemotherapy. And so I think that we’ve really moved away from starting out with chemotherapy in these patients given the significant activity that we see with the combo hormonal therapy.

DR LOVE: That’s a great point.

Dr Kaklamani presentation

DR LOVE: Virginia, let’s talk about some data.

DR KAKLAMANI: Absolutely. So I was asked to — looking at optimal duration of endocrine therapy, role of OFS, and we’ve talked a little bit about that, as well as oncofertility. And CDK4/6 inhibition in the early breast cancer setting. And then PARP inhibition as well.

So let’s talk about — oops. So we know from the Oxford Overview Analysis that risk of recurrence continues to increase after the 5 years that we initially thought patients had the high risk of recurrence. And that risk of recurrence really changes depending on the characteristics of the disease. Lymph node status plays a role, tumor size, tumor grade. Interestingly, PR and HER2 status do not predict risk of recurrence. And the numbers that I usually remember is a patient that has a Stage I breast cancer, after the first 5 years, there’s a 7% risk of recurrence every 5 years. So from year 5 to 10, it’s 7%, 10 to 15 is another 7%, 15 to 20 years, another 7%. So from 5 to 20, we’re talking about a 21% risk of recurrence in these T1N0 tumors.

And several trials have looked at this extended endocrine therapy and this is a list of them. And most of them have shown a minimal to modest improvement in outcomes.

So how do we decide? And really, genomically, the one test that has shown that we may be able to figure out who should receive extended endocrine therapy is the Breast Cancer Index where in patients here in the MA.17 trial that had a high BCI score had an absolute benefit from extended endocrine therapy with letrozole of 16.5%. So I think clinically, that’s pretty important.

And then the aTTom trial that looked at the 5 years versus 10 years of tamoxifen also showed that if you look at the BCI, it is, again, predictive of extended endocrine therapy benefit.

So how do we decide? Well I think we can decide based on some clinical factors that are listed here. But also, we have to look at tolerability. We have bone fractures, increasing risk of osteoporosis, bone pain, uterine cancer if a patient is on tamoxifen, and venous thromboembolic events.

Now when looking at chemotherapy and ovarian suppression and how do we preserve ovarian function, there is really great data to suggest that if we give a GnRH agonist during chemotherapy not only can we improve the ovarian function eventually of the patient, but also we will not impact on a risk of recurrence. And this is from one of the meta-analyses and some of the data that’s going to be presented on Friday with a little bit of a different topic. But, again, in the whole point of pregnancy is the POSITIVE trial that looks at stopping endocrine therapy in women that are young, ER-positive and they want to get pregnant and whether this will impact outcomes. And I urge you to look at this presentation. I think it’s one of the highlights of the meeting.

So I won’t go into TEXT and SOFT because Matt already mentioned that, but the one thing — one slide I wanted to show was the difference in patients that were on chemotherapy. And this is where we saw the benefit of OFS. We didn’t really see it in the patients that did not receive chemotherapy. We saw it in the patients that received chemotherapy. And obviously, my speculation is that those patients had a higher risk of disease. And so, yes, we need to look a t a relative benefit, but that absolute benefit for that specific patient is just so important.

Speaking of ovarian suppression, Dr Regan mentioned this at San Antonio, another trial actually from the SOFT trial performing the BCI assay. And interestingly, her data showed that the BCI low category was the one that seemed to get a benefit from ovarian function suppression. And their hypothesis was the exact opposite one. They thought that the BCI high patients would have a benefit from OFS, but it was the BCI low. Now is this ready for primetime? Probably not. They’re going to have a confirmatory study with TEXT. They’re going to have the exact same analysis there. Hopefully, those results will get replicated.

So the guidelines, ASCO talks about offering it in patients that receive chemotherapy, patients that have a higher risk of disease. And St Gallen talks about something similar, patients that have — that are under the age of 35, receive chemotherapy and have 4 or more positive lymph nodes.

So the monarchE trial, there was an update also at San Antonio this year and we went into the different criteria. What is interesting, and it surprises me that the FDA approved it this way, is the fact that only 9% of the patients belong to cohort B which was the Ki-67 high patients. So only 9% of the whole patient population is what the FDA looked at to approve abemaciclib in the high Ki-67 patients. And obviously, as the results showed, the benefit of abema actually increases with longer follow-up which we were all happy to see. And as Aditya mentioned, the different Ki-67 groups had similar benefits from abemaciclib. The only difference was high Ki-67 group had a higher risk of recurrence compared to the low Ki-67 group, but the benefit from abema was exactly the same.

And these are the 3 CDK trials that are already reported. The fourth one, NATALEE, I am told is going to report next year. So exciting to hear.

And then finally, talking about the use of PARP inhibitor. And we talked about this a little bit in one of the cases. What do you do? Well the OlympiA trial looked at this. And patients were 2 different groups, one was the triple-negative, the other one was hormone receptor-positive. Neoadjuvant versus adjuvant group. So these were pretty high-risk patients. If you were triple-negative, you had to have residual disease. If you were ER-positive, you had to have 4 positive nodes+ or residual — significant residual disease if you received neoadjuvant therapy.

And then the patients were randomized to olaparib for a year versus not. But there were a few issues with that study population. And Mark Robson gave me this slide. Patient population was young women, most of them BRAC1, most of them triple-negative, 82%, so a small number that was ER-positive. And then most of them were treated with mastectomies. And then, do we ever do this CPS+EG score? We can. It’s present online. We all love going online and playing little games, but do we ever do it in practice? And the answer is really no.

But the analysis was pretty striking. The latest data presented earlier this year in a plenary — virtual plenary showed an improvement in not only IDFS, but also overall survival. And you can see the curves separating early, remaining separated for the remainder of the analysis.

And this is a second overall survival interim analysis. And you can see the difference which I think is clinically meaningful. And obviously, we’re going to have more follow-up. This is just a 3-year OS rate.

As far as subgroups, all subgroups received — almost all subgroups received a benefit. You’ll see some of them that had just very few patients in there and so the 95% confidence intervals were pretty wide.

Side effects. Obviously, olaparib is going to cause some more adverse events, mostly nausea and some hematologic toxicities as well. So definitely not a benign therapy. But some of these young patients with BRCA positive tumors have a high risk of recurrence and it probably is worth giving olaparib to.

So the conclusion, extended endocrine therapy, but benefits are few and we need to find out whether the patient is going to receive a benefit from it. OFS during chemo can preserve ovarian function. OFS, I think the high-risk women in general. And can it replace chemotherapy? Who knows? The NRG trial will answer this question. And then for the CDK4/6 inhibitors, I give it to high-risk patients, the same with the PARP inhibitors.

DR LOVE: All right. Thank you. Just one follow-up question, Virginia. Next week, we’ll be doing a program off of ASH on AML. And I’m curious, you know, there’s a lot of discussion in ovarian cancer about the issue of, is there an increased risk of MDS and AML with PARP inhibitors? Which it looks like there is. It’s just a question of how much it is, whether it’s related to prior chemo. What about in breast cancer? What have we seen? Any thoughts? Do you bring this up to your patients?

DR KAKLAMANI: It looked like in the adjuvant trial there wasn’t a high risk, but there was in the metastatic trial. So we definitely have to be careful with that. And I do bring it up.

DR LOVE: Hope, any further comments about what, if anything, you say to your patients? And also, I think it was this patient that was getting IVF, but one of these last couple patients, and bringing up the issue of fertility presentation which was commented on. I’m curious, do you use the strategy of LHRH agonist during chemotherapy? And globally, what is your approach to patients who want to become pregnant?

DR RUGO: Those were all incredible questions. So first, what do I tell PARP inhibitor? I don’t — I’m not convinced that in breast cancer, we’ve seen an increased risk in leukemia. And certainly, in OlympiA, we didn’t see that. In the metastatic trials, it’s a little bit hard because some of it, and I think that’s where we see it in ovarian cancers, maybe it relates to the other chemo and interaction with exposure to chemotherapy drugs that may enhance the risk of leukemia. And I suppose if you have a breast cancer patient a lot of cyclophosphamide, maybe there would be an interaction there too. So I do talk to patients. I used to. Now, I say we give it in the adjuvant setting. There’s no risk. And I think the exposure, unfortunately, in the metastatic setting is not usually that long because people develop resistance.

In terms of fertility, we have, for a long time, used the approach that was studied actually in the POSITIVE trial and will be presented on Friday, just because I think in somebody who has 10 positive nodes, you’ve got to advise them about the risks. But for most of our patients, you’re really closing a door by saying you can’t have children the whole time you’re on endocrine therapy. We want to optimize their fertility options as much as possible. So we talk with every single premenopausal patient about harvesting eggs. And there is support or that. And our fertility group is phenomenal. You text them — I see the patient, I text them because he’ll get them in right away, or she because there’s 2 of them now. And that’s incredibly helpful. And they are very pro-ovarian suppression — ovarian function suppression during chemo. I’m thinking, you know, I don’t know if it works so well. The studies we’ve done always have issues using ovarian function suppression, but we do it. So I tell the patient this is what we do now. We don’t know if it will help for you. If you’re a little older, it’s going to be a little easier to tolerate. I think when you use ovarian function suppression, you enhance the toxicities because people go into menopause, right? So they get those side effects too. But most women choose to use the ovarian function suppression. And then, you have to pick some period of time where people could stop and try to get pregnant, but we want to keep that time relatively short. So we work with them a lot with this.

DR LOVE: So we’re going to go on to another case. But first, Matt, any comments on quality control and reproducibility of Ki-67? This has always been debated over the years. Now, it’s like in the middle of everything. How reliable is it?

DR GOETZ: This is a really important question. So Ki-67, over the years, there’s been a number of panels that have addressed the issue of reproducibility with Ki-67. So if you go from one laboratory to the next laboratory, you’re getting different numbers. Obviously, people want to control for the antibody, they want to control for the platform that you’re using. People have become better over the years at using specific software or image analysis. I think despite all that, we know that there are some issues. I think the reality is that for many of our patients, Ki-67 is something that, and we use it at Mayo, it provides — I don’t rely upon it solely, but I use it along with other factors in helping to make decisions. And obviously, what we are seeing now, of course, with monarchE is that we’re seeing benefit of abemaciclib regardless of Ki-67. There was some concern for a period of time, well what is the Ki-67 because I’m not going to be able to give them abemaciclib unless it’s higher or low. But I think we’re reassured now that maybe we’re less relying upon Ki-67 than we used to. There still, by the way, is this cohort 2 which is the lower-risk features with high Ki-67 with monarchE. We’re not going to have data from that group for a while because it’s a relatively small proportion, but it’s still a very important part of that study.

So the bottom line is I think things are better, but we’re still, you know, ultimately, I really like the ADAPT approach, the ADAPT approach where you give endocrine therapy, you look for a Ki-67 drop, and then we know that it’s prognostic in that situation. We’re not ready to adopt that across the community as of yet, but I think we can use Ki-67 as a prognostic factor.

Case: A woman in her early 50s with ER/PR-positive, HER2-low mBC with a PI3KCA mutation who experiences a dramatic response to rechallenge with fulvestrant and a CDK4/6i (abemaciclib); now with progression and cytopenias — Kapisthalam (KS) Kumar, MD

DR LOVE: So we’re going to go on to another case. And, Virginia, I’d like to see what you think about this case of a 53-year-old woman with an ER/PR-positive, HER2-low, I believe, 2+ IHC, also PIK3 mutated. But just to begin with the case, it’s really interesting in that when the patient came to Dr Kumar, the patient had already been previously treated a number of times and had been on palbo and an AI and was not able to tolerate it. The patient is very into alternative medicine, impatient with the therapy, goes on to get further therapy and he tries alpelisib and then realizes she never really had a great trial at — with — she had fulvestrant, but not with a CDK. And she actually gets a great response. Now has another question that I want to ask Aditya about. But let’s just start out, Virginia, I’d like to hear your reaction to this case. Here’s Dr Kumar.

DR KUMAR: This 53-year-old female with a history of metastatic left breast cancer. The important point to know in this patient, she’s very, very opinionated and nervous. She is very interested in alternate therapy many times in between. I tried to give her alpelisib, but after a few days of alpelisib, she developed pneumonia. She reads everything. So this is from alpelisib, I’m not going to take it.

So I said the next option is we’re going to retry fulvestrant along with a CDK4, this time I chose abemaciclib. She had a dramatic response to this, and she gradually improved.

She was on morphine and oxycodone for 3, 4 times a day. We gradually weaned her off completely all the pain medication. She started walking 2 miles a day. This lasted for 2 years, plus. She was so happy, and she even mentioned she was even able to involve in sexual activities she said. And again, she was lost to follow-up. Went for alternative therapy. Then she comes back in a very pale state, is anemic, almost pancytopenic. So just then, DESTINY-Breast04 was presented. So I wanted to give her that.

But what would they do with a patient who has a low platelet count, like this, 14,000 actually? Will they consider using low-dose T-DXd? Is that something reasonable we can consider in a desperate patient like this?

DR LOVE: Any questions you would like to hear investigators discuss about T-DXd?

DR KUMAR: Well, I have heard a lot in your meetings. The main question always comes up is the ILD. Some people indicate that they will do a scan on every cycle. Some people say they’d watch it. And if there’s minimal symptom, they do it. So, I really want to know what exactly the correct way to follow?

DR LOVE: So we’ll get into T-DXd in a second. We talked a lot about HER2-low last night and T-DXd, as you can imagine. So if you weren’t here last night, check it out when we post it online. We had Dr Modi here. But any thoughts, first of all, Virginia, about basically what happened when this patient really, they sort of decided she wasn’t going to benefit by CDK and then she has this incredible response? Any thoughts about that case?

DR KAKLAMANI: Well Kevin presented this MAINTAIN data at ASCO and it showed that CDK post-CDK may actually be beneficial. But then today at the meeting, there was the PACE trial that suggested that CDK after CDK may not be beneficial and maybe the right approach could be adding immunotherapy to this double, now a triplet. So I personally haven’t done this. A lot of my colleagues have. But I do participate in the postMONARCH trial that does exactly that because I think we need Phase III level data to make these treatment decisions.

DR LOVE: I guess the reason I wanted to present this is I wonder whether some people are being considered, you know, CDK resistant who really haven’t had a good trial of it. I don’t really think this is CDK after CDK because I don’t think she really had it long enough initially. And I’m not sure how often that happens. Anyhow. T-DXd, Aditya. We’re really looking forward to chatting with you about your neoadjuvant data. But what about in general in a patient — this patient had a lot of marrow involvement. Again, she went for alternative therapy. By the time she presented, she was pancytopenic but, again, no other options. Would you or have you treated a patient with thrombocytopenia?

DR BARDIA: Yeah. In a patient who has thrombocytopenia or myelosuppression in general, I think the question is, is it coming from the treatment or is it coming from the disease, disease progression? If it’s coming from the disease progression, treatment of the disease is likely going to make it better. Then, you worry about what’s this treatment I can give which would have least myelosuppression so I can safely give that treatment to the patient. T-DXd does cause some myelosuppression, but this patient has not received other chemo options such as capecitabine which does not cause much myelosuppression as oral. And in the metastatic setting, we tend to use therapies sequentially. So one option could be, and I’ve done that in patients with low counts or high bilirubin, is to start with capecitabine. And if the patient does well and the counts improve, you can always bring in T-DXd at that time. Technically, as for approval, T-DXd is approved for patients who have received at least one line of chemotherapy. So that would also allow the patient to get T-DXd after the patient has received capecitabine.

DR LOVE: So we’ll get into the issue of ILD and picking it up. I managed to squeeze out from the faculty last night a pretty specific algorithm. I want to see whether you all agree with it. But I just have to bring up one other thing, Matt, I think I mentioned this to the faculty. Last night, a doc came up to me after the meeting and told me about a case. And I said okay, I’m going to run it by the faculty. So this is a patient with HER2-low, gets T-DXd, and at the time she was treated, her creatinine was like about 2.5, so she had chronic renal failure. And she’s now in the ICU with tumor lysis syndrome. So not that much disease, bone mets, a couple potential adnexal mets that hadn’t been biopsied. Her uric acid went from 6 to 19, got rasburicase and uric renal failure dialysis. I don’t know — he was not able to find a case report. He thought maybe he ought to write it up. I don’t even know about TLS, in general, in solid tumors. Matt, any thoughts?

DR GOETZ: Yeah. That’s an amazing case. And certainly, I argue that the only time I ever see tumor lysis with solid tumors is when I go on the hospital service with a small cell. So we don’t typically see it, obviously, in breast cancer. Could it happen? Certainly, it’s possible. Obviously, we have a very active agent. It’s possible. Have I seen it? I have not. This patient here that you described starts out with an elevated creatinine. Perhaps, I don’t know the age, but perhaps maybe is a bit dehydrated. Maybe there were some factors that set the patient up for renal failure. It’s hard to know. But certainly, I have not seen that personally, but it’s very fascinating.

DR LOVE: So I think we’re going to move on now. Kevin, you had a comment?

DR KALINSKY: I just wanted to mention, I felt compelled. I don’t know if my colleagues have had a similar circumstance. But I had one patient who had significant liver disease, HER2-low, had progressed on other treatments, nothing for us to stent, bili was 8. And we made the decision to give her dose reduced T-DXd. And said there’s not data, we’re going to give this a go. I watched as her bilirubin, you know, monitor closely, watched as her bilirubin every week slowly increased to 16 and then watched as it went down. And then now, it’s normal. So there can be remarkable responses. I don’t know if my other colleagues have had that sort of response. But just going back to Aditya’s comment that if it due to the disease, I would treat it.

DR LOVE: Hope, in addition to your comment, Hope, one of the docs in the video said, I didn’t put it on there, that she thought she saw more toxicity when you use T-DXd in HER2-low than HER2-positive. And, of course, she’s one doc, anecdotal, et cetera. But she was hypothesizing maybe they had more prior chemo. So any thoughts about this sort of TLS thing and also this idea that you see — do you see more toxicity?

DR RUGO: Well the TLS thing is interesting because, 1, we don’t see it in breast cancer. I think I’ve seen it once in the last, and I hate to even say it, but 25 years. And that was after I did bone marrow transplant. So that’s a duration of time. But I think the interesting thing about the renal insufficiency she started with is that ILD is increased in patients who have baseline renal insufficiency based on the article by Powles that there was a group of about 1,500 patients who had gotten T-DXd. And I think that, you know, you wonder if the patient just saw a really high dose relatively because they weren’t clearing the drug. And I think that that might have been part of the cause. We certainly see that. We don’t understand the metabolism well of T-DXd at the moment. And I think, you know, the liver issue. My colleague who just finished fellowship and started, is fabulous, had this patient in the hospital. Came from the local hospital. She had metastatic hormone receptor-positive disease. She had taken her hormone therapy, finished, and then she came in orange, you know, and had a liver full of disease, but not replaced, but her bilirubin was going up. So the doc gave her Taxol/carbo and then gem/Taxol. And the bilirubin kept going up, and it was like 32. So she comes to UCSF, she gets a stent placed and her bilirubin starts coming down. It’s like okay, now what do we do? We’re like okay, bilirubin has got to get to 10. And then we gave her dose reduced — 2 dose reductions of T-DM — T-DXd. And she’s already better one week later. So it does make me think that renal dysfunction is special for T-DXd. We have to be really cautious. We may see these amazing responses in patients with hepatic dysfunction. So that’s, I think, a really important lesson for all of us. We don’t want to give full dose, but we could potentially experiment with these lower doses and follow patients very closely.

DR LOVE: Yeah. Tomorrow morning in our CLL program, of course, we’re going to be talking about venetoclax and TLS, a big, big issue. But it’s a great drug. And when I heard about this case, I’m thinking, yeah, T-DXd is a very good drug. It’s like venetoclax in CLL. It just kind of makes it go away.

Dr Kalinsky presentation

DR LOVE: All right, Kevin, let’s take a look at some data.

DR KALINSKY: Great. All right. So we’re going to be talking about selection and sequencing of therapy for patients with ER-positive metastatic breast cancer. And Virginia did a really nice job of teeing up somewhat what this discussion will be. I’ll be focusing on the CDK4/6 inhibitor trials. And then, we’ll talk about sequencing. We’ll talk a little bit about PI3K pathway inhibition. And then, briefly talk about PARP inhibition.

So this is a table that’s just demonstrating the pivotal CDK4/6 inhibitor trials. I won’t go through all of these data, but I will highlight. At the top is the PALOMA-2 study which we saw at ASCO this past year which was a frontline study where we did not see a statistically significant improvement in overall survival. And we’ve seen this in other studies with other CDK4/6 inhibitors.

I’m just going to show a smattering of studies. This is MONALEESA-7 which was the premenopausal study that Aditya had referenced earlier in patients with ribociclib. Overall survival was the key secondary endpoint. And you can see that there was a 29% relative reduction in risk of death.

There was MONALEESA-2 which was letrozole with or without ribociclib. Again, an improvement in overall survival of about a year. Again, another secondary — key secondary endpoint.

And so when the data were reported at ASCO, Claudine Isaacs did an excellent job discussing the study. And one of the things that was mentioned is a potential for why we may be seeing differences across CDK4/6 inhibitor trials in terms of OS is the fact that in PALOMA-2, 1, the definition of disease free interval or time to progression, things like that, that there were some nuanced differences. But beyond that, in PALOMA-2, there was a higher rate of patients who had endocrine resistant disease as defined as a DFI that was less than 12 months. Also, there was more missing data in the PALOMA-2 study including in the control arm.

Then following the results of that, Matt had presented some data on MONARCH-3 at ESMO looking at an interim analysis, an AI +/- abemaciclib which demonstrated numeric improvement in overall survival, but the data are not mature. Right now, the median OS is about a year in terms of the difference, but we’re still awaiting continued follow-up.

So Virginia had mentioned that MAINTAIN study. This was also presented at ASCO this past year. So this was a study that was looking at the role — a randomized study that was looking at the role of upon progression on any endocrine therapy and any CDK4/6 inhibitor, switching the endocrine therapy with or without ribociclib. And the primary endpoint was progression free survival.

And I won’t go through all of this. I just want to highlight a few things, really to contextualize some of the data that we saw earlier from PACE. So my take home point is that in the placebo arm, we did see a rate of de novo metastasis being about 50% which was a little bit higher than what we saw in the ribociclib arm. Few patients, less than 10% of patients, received chemotherapy, but 60% of patients overall had visceral metastasis. 90% of patients almost had received prior palbociclib. And the other thing just to mention here is that 2/3 of patients were on their prior CDK4/6 inhibitor for more than a year.

So when we look at progression free survival, again, this was really a study that was looking at patients who ha tumors that had progressed on prior palbociclib and received primarily fulvestrant with or without ribociclib. There was a statistically significant improvement in median PFS where you see a difference of about 2.7 months compared to about 5.3 months. And we did landmark analysis as well which showed at a year that there was this difference in patients who were still on ribociclib.

And I just want to highlight that we did try to enrich for patients who had received prior ribociclib. Only 14 patients had received prior ribo. So this is really an exploratory analysis. But if you look at that hazard ratio of prior palbo or prior ribo, I just want to highlight that the hazard ratio is about the same. And the other thing that I just want to show here is that, and this had come up in the discussion during ASCO, is that for the patients who were on their prior CDK4/6 inhibitor for less than or equal to a year, these patients numerically, based upon the hazard ratio, seemed to have a greater magnitude of benefit.

So today, we saw the results of the PACE study that was presented by Erica Mayer. This was a highly anticipated study, another randomized Phase II trial. There were 3 arms to this study where patients received fulvestrant or fulvestrant plus palbo or fulvestrant, palbo and immunotherapy.

So I just want to highlight a few things. Similar to what was seen in MAINTAIN, the same proportion of de novo metastatic disease was seen in the fulvestrant arm compared to the combination arm. There was a similar rate of visceral metastasis.

Also, the majority of these patients also had received palbociclib. So this is really a trial of palbo after palbo compared to MAINTAIN which was really ribo after palbo. And then, I also just want to mention that there was a numerically higher rate of patients receiving chemotherapy previously in this study, a slightly increased rate.

But what we saw with PACE, as Virginia had mentioned, as compared to MAINTAIN is that in PACE, there was no benefit for continuing the palbociclib. It’s also worth mentioning that the control arm of fulvestrant alone, and this was one of the comments that Hope had made in the question/answer session, the control arm did better than what we’ve seen in some of the other modern studies including, for instance, the EMERALD study. The other thing just to note is that with the addition of immunotherapy, that there was this improvement in PFS which is a very interesting finding.

And then just very briefly, I want to talk about PI3K inhibition. We have seen data from BYLieve which is a Phase II, open label, 3 cohort, noncomparative trial. These are data that have been previously reported by Hope where we see that there’s an efficacy of getting alpelisib after CDK4/6 inhibition. When SOLO1 was reported which led to the approval of alpelisib, a few patients, a small proportion of patients had received prior CDK4/6 inhibition. When you look at cohort A in patients who had received prior AI or cohort B in patients who had received prior fulvestrant, the primary endpoint had been met in terms of the amount of patients who had no PD at 6 months.

So this table is just comparing what we see in SOLAR-1 and BYLieve. And, again, just showing the rates that we see for that particular outcome.

And then lastly, I just want to mention, we’ve talked already about PARP inhibition in the adjuvant setting. Virginia had mentioned what we’ve seen in the metastatic setting. We have the OlympiAD trial as well as EMBRACA which looked at patients with HER2-negative metastatic breast cancer, it could be hormone receptor-positive, HER2-negative or triple-negative, where it was comparing PARP inhibition versus physician choice chemotherapy. OlympiAD was with olaparib and then EMBRACA was with talazoparib. For both of those studies, we saw an improvement in progression free survival, again, for our patients who have BRCA mutations.

We have seen some final OS data from EMBRACA, and you can see those rates here. And you can see that the curves splay a little bit after you start getting to 3 years, but this is a secondary endpoint. And these are the data from OlympiAD. And we did not see a statistically significant difference in the survival curves based upon whether they had hormone receptor-positive, HER2-negative or triple-negative disease.

And then, I just want to end by showing a current approach just to help further contextualize. So if we have a patient who is starting on AI or fulvestrant utilizing often fulvestrant in patients who have endocrine resistance and might have progressed on their adjuvant AI within 12 months plus a CDK4/6 inhibitor, we look for a PIK3CA mutation. If that’s present, we have the discussion about utilizing alpelisib. If they don’t, we have a discussion about switching the endocrine therapy with or without everolimus. I think there remains this question about CDK4/6 inhibition. Today, we saw results from CAPItello-291 about the potential role of the not-yet-approved capivasertib. And then considering PARP inhibition for our patients with germline BRCA mutations.

DR LOVE: Yeah. Interesting to think about what that algorithm might look like next year. But just going back to Matt in terms of alpelisib. Docs in practice, they treat 1 or 2 patients, a lot of times, we hear problems that occur. When we talk to investigators, we hear kind of better outcomes which you might expect because you all have used it more. Any sort of clinical pearls about using alpelisib, Matt?

DR GOETZ: Yeah. I think we’re learning more certainly as we’ve gone along. I think we’re aware of the toxicities. Certainly, the hyperglycemia has been an issue. We now have data demonstrating that metformin when delivered in this situation can reduce the risk of hyperglycemia. People are using antihistamines to help reduce the risk of rash. Clearly, we have a constellation of side effects which can be troublesome for patients including a little bit of diarrhea, the rash, the hyperglycemia. What’s interesting, and we were discussing this before we came up here, Hope brought this up and I’ve had this as well, is that we occasionally see patients who tolerate the drug exceedingly well and do well for a long period of time. And so I think, in general, certainly, it’s been a bit more difficult of a drug to give. But over the time, I think we’re learning how to give it better.

DR LOVE: And hopefully, you’re going to help me straighten out once capivasertib is in play, how we’re going to tease that out with genomic markers, et cetera.

Case: A premenopausal woman in her late 30s with ER/PR-positive, HER2-low (IHC 1+) IDC after adjuvant tamoxifen and OFS x 5 years, now with bone and liver metastases — Dr Agrawal

DR LOVE: But, Virginia, I’d like you to react to this case. You were talking about delayed recurrence. This is a really sad case of a 39-year-old woman who got 5 years of adjuvant tamoxifen/ovarian suppression and then relapsed with bone and liver mets. Here’s Dr Agrawal.

DR AGRAWAL: Unfortunately, CT chest, abdomen and pelvis and bone scan showed recurrence with metastatic disease in the bone as well as liver masses. Liver biopsy confirmed metastatic breast cancer, estrogen receptor strongly positive, progesterone receptor-negative, and HER2 1+.

What would you recommend as first line treatment for this patient? If planning to incorporate a CDK4/6 inhibitor, what is your thought process between selection of the agent?

This patient initiated treatment with continuation of ovarian suppression, an aromatase inhibitor and ribociclib. Any comments on toxicity of the particular agents as well as strategies to manage those? Would you utilize T-DXd at any time in her treatment course if she had a similar functional status to what I’m describing?

DR LOVE: So, Virginia, any comments about initial therapy? And then, in a patient like this, when you’d be thinking about T-DXd? If you could, would you like to give it before other chemo, for example?

DR KAKLAMANI: Yeah. So here, I would follow the MONALEESA-7 trial. We have a large Phase III randomized clinical trial with ribociclib in women that are premenopausal, so OFS, ribociclib and an aromatase inhibitor. I would give, at some point, T-DXd, but I would not give it as first line for the exact reason that Aditya mentioned. This is a drug that has been approved post-first line chemotherapy. And I would hope that this woman, even though she’s young and she obviously has aggressive disease, that she would be able to stay on endocrine therapy, potentially combination, potentially single agent, we saw the data with SERDs, maybe an oral SERD if that gets approved soon, for a while before we have to switch to chemotherapy.

DR LOVE: So, Kevin, I’d like your thoughts about another aspect to this case because I asked Dr Agrawal whether this patient had children. And, in fact, she had 2 children under the age of 10. Here are her comments.

DR AGRAWAL: In treating younger patients with metastatic disease, maybe have young kids, young families, is there anything that you’ve found to be helpful in resources you provide or counseling to the patients to help support them with this difficult diagnosis?

At our hospital, we have something called behavioral oncology which is a nurse practitioner with mental health training who focuses on the mental and emotional side of things. Another thing that we think about a lot is legacy planning. And we actually have recently initiated something called the legacy lab where patients are able to do certain things that they may be able to pass on to family. Do your centers have legacy programs or legacy planning? And what have you found to be most meaningful to your patients?

DR LOVE: So, Kevin, we’ve been going to the Oncology Nursing Society meeting for 14 years and minor children has been a big topic with nurses, but I think it’s a concern for everyone. Any thoughts? And any thoughts about this legacy kind of approach?

DR KALINSKY: Yeah. I think that — it’s a very difficult situation. And I think that we don’t have something equivalent to legacy planning. It’s a really nice idea. And I think that, you know, at our particular center, and I think there’s heterogeneity at different centers in terms of what’s available. For instance, at our center, we have excellent social work or supportive care, things of that sort. I do think the other thing just to highlight is that sometimes, this is also where support groups can be very helpful. There are specific advocacy groups and support groups that focus on specifically younger women with metastatic disease because the issues that they may be facing could be a little bit different than others. And then the other group I just want to highlight is there’s some groups like GRASP, for instance, when I have some of my young patients who are quite savvy patients that connect clinicians and researchers and that’s also been a way for various patients to also get to know one another and establish relationships.

DR LOVE: So you can see our meeting within a meeting doesn’t exactly have a plan. It’s like making rounds. Please check out what we did last night if you weren’t here last night because we spent a lot of time particularly talking about this next topic, HER2-low breast cancer. But we want to see what this faculty thinks about it.

Dr Bardia presentation

DR LOVE: So, Aditya, can you present some of the data?

DR BARDIA: Absolutely. Thank you. So I’ll review 3 things. First, rationale of ADCs for HER2-low breast cancer, talk about trastuzumab deruxtecan and review upcoming therapies for HER2-low breast cancer.

So what’s HER2-low breast cancer? It’s an operational definition based on HER2 IHC. It refers to tumors that have IHC 2+ and FISH negative or IHC 1+. And the reason there’s interest in HER2-low is because it’s potentially actionable with antibody drug conjugates like trastuzumab deruxtecan.

T-DXd binds to an antigen like HER2, gets internalized and releases payload to the cancer cells, but has a bystander effect. Deruxtecan is membrane permeable. So if there are cells that do not express HER2, it still works because of this bystander effect. And that’s why in HER2-low tumors, drugs with bystander effect like T-DXd potentially could have activity while drugs like T-DM1, which have minimal bystander effect, have not demonstrated much activity.

We saw this initially in the Phase I/Phase II trial with T-DXd. You could see responses in the HER2-low tumors. This led to the pivotal DESTINY-Breast04 trial presented at ASCO in the plenary session this year. Patients with HER2-low breast cancer randomized to T-DXd versus chemotherapy of physician’s choice. Two things to note related to the DESTINY-Breast04. The first is that the trial required patients to have received at least one prior line of chemotherapy. And second is that the primary endpoint was PFS in the hormone receptor-positive metastatic breast subgroup. The trial also enrolled patients with hormone receptor-negative breast cancer, but the primary endpoint was in patients with hormone receptor-positive breast cancer. And for the hormone receptor-positive subgroup, it required patients to have endocrine refractory disease. So these are all important considerations when we think about where T-DXd would come in in terms of the treatment paradigm.

So the trial showed improvement in progression free survival, very significant improvement in overall survival as well. The results were very significant, clinically meaningful as well. In HER2-low metastatic triple-negative breast cancer, there was also improvement in progression free survival and overall survival, but the numbers are very small. There were only 58 patients who were enrolled in this. And this was not a primary or secondary endpoint. This was an exploratory endpoint. And that’s why the numbers are small. And that’s why there was no p-value that was attached to these results.

What about other ADCs for HER2-low metastatic breast cancer? We have sacituzumab govitecan, a Trop2-directed ADC. We’ve seen activity of this agent in ER-positive breast cancer as well. This led to the Phase III TROPiCS-02 trial. Earlier this year at ESMO, we saw the results from the TROPiCS-02 looking at sacituzumab govitecan versus chemo based on HER2 status. And their hypothesis was that the HER2 status would not have an impact on efficacy of sacituzumab govitecan because it’s targeting Trop2. And that’s exactly what was seen, that regardless of HER2 status, you see benefit with sacituzumab govitecan as compared to chemo.

Now how about triple-negative breast cancer? I think it’s a similar story. Regardless of HER2 expression, whether it’s 0 or HER2-low, you see benefit with sacituzumab govitecan as compared to chemo.

The next question is how do we sequence these different ADCs? We have trastuzumab deruxtecan. We have sacituzumab govitecan. I think the idea would be to understand mechanisms of resistance. And there are ongoing studies doing pretreatment biopsies as well as biopsies at the time of disease progression to understand mechanisms of resistance. One example is the DAISY trial. In the DAISY trial, they looked at mechanisms of resistance related to trastuzumab deruxtecan and found an interesting mutation, SLX4, which potentially could confer resistance, acquired resistance to trastuzumab deruxtecan.

We’ve looked at resistance to sacituzumab govitecan. There was a patient who did very well on sacituzumab govitecan and then, unfortunately, they expired. In collaboration with Broad Institute, we did whole exome sequencing of the different autopsy lesions and identified that there were mutations in both Trop2, which is the target of the antibody, and TOP1 which is the target of the payload.

Why is this important? This is important because this could potentially guide sequencing. If a patient develops resistance because of mutations in the antibody, if you continue the same antibody with a different payload, it’s unlikely going to result in a response. But if you switch the type of antibody, even if you have the same payload, that could potentially result in response. So, for example, if a patient develops resistance to trastuzumab deruxtecan and the mechanism of resistance is because of the antibody, if you use a different ADC such as datopotamab deruxtecan, that would likely still work because mechanism of resistance is driven by the antibody. The opposite is true for the payload. If the mechanism of resistance is driven predominantly because of the payload, you can switch the type of antibody, say, from sacituzumab govitecan to trastuzumab deruxtecan because these are different antibodies, you potentially would see efficacy. This is a hypothesis and we need additional studies to look at this issue of ADC sequencing. And this would be important because there are other ADCs in clinical development, ADCs targeting LIV-1, HER3. So we really need to figure out how to sequence these different ADCs.

And then finally, how about early breast cancer? As you had mentioned at SABCS, you presented the results of the TALENT trial. The TALENT trial looked at trastuzumab deruxtecan as neoadjuvant therapy for patients with hormone receptor-positive, HER2-low breast cancer. Patients were randomized to receive T-DXd versus T-DXd plus anastrozole. Patients received initially 6 cycles, but then after an amendment, 8 cycles were allowed.

In terms of the results, this is the waterfall plot. If you look at the objective response rate, the objective response rate was 68% with T-DXd as a single agent and it was 58% with T-DXd plus anastrozole. There were 2 complete responses, both with T-DXd as a single agent as well as T-DXd plus anastrozole.

In terms of change in HER2, patients had a pretreatment biopsy and then after treatment with T-DXd and underwent surgery, looked at HER2 again. And you could see that there was decrease in HER2 in about half of the patients, so it moved from IHC 2+ to 1+ and IHC 1+ to 0. So there was some decrease in HER2 expression with T-DXd treatment.

And then finally, in terms of pCR and RCB. So RCB 0 is pCR. RCB 1 is near pCR. There were 3 patients in arm A, which is T-DXd, who either had pCR or near pCR. And similarly, with T-DXd plus anastrozole, 3 patients who had near pCR. The data are not mature at this time. There are still some patients for which we don’t have the surgical outcomes. So in the future, we’ll see the updated results.

In terms of side effects, it was similar to what was reported previously, nausea being the most common side effect. There was only 1 patient who had Grade 2 pneumonitis in this setting.

So in summary, T-DXd has demonstrated impressive efficacy in HER2-low metastatic breast cancer, both ER-positive and negative, and is approved in the second line setting. Sacituzumab govitecan is also approved for metastatic TNBC regardless of HER2 expression which makes sense because it does not target HER2. We’ve also seen activity in hormone receptor-positive metastatic breast cancer, and Dr Rugo will review that in the next session. The company has filed for approval in hormone receptor-positive breast cancer as well. In the future, we’ll likely see additional ADCs and we’ll have to understand whether the mechanism of resistance is antibody or payload because that would guide sequencing of these ADCs. And these different ADCs likely will also challenge our current receptor-based classification of breast cancer. I think that’s the last one.

DR LOVE: So we could do another hour just on the questions that are coming into the chat room, but let me just throw out a few of them. So what do we know about neoadjuvant T-DXd in HER2-positive compared to what you just presented? Any thought about whether or not you were giving the AI long enough because usually, you give it longer than you do in the neoadjuvant situation? Also, Ki-67 response has been used for endocrine therapy. Any thoughts?

DR BARDIA: Yeah. Great questions. So the first is response to neoadjuvant T-DXd for HER2 amplified or HER2 breast cancer. I have not seen any data about the response rate. One would expect that the response rate probably would be higher in HER2-positive for 2 reasons. In general, the pCR rate is higher in HER2-positive as compared to hormone receptor-positive. And, B, the degree of HER2 expression would be high in HER2-positive, so T-DXd likely would work better. But I’ve not seen any data yet.

In terms of Ki67, that’s a validated marker for neoadjuvant endocrine therapy because it identifies a subgroup of patients who have endocrine resistance. I’m not really sure it’s really a marker for response to neoadjuvant chemotherapy. So the benefit with T-DXd, I’m not sure that Ki-67 is a good metric to assess benefit with Ki-67.

And then finally, in terms of the duration of endocrine therapy. Patients received 6 cycles of T-DXd, so that’s 18 weeks, so that’s more than 4 months, so we should have seen some response. That’s a decent period of time in terms of neoadjuvant endocrine therapy.

DR LOVE: So, Virginia, Susanna, who goes to a lot of our meetings via Zoom, is on there tonight apparently. She wants to know, any experience with alpelisib alone? I’ve never heard this one. I have a patient who was stable on alpelisib/fulvestrant 2+ years, but wants to stop the fulvestrant. It’s 4 months and she’s stable. Any thoughts?

DR KAKLAMANI: I have not used it. Typically, we have the opposite problem. The patients want to stop the alpelisib, not the fulvestrant. I would urge her to wait until maybe mid-February. I’m hoping that one of the oral SERDs gets approved then and then she can use that instead of fulvestrant.

DR LOVE: Okay. Let me take a shot at pulling out of you how to screen for ILD. Okay? We did an entire program with a pulmonologist and I wasn’t sure at the end exactly. But last night, Hope, I think what we heard is ideally, if you can get insurance approval, to do scans every 8 or 9 weeks.

DR RUGO: Well we wrote a guidance paper in ESMO Open and we have another paper, hopefully, coming out in Journal of Oncology Practice, we’ll see, talking about this very area. And, in general, those trials all recommended that — all required that you do scans every 6 weeks. So I think we all feel like doing every 6 weeks is really not extremely practical in most settings in the clinical arena. However, if you have a patient who is at higher risk for getting ILD, you should do the first few sets of scans every 6 weeks. So that could be somebody who previously had ILD although they weren’t included in the T-DXd trials, but we’re all going to treat those patients eventually. It’s really important, I think, because what you want to do is to find ILD before it’s symptomatic. It’s critical because that’s the way you can treat them, hold the drug, and retreat them. And we found that retreatment can work very well in that setting. If you wait for them to be symptomatic, you have to stop. So somebody who has renal insufficiency, is hypoxic, has abnormal scans, these are the patients where you really want to be looking every 6 weeks, somebody who has been heavily pretreated. Otherwise, every 9 weeks seems reasonable for the first year. I feel a little nervous about going out to every 12 weeks. So we’ve really recommended 6 to 9 weeks for the first year. Now the papers have said — our most recent paper said 87% of ILD occurs in the first year. But you’ve got to keep in mind, those studies were patients who were really heavily pretreated, so they didn’t stay on so long. Now, there’s been patients staying on longer. There are reports out to 2 years and further that were fatal. So it is really important for us not to let our guard down. It doesn’t mean that it’s going to be a lot of patients. This is a rare toxicity. But we need to catch it early. You start seeing those ground glass opacities at 2 years, hold the drug, give them some steroids. It’s not a bad thing to do. And if they have symptomatic ILD, you need to slowly taper the steroids.

DR LOVE: So, Matt, certainly, key is whether or not the patient is symptomatic. And then the issue is, what about if they start out symptomatic? So in lung cancer, they want to use T-DXd first line and these people have COPD, they have cardiovascular disease, they’re already hypoxic to start with. What do you do with a patient like that?

DR GOETZ: That’s a good question. So if a patient, we think, is symptomatic because of disease, that’s a situation where I’d want to give the drug if I can because of the activity. If there’s any other concerns, you know, symptomatic because of some other underlying lung disease, then I’m probably going to get the pulmonologist involved, try to get more comprehensive pulmonary tests upfront, and then be able to monitor those patients very carefully. And I think, as Hope said, right now, I’m trying to follow-up the criteria as has been done in the clinical trials and not go too far until we get some more prospective real-world data.

Case: A woman in her early 90s with ER/PR-positive, HER2-low (IHC 1+) mBC and progressive disease on multiple lines of endocrine and chemotherapy receives T-DXd — Dr Astrow

DR LOVE: So let’s do another case. And, Virginia, this is the real-world implication of HER2-low. Actually, Dr Astrow presented a patient last night, he has a lot of older patients in the Bronx there, a 91-year-old woman that he treated who had dementia and had a great symptomatic response. Here’s another 90-year-old. Here’s Dr Astrow.

DR ASTROW: 90-years-old, been through multiple lines of hormonal therapy, chemotherapy. She’s had 2 lines of chemotherapy. She’s 1+ HER2. We’ve got the data for T-DXd. So I started treating her with that. And low and behold, tumor marker has come down quite significantly. Her skin metastases have also improved. So she’s responding to treatment after 6 cycles. Again, I’m not going to cure this woman. How long do I keep treating her for?

Do they always start at the approved dose? Or do they ever start at 1 dose level down, 2 dose levels down? Most of these patients, in fact, have been heavily pretreated because that’s what’s required to use it. So is the age ever a factor in how they use this agent? Do the responses at a lower dose seem to be as good as the ones they get at the full dose therapy?

DR LOVE: So, Virginia, any thoughts there about this case, about the dosing, the duration? Any thoughts?

DR KAKLAMANI: So Ian Krop reminded me a couple days ago that the dose probably is significant. And we’ve seen better activity with higher doses than lower doses. Because that was initially kind of my thought too. Why don’t we just dose reduce even more? We’ll see less ILD. But I think in a 90-year-old, we have to take that into account. And that would be probably one of the very few scenarios where I would potentially start with the lower dose. I don’t — I have never dose escalated. But, again, it depends on how this patient tolerates the treatment. But I think T-DXd would be appropriate in this setting.

DR LOVE: So, Kevin, I said last night that I wanted to ask a question, but we didn’t have time, but I was going to ask it tonight. So here’s the question.

DR KALINSKY: Uh-oh.

DR LOVE: You heard the word desperation earlier in one of the cases, the other HER2-low case. And clearly, you have patients with good performance status who’ve run out of approved options. And my question is, what kind of IHC would get you to not use T-DXd? Like IHC 0, for example. We showed data last night showing activity in “IHC 0”. I’m not even sure what that is because IHC 0 includes a little bit of, you know, Dr Modi was talking about new assays to make this more quantitative. But I just want to know right now, I know there are regulatory issues, but would you want to give T-DXd to somebody who is HER2 0?

DR KALINSKY: In that circumstance, yes. I would. I think that — and with all the caveats that you just mentioned, that this is not something that is approved in this context. There are studies that are going to be looking that we’re waiting for the results of to help answer this question of how long can we go. And also, I think there remains a lot of consideration about how we’re testing for HER2, the reliability. We had a whole session yesterday that was just talking about HER2-low and the agreement amongst pathologists. We’ve seen data from the DAISY study. It was a small study and there was a population within that who was HER2 0 and there were some responses. And so if I had this sort of patient, this may be a patient that we would think about redoing a biopsy and saying okay, well now do we have — is this HER2 1+ or 2+ and not amplified? But outside of that, I would and have given HER2 — trastuzumab deruxtecan in the context of HER2 0.

DR LOVE: Aditya, any comments? And also, any comments, I think you alluded to a little bit more granularity about the chemo-like side effects that you see. Again, we hear this from the lung people, the GI people now, T-DXd used all the time in upper GI cancers. What do we know about chemo side — alopecia, nausea, vomiting, et cetera? And, again, any thoughts about HER2 0?

DR BARDIA: Yeah, absolutely. I think even HER2 0, as you were saying, does have some HER2 expression. So potentially, ADCs with this strong bystander effect could work in that setting. In terms of the approval, the approval is you need IHC 1+ in any specimen. And given that the HER2 expression changes over time, you likely can find a specimen that would have HER2 IHC 1+. And so from an insurance perspective, you can justify the use of T-DXd. We’ll see results of DESTINY-Breast06 which specifically is looking at the question of T-DXd in IHC 0. In terms of side effects, it is targeted chemotherapy. These are antibody drug conjugates with payloads. And T-DXd does have some chemo-like side effects, nausea being the #1 side effect. And often, patients can have significant nausea. And it’s my practice to actually give patients a prescription of either olanzapine or Compazine to take home because they can have nausea at home a few days after treatment with T-DXd. Alopecia can be seen. Different studies, different incidence. In the TALENT trial, which was the neoadjuvant trial, the incidence of alopecia was about 40%, so it is a side effect that can be seen. The third side effect is neutropenia. It’s lower than what we see with chemotherapy, but definitely a side effect that can be seen.

Case: A woman in her mid 40s with ER/PR-positive, HER2-low (IHC 2+) mBC who has received fulvestrant/abemaciclib, now receiving exemestane/everolimus – ESR1 and PIK3CA mutations — Dr Dallas

DR LOVE: So, Hope, I’d like you to respond to this next case from Dr Dallas, a 45-year-old woman. Again, I’m flashing back to the ATAC trial days and now, here we are talking about ESR1, PIK3, HER2-low. Wow. Interesting being in oncology nowadays. Here’s the case.

DR DALLAS: She was started on fulvestrant and abemaciclib at that time and had a good response to that.

But most recently, she had progression of her hepatic metastases. She was transitioned to exemestane and everolimus and came to me to ask for another opinion.

I did send molecular testing and she has an ESR1 as well as a PIK3CA mutation.

So my question for the experts here is about the ESR1 mutation. Is there any role to continue the AI? Or would you just continue with everolimus monotherapy? Or add in a different medication?

And then also, the initial pathology had shown HER2 IHC 2+ which was considered not amplified, but now I believe she would be considered HER2-low and possibly a candidate for trastuzumab deruxtecan. And so with that and the PIK3 kinase mutation, how would you sequence these medications in this patient?

She hasn’t really had chemotherapy in the metastatic setting. So I think she has to have at least one line of chemotherapy.

DR LOVE: I was just thinking, we’re presenting — she’s presenting cases tomorrow in CLL, myeloma. Amazing being in general oncology.

DR RUGO: That is amazing.

DR LOVE: Any thoughts about this case?

DR RUGO: So because the patient has an ESR1 mutation now, I think we feel fairly secure in the data that shows that aromatase inhibitors are less effective than a selective estrogen receptor down-regulator. And we’ve seen, as I’ll show you, that these new oral SERDs seem to be even more effective in patients whose tumors have ESR1 mutations than those that are wild type. So what do you do now? We don’t have an approved oral SERD although we certainly hope to next year. And so in that situation, we’ve actually talked about it quite a lot, I would leave her on fulvestrant. I’d put her back on fulvestrant. And if she’s responding or she just started everolimus, I would continue the everolimus. She’s already been on — she has a PIK3CA mutation. I’m not sure why they didn’t give her alpelisib. My choice is alpelisib in somebody who has a known mutation and everolimus if they don’t.

DR LOVE: Yeah, she found out after she got to her.

DR RUGO: Right.

DR LOVE: She was already on it.

DR RUGO: So they hadn’t tested which is really surprising. So as long as she didn’t have a contraindication, I would probably switch her over to fulvestrant and alpelisib. We’ve actually seen activity even in patients whose cancers had already progressed on fulvestrant. So I think that would be a reasonable approach.

For her other question about when to use T-DXd or trastuzumab deruxtecan, I would use first line chemotherapy with capecitabine. That tends to be our first choice. Or a clinical trial if there’s an appropriate trial for her. And use T-DXd in the second line setting.

DR LOVE: So, Matt, I asked Dr Dallas, you know, this young woman, the patient, I said what’s she like? Is she very much involved? I said what do you think she would want to do if she had disease progression? Do you think she would — we talked about chemo, capecitabine. Which, incidentally, was part of the control arm, right? Against T-DXd that it beat. But in any event, she said well I think this patient would maybe prefer to have T-DXd. But can you talk a little bit about in a patient like that, when you would think about bringing in T-DXd? She’s got a lot of liver disease too.

DR GOETZ: Yeah, I saw that, an extensive amount of liver disease. And you worry a little bit about, you know, a PI3 kinase inhibitor here, let’s say, along with fulvestrant, which I think is a reasonable thing. The best response rates sort of post-CDK4/6 we might expect might be in that 20% range from the BYLieve data that Hope has presented. And so the question here is, do you really, you know, if you really want to get a response, might one consider in this situation, combination chemotherapy or at least perhaps capecitabine? And I think we know that when you have an ESR1 mutation, specifically these ESR1 mutations and PIK3CA mutations that co-occur, disease can be a bit more aggressive. And I’m kind of seeing that here from the description. So the question I think is, if we’re expecting relatively stable disease which is kind of what I’m hearing in this situation, is that enough and might chemotherapy be the right choice for her? I’d have to look — obviously, I don’t have her laboratories, her bilirubin or things like that, the pace of disease. These are all things I would take into account. The bottom line is that a PIK3 — excuse me, a PI3 kinase inhibitor, alpelisib, I agree with Hope, fulvestrant would be my choice in this situation, would be reasonable. And then depending on that issue of the pace of the disease, bilirubin, I may consider chemotherapy. I think the big question, of course, is could we just skip right forward and use T-DXd which I think is the question that you’re getting at. Or do we have to go through this hoop first? And I still think that capecitabine is a really good drug. I’ve had patients who have — I can think of one patient right now in my clinic who was on one of the original trials testing fulvestrant and abemaciclib. It progressed in her liver. She’s now been on capecitabine as a single agent for 6 years in a complete response. So we see these responses. We know capecitabine is an active agent. It’s well tolerated. These are the things I would consider.

DR LOVE: Great.

Dr Rugo presentation

DR LOVE: Okay, Hope, we’d like you to review some of the novel strategies. A lot of stuff coming out at this meeting of great interest here.

DR RUGO: Yeah. So there was a lot of stuff at this meeting. And hopefully, I’ll be able to get through it with you. And I agree with Matt that you really do have to look at the pace of disease and the liver function, et cetera.

So novel strategies under investigation for hormone receptor-positive metastatic breast cancer. What is our first understanding? We talked about ESR1 mutations. So estrogen receptor dependent mechanisms of resistance. And then there’s also the estrogen receptor independent mechanisms of resistance like activation of the PI3 kinase pathway. And we know you can have activations of that pathway through a number of different areas as well as multiple other mechanisms of estrogen receptor independent resistance mechanisms for CDK4/6 inhibitors and for endocrine therapy.

And now, understanding how to treat patients who’ve gotten CDK4/6 inhibitors and have progressive disease is a really critical and unmet need. So first, we’ll talk about inhibiting AKT with capivasertib and then we’ll talk about the SERDs, and last the ADCs. So inhibiting AKT. So AKT pathway activation is part of this whole PIK3CA mutation pathway so that you — if you have an activated mutation in PIK3CA, you’re also activating AKT. You can have mutations in AKT. You can also have deletion of the tumor suppressor gene, PTEN. And you can have actually activation of the pathway even in patients who don’t have the alterations. And it’s been associated with endocrine therapy resistance. Capivasertib is this potent inhibitor of all 3 AKT isoforms. We had a Phase II FAKTION study that showed that the addition of capivasertib to fulvestrant improved progression free and overall survival, but only in the patients who had a mutation in the pathway. And it wasn’t just PIK3CA, it was just pathway alterations.

So CAPItello-291 was already ongoing when we saw the results of FAKTION. And so we actually were really interested in understanding the different effect of this drug in the altered and non-altered patient tumors. So in this trial, 700 patients were randomized in the second or so line setting to receive fulvestrant with either capivasertib or placebo. And capivasertib is given for 4 days on and 3 days off. So it’s an intermittent dosing schedule which is quite interesting. And the patient population is shown at the bottom of this slide. Most of the patients had CDK4/6 inhibitors. And almost 70% had visceral metastases. Unfortunately, the black population was very low, but that’s because they enrolled a lot of patients in Asia, I think. The primary endpoint was progression free survival by the investigator evaluation.

You can see any AKT pathway alteration here was seen in about 40% of patients. But interestingly, PIK3CA mutations were only seen in about 30% and the rest were made up of AKT and PTEN. There was also a group of patients, about 15%, that had unknown alteration status. It was 16% in the capivasertib arm. So that has to be taken into account as we look at the results.

So as you know, the addition of capivasertib to fulvestrant improved progression free survival with a hazard ratio of 0.6, so very good, going from 3.6 to 7.2 months in the overall intent to treat population. When we looked at the patient population who had the altered pathway, it was very similar. Hazard ratio of 0.5, if anything, a little better. And going from 3.1 to 7.3 months. So the trial met its primary endpoint.

But, of course, you want to know if there’s a difference in the non-altered population. So that’s shown here where you can see there’s a hazard ratio of 0.7. Well not quite as good, but pretty good. The PFS still goes from 3.7 to 7.2 months. It’s just we’ve got that little 16% unknown we don’t know what to do with. So cell-free DNA will be evaluated next year in this trial population. That might give us a better idea of how effective the drug is in the non-altered population. In the forest plot, you can see it’s active in patients who had CDK4/6 inhibitors and had liver metastases, really important endpoints. And so that actually gives up a lot of hope that this will be a very effective agent.

Overall survival is still immature. There’s less events in the capi arm, but it’s still very immature. In terms of safety, this drug causes diarrhea and rash, primarily rash in 38%, 12% Grade 3 and then 72% had diarrhea with 9% Grade 3. So this is important. It did lead to some interruption as well as dose reductions and 9% discontinued. So that’s going to be really important to understand how we manage this when this drug is approved sometime towards the later part of next year.

So this is exciting. It’s a new agent that is effective in altered pathway tumors as well as the non-altered pathway tumors as far as we know now. And that would be a great option for our patients. It does still have this toxicity of the pathway. We’re all worried about hyperglycemia. In this patient population, they allowed patients who had a hemoglobin A1C up to 8 and they could have controlled diabetes and they still only saw a Grade 3 hyperglycemia under 3%. So that’s encouraging as well. There’s an ongoing trial, CAPItello-292, studying fulvestrant/palbociclib with or without capivasertib, and a number of other novel PIK3CA inhibitors that are being studied. So we’ll look to see what happens with the approval and that will be exciting.

There’s a lot of new endocrine agents targeting the ER domain and they’re called, you know, there’s a lot of acronyms, SERDs, there are new SERMs, there are SERCAs, there are PROTACs as we heard about today, and there are CERANs, so lots of different drugs that affect the ER pathway in different ways.

We have looked at the oral SERDs. The EMERALD trial is the only trial that’s shown a significant improvement in progression free survival. We saw this year the negative results of AMEERA-3 with amcenestrant that actually led along with negative results from another trial to the discontinuation of development of amcenestrant, and then acelERA with giredestrant that also was a negative trial. But in both trials, we actually saw a benefit in the patients who had ESR1 mutations which is interesting. And this was also an amplified PFS benefit in the EMERALD trial. SERENA-2 was presented here. We’ll talk about it. And then, EMBER-3 has not yet reported. That’s with imlunestrant and SERENA-2 with camizestrant. So lots of names.

So we have seen that there does seem to be a selective benefit of these new oral SERDs in patients who have ESR1 mutations. And EMERALD, the only positive trial, actually had a hazard ratio of 0.55 in the patients who had ESR1 mutations and improvement in median PFS that was greater although still quite modest in this very resistant population.

Virginia presented here at this meeting very interesting data looking at patients in the EMERALD trial based on duration of prior CDK4/6 inhibitor with a cutoff of 6 months. And what’s interesting here is that even in all patients, but amplified in the patients who had ESR1 mutations, we saw a really big difference in the progression free survival. So if you select this endocrine — relatively endocrine sensitive population, you see a big difference. And, in fact, if you looked at the PFS rate at 12 months in the ESR1 mutant population, small numbers, but it went from about 8 months to about 36 months. So it’s really big and quite intriguing. So we saw this interesting differential benefit in patients who have endocrine sensitive disease and more marked in the ESR1 mutant population. And now, there’s a trial going on looking at the combination of elacestrant with a number of targeted agents that we usually use in this patient population.

So SERENA-2 actually, if you just go back one slide, I don’t think I can go back, but SERENA-2 is a randomized Phase II trial that looked at 2 different doses of camizestrant and compared it to fulvestrant. So 240 patients. They started out with a little tiny — a bigger dose that they discontinued. These patients, interestingly, had — there was a little imbalance in liver metastases and ESR1 mutations that actually favored the camizestrant arm. So they’ve done some modeling and figured that that doesn’t make a difference, but we haven’t seen that yet. In any case, there was a — the primary endpoint was PFS by investigators. It was significantly longer in patients who received camizestrant. No real difference in the 2 different doses, went from 3.7 to 7.7 or 7.2 months. So important difference there. And it’s very encouraging to see that in a Phase II trial since we’ve seen so many negative trials.

They looked at patients who had prior CDK4/6 inhibitors or not and saw a benefit. In the ESR1 mutant population, remember there were a lot more in the fulvestrant arm, it appeared that it worked much better in the ESR1 mutant population and not quite as well with no differences in the small population with wild type. And then the same was true in patients who had lung and/or liver metastases. There seemed to be a better benefit from the oral SERD and less of a benefit in the patients who did not. Very low rate of Grade 3 AEs, but they do see some photopsia, which is seeing light flashes, and sinus bradycardia, some liver function elevation. So now, there’s Phase III trials ongoing at a 75 mg dose.

So there’s just 2 to briefly mention, we’ll go through. They also saw this really interesting decrease in ctDNA. Imlunestrant is the last oral SERD to talk about. That can be given with abemaciclib. It’s made by Lilly, so of course, they’re looking at it with abemaciclib. There is some diarrhea, but very reasonable. Response rates in the 30% range. And there are Phase III trials going on in the metastatic and early-stage setting. You have all of these slides to look at.

And then there are a number of different trials, which I won’t go through, in the metastatic and early-stage setting. The one that we really just should briefly talk about is this PROTAC, a novel mechanism agent that degrades the estrogen receptor by triggering ubiquitination, a big word. But it’s very cool. And they saw responses in heavily pretreated patients, reasonable, short PFS. And there’s a Phase III trial going on now comparing it to fulvestrant. One of the key differences here is it doesn’t seem to have much toxicity of Grade 3 at all, only up to Grade 2. There are a number of other agents that are being studied as well, new SARMs, SERMS, as I mentioned, the CERANs and SERCAs.

And then lastly, just the — if you just go back one slide. Sorry, I pressed too many times. If you — the antibody drug conjugates, we presented updated data with sacituzumab govitecan at ESMO showing not just a PFS, but an overall survival benefit compared to chemotherapy of physician choice in heavily pretreated patients with hormone receptor-positive breast cancer. And at this meeting, we showed no impact of TROP2 expression on efficacy. There is a Phase III trial planned in the first line setting. And then, we saw data from datopotamab deruxtecan, another TROP2 ADC in patients who had hormone receptor-positive disease with a response rate of 27%. We’ve actually already completed accrual to a Phase III trial in patients who received 1 or 2 lines of prior chemotherapy with hormone receptor-positive disease. So we’ll look for that data maybe in the next year or so. So with that, I’ll — since I’m over time, I’ll finish. But there’s a lot of exciting agents out there.

DR LOVE: I always love to watch the audience when you’re talking. They’re like holding their breath. Susanna —

DR RUGO: I had a lot of topics.

DR LOVE: Yeah. Susanna, the same doc who has a patient on alpelisib for 2 years, says thanks, the patient is well informed and waiting for an oral SERD to be approved. I think that’s interesting.

DR RUGO: Well the PDUFA date, as Virginia mentioned, for elacestrant based on the EMERALD trial is in February. So we’ve got our fingers crossed.

DR LOVE: So one question about, I don’t know if it’s called capi or capi, but I need —

DR RUGO: Capi. Capi.

DR LOVE: Okay, capi. That sounds good. Okay. Can you talk a little bit about quality-of-life issues, like what you actually see? And what are you going to do if you have PIK3 — who knows what the approval is going to be, but if you have a PIK3 mutation, do you use alpelisib or capi?

DR RUGO: Well it’s a good question. But there’s a little diarrhea, in my experience, because you take 4 days on and 3 days off, people get the diarrhea sort of around the end or at the beginning depending on the patient and then it goes away. So it wasn’t actually a big issue for the patients I treated on 291. And I actually still have a patient on who gets occasional diarrhea. We haven’t unblinded patients. She’s been on for a very long time now, so we’ll see. I’m encouraged. So that’s not bad. The rash, although there was a fair bit of rash, I haven’t seen bad rash. So we use a lot of anti — oral anti — non-sedating antihistamines. So maybe they play a role as well. And then the whole issue about hyperglycemia is complicated depending on your patient population. If you have a patient population that has a lot of insulin resistance, it can be really difficult to treat the hyperglycemia from alpelisib. So that would be the one reason why I would choose capi first before alpelisib in patient population where I was worried about hyperglycemia and managing it. And then we just have to see how we do. And maybe the intermittent dosing plays a role here which we didn’t really study with alpelisib.

DR LOVE: So, Aditya, one final question from the chat room from Preethi from the real-world. I have a patient with leptomeningeal disease who has had a complete response to T-DXd, but has asymptomatic pneumonitis. It’s not resolving on CT with steroids. Would you restart?

DR BARDIA: And a good question. So if the patient is asymptomatic, this is Grade 1. And in a Grade 1 setting, one can consider the use of T-DXd and actually don’t have to discontinue. If it becomes Grade 2 or higher —

DR LOVE: Yeah, but it didn’t clear.

DR RUGO: So she held and took steroids.

DR BARDIA: So it’s still Grade 1, but with the leptomeningeal disease, I think it’s a risk/benefit discussion. With close monitoring, and given that we don’t have effective treatment options for leptomeningeal disease, with close monitoring, that could be one. Sacituzumab govitecan is the other agent which has shown some activity in patients with brain metastases. That could be another option of consider in the future.

DR LOVE: Just a quick show of hands. How many of you’ve seen a response to T-DXd with leptomeningeal disease? Okay. Well at least there are 2 of them. So, audience, thanks so much. Tune on tomorrow morning. We’re going to be talking about chronic lymphocytic leukemia. Thanks so much to the faculty. Have a great night.