Updates from the 2024 San Antonio Breast Cancer Symposium

LBBC welcomes Neil Vasan, MD, PhD, to share the most impactful breast cancer findings from the 2024 San Antonio Breast Cancer Symposium. Join us to learn the latest medical breast cancer research presented and how this news may impact you. This webinar is for both those diagnosed with early-stage and metastatic breast cancer. Attendees had the opportunity to ask Dr. Vasan questions during the free webinar.

Webinar Transcript

Jean A. Sachs, MSS, MLSP [00:00:10]

I’m honored to introduce today’s speaker, Dr. Neil Vasan. He’s a breast oncologist, physician-scientist, and assistant professor of medicine at the Division of Hematology and Oncology at Columbia University, where he also serves as the principal investigator at the Vasan Laboratory at Columbia University Medical Center.

We are really excited to have him today. He worked so hard — the meetings ended on Friday — to put together this presentation, and if you want to learn more about him, click on lbbc.org for his full bio.

Neil Vasan, MD, PhD [00:00:50]

All right. Thank you so much, Jean.

I’m really excited to be part of this event, and good evening to everyone.

Breast cancer is such a fast moving field. It’s been really wonderful to go to San Antonio every year and hear about all of the incredible advances in our field. And I will say that it’s interesting. Before the conference, we know some of these advances, but then it’s really during the conference that it totally expands and it’s a wonderful surprise to us, even as investigators who have some insider knowledge. And as Jean said, I’ve been really privileged to be part of the planning committee.

These are my disclosures. I would like to point out, I’m also a member of the FDA ODAC, or Oncologic Drugs Advisory Committee. This is something that is a near and dear role to my heart, and I’m happy to chat about how I think about some of these topics.

It was a banner year for breast cancer research and findings, but I also think it was a banner year for patient advocates, for you all. I think that a lot more studies now, especially as we’re starting to combine therapies, moving them up into the treatment landscape, thinking about toxicities and how they affect patients, making sure that patients have a seat at the table when trials are being conceptualized. This was a real banner year.

And then also from a San Antonio conference level Drs. Carlos Arteaga and Virginia Kaklamani, who are the organizers of this conference, did a really fantastic job of integrating patients into so many of the panels. That’s a big change from even 5 years ago. And I think that this is a really developing area that helps everyone. It helps me as a scientist, it helps me as a clinician, and it helps everyone communicate these findings.

So this is a very acronym-filled outline about some of the trials that I’d like to discuss. I’m going to focus most of it on metastatic breast cancer advances and hopefully have a little bit of time to touch on some of these other areas in early-stage breast cancer surgery, DCIS, and screening.

This was not necessarily covered in the conference, but it was an important approval that we’ve had in the last year. What we know in the PI3K field is that we have this, what I like to term a therapeutic symmetry in how we target the PI3K pathway in 2024. We have all these different nodes in the pathway and different drugs that now target each of these nodes. We have biomarkers of sensitivity and some biomarkers of resistance. And these are all genetic biomarkers. So these are mutations that are found in the tumor, not found in the germline, not found in the genes that you get from your parents that you pass on to your kids.

What’s really interesting is that we now have a therapy called inavolisib, that is a PI3K-inhibitor. And this was investigated in patients with endocrine therapy-resistant, ER-positive breast cancer bearing PIK3CA mutations. It’s a mouthful, but bottom line is that we know that PIK3CA mutations are found in about 40% of patients with ER-positive breast cancer.

This was a really interesting trial for a couple reasons. Number one, they tested this triplet combination, so a combination of a PI3K inhibitor, palbociclib, or Ibrance, and fulvestrant in the first line setting compared to just the standard of care, CDK 4/6, palbociclib plus fulvestrant.

This was an interesting trial, I think, and I hope this resonates with you all. Many breast cancer trials in the past required tissue biopsies for enrollment. And this was a trial that was very patient centric. It was a very smartly designed. It enrolled based on circulating tumor DNA, on liquid biopsies, and it enrolled 93% of patients based on ctDNA. That is incredible. That is what we hope for in the field, that we can have a way to enroll on trials, a way to reach patients more through diagnostics that are essentially just as good as the tissue biopsy. And we can hem and haw on the differences, but for all intents and purposes, this is essentially equivalent.

Neil Vasan, MD, PhD [00:04:56]

This was a patient population that was very resistant to endocrine therapies. They progressed during or within a year of finishing adjuvant endocrine therapy in the curative setting. So this is a patient population that is very resistant to therapies, or the therapies really fail these patients. And this is a timeline illustrating the PI3K inhibitors over time and the real advances we made in the field. The blue squares are drugs that are approved. So this trial found that in patients with breast cancer bearing PIK3CA mutations, that the combination triplet therapy was better than the doublet therapy for progression-free survival. It almost doubled progression-free survival. This is in the first line.

I’d like to point out, this control arm, the patients who got the standard of care CDK 4/6 inhibitor had a progression-free survival of only 7.3 months. This is a patient population we have to do better in. We as oncologists have to address these issues. This is a patient population that’s resistant to many state-of-the-art therapies that we have right now. This was FDA approved in November, so just very recently.

The first trial that I wanted to discuss was called the PADMA trial. This was a trial comparing CDK 4/6 inhibitor in the first-line setting with chemotherapy. This is an interesting question because I think the field has been moving towards answering this question definitively. We know that CDK 4/6 inhibitors have completely transformed how we treat ER-positive metastatic breast cancer, and we know that chemotherapy is an option for some patients. But in patients who have similar types of diseases, one is better than the other. And because there’s a lack of prospective data, this is an outstanding question in the field.

This was a trial that was looking at Ibrance plus endocrine therapy versus mono-chemotherapy — if we give chemotherapy the standard therapy — with or without maintenance endocrine therapy. This was a small trial, only 150 patients. I think it illustrates how even small trials can illustrate important clinical points. And they randomized patients to receiving Ibrance plus endocrine therapy versus chemotherapy of physician’s choice. And they could use endocrine maintenance therapy. It’s an interesting concept. We don’t do this as much in the U.S., but it is done more in Europe. And this trial was was done in Europe.

We’re used to seeing progression-free survival. How long is a patient on therapy before a patient progresses or, unfortunately, before a patient dies. This was an endpoint called TTF, which is time to treatment failure. How long do patients stay on the therapy, and when does the therapy stop working for patients? This trial showed that the time to treatment failure was improved in the patients who received palbociclib versus chemo.

I think this is a really important benchmark in the field. I think this is a question that’s been lurking for a while, and we can say definitively that palbociclib plus endocrine therapy is better than chemotherapy. These were the secondary endpoints as well, looking at progression-free survival and overall survival. Overall survival was numerically higher, but the study wasn’t really powered to look at this.

I think the bottom line here is that we know that targeted therapies can sometimes be better or worse than chemotherapy, both in terms of survival and in terms of side effects. Are patients living longer or are they living better? And I think that, with CDK 4/6, we can definitively say now that not only are they living longer they’re also living better compared to chemotherapy. And I think this is a really important benchmark for the field.

The next trial is actually one of the trials that had a big splash at San Antonio looking at oral SERDs, or oral selective estrogen receptor degraders. Before going into the trial, let me just talk a minute about these drugs.

We know that fulvestrant, which is an intramuscular, intragluteal injection, it’s an injection into the buttock. It’s painful. It is a very viscous solution, the actual drug itself. And there’s plenty of data showing that something called bioavailability — how much of the drug actually gets into the cancer cell, into the tumor — that amount is low and variable with fulvestrant for a variety of reasons.

Neil Vasan, MD, PhD [00:09:43]

It was thought in the field for 10, 15 years now, if we had an oral version of this drug, it would be better bioavailable, it would reach more cancer cells, it would kill cancers better. And that hypothesis, I think was partially true. But what we’re seeing now in the field is that it’s patients who have breast cancers bearing ESR1 mutations. ESR1 is a mutation in the estrogen receptor itself. These therapies seem to work better in patients who have these mutations in their breast cancer.

There’s a drug right now called elacestrant, or Orserdu, that is FDA approved in this patient population, patients who have breast cancers bearing ESR1 mutations. These drugs are FDA approved now, and we do use them. They’re certainly not home runs. They are singles, doubles on a good day, from a baseball metaphor point of view.

This is another drug that’s now in a phase III trial called imlunestrant. I don’t believe this has a brand name yet. It’s from Eli Lilly. And so this was a complicated trial looking at the combination of imlunestrant versus the standard of care endocrine therapy, which could be either fulvestrant or exemestane, versus the combo of imlunestrant plus Verzenio, or abemaciclib. This was an even randomization. It was pretty large trial, 874 patients, and really looking at patients who had progressed on CDK 4/6 inhibitors either in the adjuvant setting or in the advanced setting. So already it’s a heterogeneous population. Some patients came off of adjuvant therapy and some patients were treated in the second line in the metastatic setting. So it’s a little bit of challenge to think about who are these women, who are these patients, and how do they respond to therapy.

The primary endpoints here were toggling back and forth looking at the oral SERD imlunestrant versus endocrine therapy in the patients who had breast cancers with ESR1 mutations and then other combinations of comparisons.

In the patients who had breast cancers with ESR1 mutations, this drug beat out endocrine therapy standard of care, it was a delta, meaning the difference of these two arms, of about 1.7 months. That delta is similar to what we see with elacestrant, the FDA-approved oral SERD. This is clearly better than the standard of care. It’s a small improvement and it is a similar delta, similar improvement, to what we see with elacestrant.

Importantly, when they looked at the all-comer patient population, patients who had breast cancers with and without mutations, that number is essentially the same. And so there’s no benefit in patients who have estrogen receptors without mutations. This did not reach significance. This is consistent with what we know in the field of how these oral SERDs work.

Then they looked at this combination, and this is an interesting idea. Most of our patients get CDK 4/6 inhibitors in the first line like ribociclib, or Kisqali, or abemaciclib or palbociclib. And then the idea is if a patient progresses on that, why don’t we try switching the CDK 4/6 inhibitor to Verzenio and then adding in an oral SERD like imlunestrant instead of fulvestrant.

I would argue that I think the better comparator here would’ve been imlunestrant plus abemaciclib versus fulvestrant monotherapy or fulvestrant plus abemaciclib. This was the comparator that was provided in this trial. There was an improvement of about 4 months in progression-free survival. Again, I think it’s really hard to interpret because, if you’re comparing these two arms, really it’s looking at the benefit of Verzenio rather than the benefit of the oral SERD, per se. And I think that, we already know that Verzenio is actually approved as a single-agent therapy. So it’s not clear to me as a breast oncologist what to do with these data. Is this a combination that will get FDA approved? I don’t know. And we’ll have to see what the FDA thinks about this.

In terms of overall survival, I think this is an important endpoint, that the data are not mature yet. It does look to trend to an overall survival benefit, which I think is really important in the field. It’s not clear to me if elacestrant, the FDA-approved oral SERD, Orserdu, is going to improve overall survival. I think we just have to see.

The one thing I will say about this drug is that oral SERDs, we’ve heard a lot from companies and from everyone, all the stakeholders in the field that we think these drugs are going to be better than fulvestrant because they’re going to have very few side effects. What we’ve clearly seen in the field is that is not true. I’m sure that there are patients in this audience who have received elacestrant, who have received other oral SERDs, and these drugs can have rather peculiar side effects. We’ve seen things like ocular toxicity, changes in vision, floaters; decreases in the heart rate, rash and nausea. I think with elacestrant, nausea is a big deal side effect. I think what’s interesting with this drug is that I do think that compared to other oral SERDs, there are fewer side effects. Now what’s highlighted here in the red boxes is the number of patients with any grade three or higher side effect, but you can look down the list and reassuringly it is smaller with imlunestrant as a monotherapy. That’s on the left hand side. With the combo on the right hand side, obviously, things like neutropenia are frequent and anemia, but those are really side effects of the abemaciclib, not of the imlunestrant.

As an oncologist, to put it bluntly, this is the cleanest of the oral SERDs I think that I’ve seen with respect to adverse events. I think this will be of interest to this group because it really does seem like when we look at these individual side effects, that the side effects that we’re seeing are less than grade 3. That’s not to minimize these side effects. We know that grade 1 and grade 2 diarrhea can be a big deal for patients. But hopefully these are things that we as a field can manage better. And I think it’s fair to say, compared to the other oral SERDs that are either approved therapies or in late-stage trials, I do think this looks like a best-in-class drug from a side effect profile.

Jean A. Sachs, MSS, MLSP [00:16:10]

Dr. Vasan, I just want to ask you a question.

A question that I have from the audience, and I know imlunestrant hasn’t been approved yet. But if it is approved and if someone has had progression on Orserdu, do you think you’d be able to try another SERD like they’re doing the CDK 4/6 inhibitors now?

Neil Vasan, MD, PhD [00:16:34]

Yeah, it’s a great question. This whole idea of re-treating with a different drug of the same class after progressing on that drug is a really important clinical question. And I think we just need clinical trials to help address this. We have a little bit of data for an analogous question with CDK 4/6 inhibitors. So we know that changing the CDK 4/6 inhibitor in large populations does improve progression-free survival. This is the MAINTAIN trial, which was published I think 1 1/2 to 2 years ago. So we do have a bit of a track record in that, but it’s hard to know. And this is where we see differences between populations and individuals, right? These trials are all about populations, but on an individual level, there certainly might be a patient where, if they progressed on elacestrant, would be a good candidate for this drug if it is approved. And this is just again, conversations that you all should have with your oncologists.

Jean A. Sachs, MSS, MLSP [00:17:32]

Right. And then can I ask you a question about side effects? Because I have talked to a lot of the advocates at the meeting, and I know a lot of these grades were created when you were on chemotherapy, right? So you’re on chemotherapy, you might have bad days, but then you had time where you recover. For patients who are now on these drugs, taking these oral medications every single day, even if it’s grade 1 diarrhea, that’s not so great.

I’m just wondering if they’re thinking about rethinking how they talk about it. Just wondering about your thoughts on that.

Neil Vasan, MD, PhD [00:18:11]

This is such a great question, and I would even argue this is a question where patient advocates and you all can lead the discussion at a national level and an international level in these issues. Just as you said, these are 1970s metrics for these side effects based on chemotherapy. And I would argue that many side effects that are graded in a certain way — grade 1 is not the same in every side effect, grade 2 is not the same in every side effect. I’ll just give some hypothetical examples. Things like neutropenia, some of these lab abnormalities where patients may not necessarily feel a side effect if they just have a low white blood cell count. But you have another side effect like stomatitis, inflammation of the lining of the mouth, where even grade 1 stomatitis is a big deal for patients. We call it grade 3 if they’re losing weight, if someone has such bad stomatitis that unfortunately they’re actually losing weight. I mean that is so drastic.

It’s definitely in need of a rehaul, and I think that this is a real area where you can lead the way in helping all of us think about side effects and change how we think about side effects. And I think that this is a great area for a revamping.

Jean A. Sachs, MSS, MLSP [00:19:28]

I appreciate that. And we will lead the way. So keep going.

Neil Vasan, MD, PhD [00:19:33]

Great. So just to conclude these first three trials. The first is that CDK 4/6 inhibitors are superior to chemotherapy as first line treatment in ER-positive metastatic breast cancer. Imlunestrant, which is an oral SERD, is superior to endocrine therapy in patients whose breast cancers have alterations in ESR1, and this is after CDK 4/6 inhibitor. Unclear benefit for this combo, and we’ll have to see what the FDA says. And then this triplet therapy of inavolisib with Ibrance and fulvestrant, this triplet therapy, is superior to Ibrance plus fulvestrant in patients with endocrine-resistant, ER-positive metastatic breast cancer bearing PIK3CA mutations.

A lot of this is interesting groups of patients, groups of patients within the ER-positive metastatic breast cancer sphere.

I’ll move on to this study called the PATINA study. Sometimes we go to these conferences and we have a sense of what trials are going to be a big splash and sometimes we don’t. This was a huge surprise for the field. I think it’s really an amazing finding.

This was a trial looking at patients with metastatic, what we call sometimes triple-positive disease: estrogen receptor-positive, progesterone receptor-positive, HER2-positive. And I’m sure many of you in the audience have breast cancer with all three of these markers being positive. Oncologists have traditionally treated this cancer more in the HER2 avenue because we know that that is a more aggressive breast cancer. And then after the HER2 treatments finish after the chemotherapies finish, we then introduce hormonal therapies.

This is an area where I have to say, as an oncologist, we have a lot of therapies because there’s so many available, and commonly after the first, second line we sometimes mix and match therapies because we don’t know what the best therapies are. It’s fair to say that in this field, every therapy that we have targets HER2. HER2 is such an exquisite driver of this type of breast cancer. So we know that CDK 4/6 inhibitors have transformed ER-positive breast cancer. What about the idea of combining, or bringing in, palbociclib, Ibrance, into patients whose breast cancers have HER2-positive features, but also estrogen receptor-positive features. So this was the PATINA study.

The background here is summarizing what I just said, that 20% of breast cancers overexpress HER2, about half of those, this is about 10% of breast cancers, also co-expressed the estrogen receptor. We know that CDK 4/6 inhibitors have transformed ER-positive breast cancer, and there is a preclinical rationale to blocking CDK4 in HER2-positive disease. This is work from one of my colleagues Shom Goel who’s a PI at Peter Mac in Melbourne, Australia. So this question was really adding palbociclib into this treatment regimen.

This is the scientific background, but just to say that targeting HER2 and targeting CDK 4/6 converges onto the PI3K pathway. This is a pathway that I work on intensely in the laboratory. This is the pathway that has mutations in PIK3CA in many of our patients. And so this question was really trying to introduce both of these drugs.

This was the trial design, it was through the Alliance, which is one of our cooperative groups and I think just a shout out to Alliance and SWOG and many of these incredible cooperative groups that have completely changed the standard of care with really beautifully designed, statistically rigorous trials.

This was a trial looking at patients in the first-line setting getting anti-HER2 therapies. And the way it worked is that patients received six cycles of the traditional therapy THP. This is the CLEOPATRA trial, which many of you’re familiar with. This is a combination of a taxane chemotherapy with trastuzumab, or Herceptin, and pertuzumab, or Perjeta. So we call this THP for the letters.

After completing six cycles of the chemo, normally we give Herceptin and Perjeta with endocrine therapy, and then they randomize the trial to receiving that standard arm versus the same therapy with the addition of Ibrance, or palbociclib. There have been a lot of trials in the field looking at CDK 4/6 inhibitors in the treatment of these patients with ER-positive, HER2-positive breast cancer. But it hasn’t deployed it in exactly this manner. And I think that we were all really surprised and there were actually gasps in the audience when these survival curves came up.

The progression-free survival was improved by almost 14 months, by over a year. You can see here that the survival curves separate right from the beginning showing that this is a real sustained benefit. The hazard ratio was 0.74. That is a favorable hazard ratio for progression-free survival. This was a really incredible finding for the field. The overall survival data are not mature yet, and we’ll see where this ends up. As an oncologist, I would be really surprised if this did not improve overall survival. But again, I think we have to see.

Neil Vasan, MD, PhD [00:24:50]

When they looked at the specific groups of patients — patients who had received anti-HER2 therapy or had not received anti-HER2 therapy — or had different types of responses — a complete response, a partial response, stable disease — all of these patients benefited from the addition of palbociclib.

When we look at the side effect profile, I think this is where we have to think a little bit more, as a field. There were a lot of patients who had a lot more diarrhea with the addition of palbociclib. This was a little surprising to me because we don’t associate diarrhea as much to Ibrance. Ibrance certainly, as a breast oncologist, the side effects I see the most are fatigue, nausea — and those can be very debilitating — neutropenia, the decrease in the white blood cell count, that’s to be expected of course. But I think the diarrhea is something that we have to do better as a field on. And I think that, as we start to think about these triplet therapies, I mentioned the, INAVO120 triplet therapy earlier, we start to see these side effects compounding. This is another area where patients can really lead the discussions in thinking about how to confront this. There’s no doubt in my mind that this will lead to an approval, but we need better ways to manage diarrhea for this patient population.

Jean A. Sachs, MSS, MLSP [00:26:11]

Can I ask one question?

I knew this question would come up, but there are a couple of people saying, what if you’re HER2 low or HER2 ultra-low? Are they in this trial?

Neil Vasan, MD, PhD [00:26:24]

Yeah, great question.

They’re not in this trial. Dr. Sara Hurvitz, who’s the head of medical oncology at the Fred Hutch Cancer Center in Seattle, gave the discussion on this trial— it was an amazing discussion and if any of you have access to the slides or to the presentation, I would encourage you to watch it. She proposed several really interesting trials looking at patient populations with treated with T-DXd, trastuzumab deruxtecan, or Enhertu. And she proposes a lot of really interesting trial concepts.

It’ll be really interesting to see if this is effective in patients with HER2-low breast cancer. Certainly the patients with ER-positive, HER2-low disease, we would treat as ER-positive with CDK 4/6 inhibitors. But this is a first example of a trial that met its primary endpoint. And I think we’re going to see a lot of iterations of this maybe looking at different CDK 4/6 inhibitors, different targeted therapies. I would love to see a trial where they maybe do a much more focused diarrhea management.

I learned from one of my colleagues and good friends now Abigail Johnston, who’s an amazing patient advocate, an amazing woman. I learned recently from her that there’s a drug now that is FDA approved in patients with HIV for diarrhea, and this is now being tested in a phase III setting in breast cancer because now many of our targeted therapies cause diarrhea.

I think that this is a first example of a combo that makes sense. Hopefully this will result in approval. This was really a first step on the mountain, and I think this will result in a lot of new innovations in the field.

Jean A. Sachs, MSS, MLSP [00:28:10]

Yeah, and Abigail is good, I get my best advice from her.

Some people are asking, and obviously this hasn’t been approved yet by the FDA, this combination, but if they are triple-positive MBC, should they start talking to their doctor soon about the possibility of adding palbociclib?

Neil Vasan, MD, PhD [00:28:34]

I think so. This is a really interesting space we’re in right now because breast cancer is such a fast-moving field. Five years ago, I would say, all virtually all of our treatment decisions were based on phase III trials that had reported and drugs that were approved — the FDA follows suit after those phase III trials are performed. We’re now seeing, because the field moves so quickly, changes where we see the data very quickly, and then we make recommendations based on that data, regardless of if the drug is approved or not by the FDA in this particular setting.

Now this is another discussion where I think patients can lead the way. There are going to be examples, unfortunately, with the healthcare system where if a certain insurance provider isn’t going to approve a drug if it’s not FDA approved in that setting. These are also areas where I think you all can be very helpful and lead the way as we try to really improve health for all of our patients. But it really speaks to the testament of the fast-moving field.

I should also say, this was a late-breaking abstract, it was advertised as late breaking because, my understanding is, that these data, the authors found out 5 days before the conference. So we’re in a mode now with the 24-hour news cycle and all of these changes in our fast-moving world that we’re able to get these data out to patients and to oncologists as quickly as possible. And I think this is a really great advance in the field.

Jean A. Sachs, MSS, MLSP [00:30:00]

I want to ask you two questions. One is, someone’s asking, is the drug for diarrhea called colestipol?

Neil Vasan, MD, PhD [00:30:09]

I believe it is, yeah.

Jean A. Sachs, MSS, MLSP [00:30:11]

OK. And then this is not particularly about the study, but I think it’s important. For metastatic patients, how often should they be redoing genomic testing?

Neil Vasan, MD, PhD [00:30:22]

It’s such a great question, and it is a changing question. With the INAVO120 study, that was the first-line study, those patients who are eligible should be tested in the first line, I would argue.

This testing, please keep in mind, is all based on what’s called immunohistochemistry, or IHC, it’s technically not genomics, it’s looking at the protein levels of HER2 that is based on staining. So this is technically not a genomic-driven trial, but this whole question about genomic testing — when should we do it, I mentioned ctDNA is now being used to enroll patients on trials much more frequently — this is another area that is in flux right now.

Most of the patients who I’ve spoken with really endorse wanting to know this data right from the beginning. And I think this is something where patients can lead the way and patients can teach oncologists about what they want in terms of their knowledge of their disease.

I don’t think I’ve ever, I had a case of a patient I’ve treated where the insurance companies didn’t approve it, even if it was obtained twice. So again, this is an area where we need to understand what patients want.

Jean A. Sachs, MSS, MLSP [00:31:42]

Thank you.

Neil Vasan, MD, PhD [00:31:45]

So these are the conclusions of the trial. I think it’s very exciting, and I think we’re going to see a lot more updates in this area.

Those are the trials that I considered the most important for metastatic breast cancer patients. Now I want to move on to early-stage breast cancer.

This was a really interesting study. All the studies that we’ve talked about so far are prospective studies. They eliminate biases in patient populations as best as they can. This was actually a retrospective analysis, but it was so provocative and I think that you would be interested in this.

This was looking at the impact of anthracycline. So these are drugs like doxorubicin in patients with hormone receptor-positive, HER2-negative breast cancer whose lymph node status is negative. So no cancer in the lymph nodes.

I put this [picture of doxorubicin IV drip] up here because I think this will have emotional resonance for many in the audience. This is an anthracycline, this is doxorubicin; in the lay press and by many people it’s called the red devil. It is a drug that’s the hardest drug that we give in breast cancer. It’s a drug that causes tremendous side effects, nausea, changes in the heart pump function. It can cause leukemia, unfortunately, in 1 in 200 women. This is a really, really hard drug. It’s a drug that even emotionally, some patients, if they have recurrent breast cancer, when they see the drug, they can actually develop anticipatory nausea or vomiting.

I say this not to be fatalistic or anything, but just to say this is a really, really big deal for patients. We as a field have moved away, I think from anthracyclines to try to tailor to the patients who really need this drug and don’t need this drug.

This was an analysis of the TAILORx trial. This was a trial that I think many of you are familiar with. This was testing the role of Oncotype and using Oncotype as a diagnostic to try to say who doesn’t need chemotherapy.

Tn this trial, patients got a lot of different chemo regimens, and they were looking at patients who had gotten one of the standard care therapies we give called TC, which I’m sure many in the audience have received, versus a combination of therapies involving the anthracycline, so AC-T or T-AC, which again, I’m sure many people in the audience have also received.

This was a retrospective study, so there are biases that may be present here that we can’t account for. What they tried to look at is in the patients with the really high Oncotype scores who got TC versus T-AC or AC-T: Was there a difference in survival? This was very provocative data, because what you can see is, RS is recurrence score, that’s the Oncotype score. So in general, and I’m sure many of you are aware in the audience, when the Oncotype score is less than 25, we don’t recommend chemotherapy, and when it’s greater than we do. This is looking at the higher Oncotype scores of 31 or greater.

You can see on the left-hand side, if your Oncotype score was less than 31, it didn’t matter whether you got an anthracycline or not. The distant recurrence rate was the same. But in patients who had very high Oncotype scores—aggressive breast cancers, breast cancers that have a high risk of recurrence—it did seem that in the retrospective studies, these patients benefited with the addition of the anthracycline. This was a significant hazard ratio, 0.32, that’s a very, very significant hazard ratio. Again, these are retrospective studies and so they have to be viewed with some caveats.

The OS, the overall survival, it looks like was not changed. Again, these are smaller numbers, but the overall survival didn’t seem to be improved. When they looked at who were these patients, what were the characteristics of the patients who benefited, it looked like the patients who had larger tumors, greater than 2 centimeters. So these are T2 lesions or higher had the greatest amount of benefit. When they looked at patients who were premenopausal or postmenopausal, both groups benefited.

Then finally, we know that Oncotype is what we call a continuous variable. It’s not binary yes, no; it’s a score. It’s a spectrum. This is a really interesting type of analysis called a regression splines analysis where they basically look at on the x axis here, when I’m pointing with the laser pointer, this is the score going up and up and up. And then the y axis here is the hazard ratio. And so the fact that this blue curve is going down means that the benefit of the anthracycline is continuously increasing as the Oncotype score goes up. And that 31 cutoff is in the middle of this. But you can see here that these hazard ratios, they go down exactly as you would expect. They did some additional analysis looking at other types of chemotherapy that patients got as well.

Jean A. Sachs, MSS, MLSP [00:36:56]

Can you just go back to that slide? So your Oncotype score is across the bottom?

Neil Vasan, MD, PhD [00:37:02]

Yeah.

Jean A. Sachs, MSS, MLSP [00:37:03]

OK. So it’s once you get to a 30?

Neil Vasan, MD, PhD [00:37:06]

Yeah, so, the argument here is there’s obviously going to be a score where the difference between these two chemo regimens is negligible. That’s around the 15-20 range. But then as that number goes up, it’s a continuous variable.The argument here is that it’s not as if 31 is some special number. It’s that actually when you look across this entire spectrum, there’s a continued benefit that that increases when the Oncotype score increases, when the cancer is more aggressive.

Jean A. Sachs, MSS, MLSP [00:37:37]

Obviously this isn’t an FDA approval, but is this something where the NCCN guideline might change? How does this get into the clinic?

Neil Vasan, MD, PhD [00:37:45]

I don’t think this will enter NCCN guidelines. I think this will spur the design of a prospective clinical trial to answer this question. And that will take time. But I think it’s an interesting idea that, previously, based on Oncotype and TAILORx, we would commonly give TC and we would sometimes save anthracyclines for patients who had lymph node involvement. This is showing that there is a subset of patients who may benefit from anthracyclines without lymph node involvement. But as you said, we really need prospective data. However, I do suspect that for patients who have really high Oncotype scores, I do think we’re going to see a shift now in including anthracyclines for that patient group based on these data. This was an example of a retrospective study that I think was very disruptive in the field and I think will change practice for some people, more on an individual basis.

Certainly I think this is a conversation worth having with every patient where, , you’re recommended a particular chemo regimen to really discuss the risks and benefits of the most aggressive chemo regimen versus something that might be in the middle.

Jean A. Sachs, MSS, MLSP [00:39:00]

Yeah, thank you for bringing this up. It’s really interesting. There’s so much in the chat about side effects from lots of drugs. So I’m going to let you keep going.

Neil Vasan, MD, PhD [00:39:09]

Yeah, and I want to be really clear, this is not a prospective study, this is not practice changing, I would say, but I think that it’s going to make oncologists think a little bit more about who we’re giving anthracyclines to and who we’re not recommending them to.

This is the conclusion here, and there are some caveats. We’re going to be thinking about it more in larger tumors where that the Oncotype score is much higher.

Shifting to some other really interesting trials. This was actually a surgery trial looking at the role of axillary surgery. There are many trials looking at the omission of axillary surgery. Normally when women have early-stage breast cancer, we always do what’s called a sentinel lymph node biopsy. We sample the lymph nodes in the armpit because those are the lymph nodes that cancer cells most likely drain into and are most likely to be positive. There are already many trials that have been designed looking at the question: Are there women where we don’t need to do a sentinel lymph node biopsy? Nothing changes in terms of their therapy, their survival is the same. And that’s already been shown in older women, women over the age of 70, with early-stage estrogen receptor-positive tumors.

This is a really important idea because we know that sentinel lymph node biopsies, and, more importantly, axillary lymph node dissections, removing all the lymph nodes in the armpit, have a very high rate of lymphedema. I don’t think this is news to anyone in this audience. I’m sure many of you battle with lymphedema every day. As an oncologist, I find lymphedema very challenging to manage, to be honest. It’s very unpredictable. There are some days when patients are doing really well, and there’s some days where no one knows why, but then the arm can blow up, and the arm can increase in size. This is where the wrapping and lymphedema therapy by very dedicated specialists who really are artisans in their field have been transformative for symptom management. So this is a big deal, quality-of-life issue.

This was an interesting trial because what they were trying to do is ask the question, if we completely omit axillary surgery compared to just a standard sentinel lymph node biopsy, does this change disease-free survival? This was a very, very select group of patients. These were patients who had smaller breast cancer, so less than 5 centimeters, node negative, planned for lumpectomy and radiation. That’s very important: They plan to get radiation. And this was a very large trial, 5,000 patients randomized to either no sentinel lymph node biopsy or sentinel lymph node biopsy. And then if they got the sentinel lymph node biopsy, they would proceed as the standard of care. This was a trial that was primarily recruited in Germany and Austria. This was done by the European groups.

What was interesting is that, this was what’s called a non-inferiority trial. The question is: Is one approach non-inferior to the other? In other words, are they equivalent? And the answer here is that they were equivalent. You can see that these curves practically overlap and that the disease-free survival is really similar. I’m copying the slide here and I say this because I was on a panel with an amazing patient advocate who talked a lot about the term de-escalation and how, for many patients, that’s a triggering term. It’s really more of a one-size-fits-all approach.

I would argue here that the one-size-fits-all approach might be suitable for patients, not just patients above the age of 70, but with more liberalized parameters. Maybe patients who are above the age of 50 with low-grade, estrogen receptor-positive breast cancers, tumors up to 2 centimeters, T1 and T2.

There are other studies that are looking this at this question as well, in American populations, in more diverse populations. But I think what we’re seeing is that this idea of the best treatment, the Goldilocks treatment is not just in patients who are much older, but that there might be more patients who don’t need a sentinel lymph node biopsy. This is really an interesting study and I think will affect patients, certainly in Europe, but I think that in America we need to have a more diverse American trial that really looks at this question as well.

Why don’t I just stop there. I don’t know if there are any other questions before going into the next topic.

Jean A. Sachs, MSS, MLSP [00:43:38]

Well, people who are living with triple-negative breast cancer are just wondering, was there anything, do you have anything to share?

Neil Vasan, MD, PhD [00:43:50]

So for this study it was just looking at ...

Jean A. Sachs, MSS, MLSP [00:43:52]

No, not for this study. But those with triple-negative metastatic. I think they’re just asking in general.

Neil Vasan, MD, PhD [00:44:00]

It’s a great question. Metastatic triple-negative breast cancer is the one of the most challenging disease subtypes that we treat. There was nothing directly addressing this patient population. I will say that T-DXd, or trastuzumab deruxtecan, for these patients who are HER2 low and many patients who are so-called triple-negative breast cancer patients are HER2 low. I think we’re going to be seeing more examples of that moving up in the treatment landscape. There was nothing though directly this year for those patients. But I do think in the future we’re going to see more trials in this area.

Jean A. Sachs, MSS, MLSP [00:44:41]

And then what about for triple negative in the early stage? Anything?

Neil Vasan, MD, PhD [00:44:45]

Yeah, so this trial was just looking at patients with estrogen receptor-positive breast cancer. I do think that there are trials that are trying to enroll patients with early-stage triple-negative and look at some of these questions. We do know, as you all know, this is a more aggressive type of breast cancer. And so I think that these studies where we try to remove certain aspects of the therapy like sentinel lymph node biopsy are more challenging in breast cancer subtypes like triple negative where we know that the rates of recurrence are higher.

These are ongoing trials and I’m looking forward to seeing if we’ll be able to apply this to patients in the earlier stage settings.

Jean A. Sachs, MSS, MLSP [00:45:26]

OK, thank you. Yeah, keep going.

Neil Vasan, MD, PhD [00:45:28]

Two more studies to discuss. The first is in DCIS. This is a really interesting trial called COMET. This was published in JAMA, the Journal of the American Medical Association. And this was answering a really, really important question that I think comes up in clinic a lot with these patients, which is: Do we need to actually do treatment?

We know that DCIS is not cancer, it’s a precancer. Some group of patients progress to invasive cancer. We don’t know what that number exactly is. It’s very variable, it’s very heterogeneous. These studies are really challenging in the real world to execute because of this heterogeneity. And the standard of care treatment, the reality is it’s not so different from the standard of care treatment for estrogen receptor-positive breast cancer. We do surgery, we do radiation, and we give tamoxifen or an AI. That’s not so different from a low-risk estrogen receptor-positive breast cancer.

We know that DCIS may but does not always progress to invasive cancer. So is there a way we can do active monitoring?

This was a trial that looked at about a thousand women with DCIS, low-grade DCIS and it could have actually even been larger than 4 centimeters if they had multiple biopsies, and they were randomized to receiving the standard of care exactly as I said, surgery, radiation, hormonal therapy versus what they call active monitoring, which is getting mammograms every 6 months, biopsying if there is a change in that imaging, and, if a patient does develop invasive breast cancer, then treat it as needed.

Interestingly, adjuvant endocrine therapy was permitted and I think that’s interesting. I think it reflects more of like a chemo prevention idea rather than treating active DCIS. But in any case, this was a really interesting question, and the question was what were the rates of invasive breast cancer. So this was a randomized non-inferiority trial, basically asking are these the same.

I will say that while these curves did separate and in the active monitoring group what’s interesting is that the invasive cancer rate was actually a little lower than in the standard of care arm. What that really reflects is the fact that most likely these cancers that were detected were already there and patients got what’s called upstaged. We think it’s DCIS on the biopsy, but then when we actually do the surgery, it turns out to be invasive cancer. That happens not uncommonly. But you’ll see this dotted line at 0.1. This was the prespecified endpoint for non-inferiority, and you can see that both these curves are under that dotted line, both are under that 0.1. This was very interesting because the conclusions were that at 2 years, and it’s only 2 years so we really need longer-term follow up, women with low-risk DCIS who got active monitoring had a non-inferior rate of invasive cancer. I think this is really, really interesting and I’m really encouraged to see how following these patients in the long term shows if this might be a feasible approach.

I think this is a really interesting question. It comes up a lot in clinic, and I think it also necessitates a really good relationship between patients and oncologists. We need patients to come to all the follow-up appointments and make sure that they’re participating in this active monitoring.

I’ll stop there. The last trial I was going to present was on surveillance.

Jean A. Sachs, MSS, MLSP [00:49:03]

OK, thank you. I have a lot of random questions that—I’m not saying you’re going to be able to answer them all, so just tell us which ones you can.

We have questions about was there anything with triple-negative vaccine trials or anything you have to share about that?

Neil Vasan, MD, PhD [00:49:25]

No trials for triple-negative vaccines that I’m aware of, but there is a lot of interest in vaccines in the HER2-positive space. There’s an active trial called Flamingo that’s going on right now, and this is looking at a HER2 vaccine in patients with early-stage, HER2-positive breast cancer. So I think it’s a really interesting area. We know that HER2 can have pieces of the protein that get presented to the immune system for clearance. That’s actually been known for decades now, and it’s very interesting to think that we could exploit that for a therapy.

I do think that the vaccine space is a really interesting space, especially since triple-negative breast cancer responds to immune therapy in the curable setting and in the metastatic setting. And so hopefully we’ll see more trials in this area.

Jean A. Sachs, MSS, MLSP [00:50:14]

Thank you. And anything new about whether you should extend endocrine therapy past 10 years, particularly if you were diagnosed with lobular breast cancer?

Neil Vasan, MD, PhD [00:50:27]

That’s such a great question. The 5 versus 10 was something that, as a field, we answered I think a couple years ago. There were many, many trials showing that more than 5 is better than 5 with respect to disease-free survival. In terms of side effects, obviously there’s more side effects and so this is always an individual conversation we have with patients.

There is a suggestion that the lobular patients may benefit from longer therapy durations. Whether longer than 10 years, though, I don’t know any trials that are looking at that specifically. But we do know that patients with lobular breast cancer, I mean this is an underserved patient population. It’s a type of breast cancer we can define very easily, but we treat exactly the same way as invasive ductal carcinoma. So this is another underserved area.

Jean A. Sachs, MSS, MLSP [00:51:20]

OK. I’m not sure you’re going to know the answer to this, but it sounds like there was a poster presentation that was called out in one of the highlight videos that concluded that CDK 4/6 inhibitors may be less effective for those with IBC subgroup. Did you take a look at that or?

Neil Vasan, MD, PhD [00:51:38]

IBC! Oh, that’s interesting. I didn’t see those data. IBC meaning inflammatory breast cancer?

Jean A. Sachs, MSS, MLSP [00:51:44]

I assume that’s what they mean. Yeah.

Neil Vasan, MD, PhD [00:51:47]

That’s very interesting. I didn’t know that. I’ll have to take a look at that.

Jean A. Sachs, MSS, MLSP [00:51:51]

OK, thank you. Yeah, we didn’t think that you saw every poster and read everything.

And were there any discussions around immunotherapy options for ER-positive breast cancer?

Neil Vasan, MD, PhD [00:52:06]

Great question. The trial that I think we’re all waiting for, and I think it’s about to be released, hopefully pretty soon, is called KEYNOTE-756.

This is a trial that is looking at pembrolizumab in patients with early-stage, locally advanced, ER-positive breast cancer with lymph node involvement and high-grade features, grade 3. We think that these breast cancers are more like triple-negative breast cancer, but they are ER-positive. That trial has already reported that the pathologic complete response, meaning how much of the breast cancer is killed at the time of surgery is improved with the addition of immune therapy. So this is a trial that I think that hopefully next year, maybe another year, we’re going to get the readout. And I’m hopeful that it will be positive because the trial improved the response rates of this drug. So definitely an area to look out for.

Jean A. Sachs, MSS, MLSP [00:52:59]

OK, great. Thank you. Lots of questions about the ESR1 mutation and the SERDs. I believe there are a number of other SERDs that may be approved over time, is that correct? Are there other ongoing trials?

Neil Vasan, MD, PhD [00:53:15]

That’s right. A couple drugs I’d be on the lookout for: One is called camizestrant, which is AstraZeneca’s drug. That had a positive phase II trial last year at San Antonio. A second drug that’s called giredestrant, which is Eli Lilly’s drug. I think those trials we’re going to see in the next year. Those are what are called traditional oral SERDs. They degrade the estrogen receptor. They have a similar mechanism as fulvestrant.

There has been an explosion in chemistry and the ways that we can inhibit these targets. And there’s a new class of drugs that you may have heard of called PROTACs. So these are really interesting drugs that degrade targets not through the way that fulvestrant does, by basically directing the protein to something called the proteasome, which is in every cell in the bod and is a machinery that can degrade proteins. The company that’s the leader in this is called Arvinas, based in Connecticut. They have a drug called vepdegestrant, and it’s an ER-PROTAC. This drug looks really interesting in clinical trials. It looks like it has very few side effects in patients who have been heavily pretreated with lots of different therapies. And it’s in a first-line, phase III trial right now. So hopefully we’ll get the readout of that in the next 1 or 2 years.

There’s also another drug called palazestrant, and Olema is the company. This is another type of estrogen receptor inhibitor called a complete antagonist. Think about it like turning on a car. Basically what this does, it’s like one of those permanent keys that can turn off the engine. This is another very interesting drug that’s also in phase III trials.

The thing that I would be wondering as a patient is, I think that the patients who have breast cancer with ESR1 mutations are going to benefit from all these drugs. But I think it’s the patients without the mutations in that estrogen receptor, and that’s most of our patients. I hope that one of these drugs will show a benefit in that much larger population. Because I think that will be a way that these drugs can reach more patients.

Jean A. Sachs, MSS, MLSP [00:55:24]

Yeah. We know there was a lot of frustration that Orserdu wasn’t approved for those without the ESR1 mutation. But I guess all these drugs are figuring out how to outsmart the cancer. Like the cancer keeps getting smarter.

Neil Vasan, MD, PhD [00:55:45]

That’s right.

Jean A. Sachs, MSS, MLSP [00:55:47]

I wonder if you can just talk a little bit about dosing. This goes into all these new drugs, which are great to have, but they come with some side effects that can be hard to tolerate, whether it’s Enhertu or these CDK 4/6 inhibitors. And so is there more work being done on these questions? Do you have to start at the maximum dose? Can you change the cadence if you’re doing well? What can patients do to make sure they can maintain quality of life while staying in treatment?

Neil Vasan, MD, PhD [00:56:19]

Yeah, so this is a huge endeavor. Another area where you all lead the way in how we think about this. So the FDA, as many of you know, launched something called Project Optimus. At the first day of the conference Mirat Shah, who’s the leader at the FDA who leads this initiative, was one of the speakers. This is a really important area, I think an area that we’re learning much more about. I’ll just paint a couple themes. One thing we clearly see in a lot of these targeted therapy trials is that even if the dose is at the lowest dose, patients still benefit. So that really tells us that for every patient the dose is different. Every patient is unique. We have to find out as oncologists. We have to trial different doses and see what the sweet spot is.

But one of the challenges is it’s not black and white, it’s a lot of gray. I see patients all the time who say, “Oh, maybe I can play through this terrible side effect getting the highest dose,” and “Oh, I don’t want to go down on the dose.”

And it goes both ways. There are oncologists as well who are a little fearful of going down on the dose. So we need data to help guide these decisions. This is an initiative that ASCO is taking very seriously. There’s the launch of the CDK 4/6 inhibitor trial looking at changes in dose in older women who are receiving CDK 4/6 inhibitors. One arm is doing the standard approach where we start at the highest dose, and then if patients are tolerating, we can go down. Then one strategy is doing the other way, where we start at the lowest dose. Then if patients tolerate, if the therapy works for the patient and there’s no side effects, maybe you go up.

This is a really interesting idea. And I think the devil will be in the details about how to interpret those data. I think about this as a scientist a lot. This is a hard question to answer rigorously, but I will say that by bringing this issue to the forefront, I think what we’re also seeing concurrently is a much more concerted effort in side effect management. This is something I think about a lot, because most of my work is in the PI3K field where these drugs cause huge numbers of side effects for patients. I think we’re seeing a lot more aggressive ways of managing side effects. I say aggressive meaning being tested in the trials, like I talked about before with colestipol; in the PI3K inhibitor trials, really having good ways to manage hyperglycemia; or even coming up with new drugs that don’t even cause those side effects.

This is a really important conversation because not only are we finding ways in clinical trials to address dose, it’s forcing the field to change the way it thinks about side effects. And that has a lot of trickle-down effects into all branches of breast oncology that are really important. And again, I think you all lead the way in helping us answer these questions and conceptualize these questions.

Jean A. Sachs, MSS, MLSP [00:59:07]

Yeah, and I think for everyone listening, you need to talk to your doctor if you are really struggling with your side effects. Because they’re not necessarily going to know how your quality of life is.

I just want to switch subjects a little bit and see if you can talk a little bit about the ZEST study and ctDNA for surveillance.

Neil Vasan, MD, PhD [00:59:30]

Yeah, great. It’s a great question. So ctDNA, of course, in the metastatic setting has changed how we diagnose patients. We’re commonly doing ctDNA to look for cancer, to look for mutations. It’s essentially as good as tissue, obviously some caveats. But in the early-stage setting, of course, we’re really interested in trying to find, it’s really the holy grail. What is the biomarker that tells us who is going to progress?

This is a question that comes up in clinic all the time. A patient has a curable breast cancer, we don’t get systemic imaging, meaning CT; chest, abdomen and pelvis; PET scan; et cetera. We don’t do that for surveillance, we just get mammograms. So how do you know? We don’t know.

This is the inchoate netherworld that I think patients have to live in, this very liminal space where you’re always afraid of progressing, right? You’re always afraid the breast cancer is going to come back. And we don’t have a test that can tell us who those patients are.

This is where ctDNA is really encouraging. ZEST, as you mentioned, is a trial that looked at the patients who had the highest chance of recurring: patients with triple-negative breast cancer, who got neoadjuvant therapy, who still had disease left over in the breast. The drugs did not kill all the cancer. Those are the patients at the highest risk of recurrence. They took those patients and they randomized them to either just getting the standard of care therapy versus serially testing those patients for ctDNA, and if they turned positive, adding a new therapy on top of that.

It’s a really interesting idea. But what was challenging is that the testing was not the most sensitive. So that trial, we actually opened even at my institution at Columbia, and I don’t think we were able to enroll a single patient. What that means is that even the patients who are very, very high risk, when they did the ctDNA testing, very few patients tested positive. What that tells us is that we need more sensitive tests. So I don’t think the technology is there yet to really find the patients who might have higher levels of ctDNA so that we can take those patients, add a therapy or change their therapy, and then be able to show by doing that change, we improve their survival. That’s the holy grail in the field. We are going to see more trials in this area, I suspect.

I think while this was a negative trial, it was an important finding that the technology has to be improved.

Jean A. Sachs, MSS, MLSP [01:02:00]

Right. But we still have to keep watching it, right? Because there is potential and there’ll be more to come.

Neil Vasan, MD, PhD [01:02:09]

There is potential. And I’ll even highlight one study that was really interesting. This was published in Science a couple months ago. We’ve known that ctDNA can get processed by the liver, meaning that the tumor DNA can get eaten up by the liver so that you don’t see it when you do the blood test. So they actually asked a question: If we give an IV molecule, if we give patients an agent that can prevent the liver from doing that, can we increase the positive positivity rates? And they basically showed that they were able to do that.

That’s really interesting. It means that maybe this is a way to increase the diagnostic yield of these tests. So a very fast-moving area, definitely a space to watch.

Jean A. Sachs, MSS, MLSP [01:02:59]

OK, great. We’re almost out of time. Some of the comments in the chat are that their insurance isn’t always covering this test, which is another issue. And we also know, even with biomarker testing, we don’t have a federal mandate for biomarker testing, even though it is, in the metastatic setting, mostly being covered. So we have to continue to get our insurance companies to keep up with these.

Neil Vasan, MD, PhD [01:03:24]

That’s right. And I urge you all to really keep pressuring our oncologists and pressuring the field as you have been doing to really come up with trials that answer these questions. Because the biggest ammunition is to have a clinical trial that answers the question and the answer is yes. And then everyone will fall in line. Everyone being insurance companies.

Jean A. Sachs, MSS, MLSP [01:03:42]

Do you have any final thoughts? You’ve been amazing and I’m sure you were really busy last week, so we cannot thank you enough for putting this together for us.

Neil Vasan, MD, PhD [01:03:54]

No, thank you. It’s really wonderful to talk to this audience. The questions are all phenomenal questions. You all are very knowledgeable and it helps us as oncologists to keep these dialogues open, to ask us the hard questions. No question is a dumb question. Some of these simple questions are still big questions in the field. I personally have learned a lot from patient advocates, both as a scientist and a breast oncologist. And I really applaud LBBC for providing this really wonderful forum, not just for information, but really timely, just a couple days. It’s very fresh, ripe data.

Thank you to you all for this opportunity.