Breaking news: Updates from the 2023 ASCO Annual Meeting

Medical advisory board member Kathy D. Miller, MD provides an overview of the findings presented at the 2023 meeting and learn how the latest breast cancer research impacts you. Attendees had the opportunity to ask questions during this free webinar.

Transcript

Janine Guglielmino, MA (00:00:00):
Dr. Miller, while we’re polling for questions, I thought we could start by talking about some of the studies that were presented on the CDK inhibitors since they seem to get a lot of discussion in the news. Why don’t you share a little bit about what we learned about those medications?

Kathy D. Miller, MD (00:00:21):
Really exciting. The CDK 4 inhibitors — just to remind everybody how they work — they are helpful when added to hormone therapy. And we’ve known for several years now that adding them to the first hormone therapy for metastatic or recurrent disease or adding them to the second hormone therapy for metastatic or recurrent disease, it always has improved response rates and progression-free survival. And in some of those studies, we’ve seen an improvement in overall survival.

About two years ago, we saw the first results of studies moving those treatments into the adjuvant setting in women with hormone sensitive disease at high risk of recurrence. Different results. Really positive results with abemaciclib, otherwise known as Verzenio, but no benefit for adding palbociclib otherwise known as Ibrance.

And we’ve struggled to understand those differences because in the metastatic setting, their results look much more similar. And in the adjuvant setting, they looked really different.

This year we saw the results of the adjuvant study with ribociclib or Kisqali is the other name that it goes by. That’s a trial known as the NATALEE trial. And we’ve all been waiting for those results as sort of a tiebreaker to try to understand, Should these drugs really have a role in the adjuvant setting? And the NATALEE trial was also a positive trial.

Now there are a couple of things that are important here, and I think that NATALEE investigators were very smart in designing this trial. In the metastatic setting, the dose of ribociclib is 600 milligrams once a day, three weeks on and one week off, so it’s one that’s given in cycles. But in the adjuvant setting, we know that to get the benefit of hormone therapy, women need to be able to continue therapy for a long time, for several years. So to try to reduce the side effects in hopes that women would be able to continue the ribociclib for a much longer time. The dose in the NATALEE trial was 400 [milligrams] with a plan to administer therapy for three years.

Now the first time we’ve seen the results, there’s a little over a 3% reduction in the risk of recurrence, looking at all recurrence events, both local or distant recurrence. Way too soon to know if this is an improvement in survival. And those results at a similar period of follow up look very similar to the early abemaciclib results. This really challenges us to think about what might be different about these drugs that we used to think were so similar and really great to give options for patients in this high risk adjuvant setting.

Janine Guglielmino, MA (00:03:18):
Thank you so much. And we actually have a couple of follow-up questions already about this NATALEE trial. One person is asking how do you select the type of person who might get a CDK inhibitor? What factors need to be present? Do they need to be things like grade or Ki-67 score? What is the genomic risk profile?

Kathy D. Miller, MD (00:03:43):
None of the trials required a specific genomic risk profile to be eligible for the trial and for treatment with CDK 4/6 inhibitors. And in the metastatic setting, when we’ve tried to look for predictors of benefits of the CDK 4/6 inhibitors, we really haven’t found it.

Now the adjuvant trials, because of concerns about toxicity of these agents, really were targeted to patients at higher risk of recurrence. And all three of the adjuvant trials had slightly different definitions of high risk. They were almost exclusively studied in women who had disease involving at least one lymph node. The Ibrance, palbociclib, adjuvant trial known as the PALLAS trial, enrolled at least a small group of patients who were lymph node negative but the majority were lymph node positive.

For the abemaciclib, in the NATALEE trial, all of those patients had lymph nodes involved. The trial also required patients to have slightly larger tumors, so not very tiny tumors. Patients could have had chemotherapy or not, depending on whether that was appropriate for their disease. But given that this was a higher risk group, the majority of the patients in all of those trials did have chemotherapy.

The Ki-67 was an additional selection criteria that was added to the abemaciclib trial after it was already enrolling patients. Initially, the abemaciclib trial was limited to patients who had disease in involving four or more lymph nodes. So that is both a really high risk group of patients and it is thankfully not something that we see that commonly, particularly in a group of women with access to screening. So they opened that trial a bit more broadly and allowed patients with one to three positive nodes, but they required those patients to have some other indication of high risk. Either a really large tumor or a tumor that was proliferating really rapidly, and that’s what the Ki-67 marker identifies.

A requirement for Ki-67 was in the initial FDA [Food and Drug Administration] approval of abemaciclib. With further follow-up and additional looks at the data, they’ve realized that we really don’t need to require that marker to find patients who benefit.

Janine Guglielmino, MA (00:06:16):
Dr. Miller, we have a couple of questions from people who could use some help with some of the terminology. Can you explain what adjuvant means for an adjuvant trial and what Ki-67 measures?

Kathy D. Miller, MD (00:06:31):
Sure. My apologies. We talk in code and we frequently give things two or three names to confuse people. And it usually works, it usually makes it really confusing.
Ki-67 is a test that is done in the pathology laboratory. It is one of the many stains that the pathologist can put on the tumors. And this stain specifically measures how many of the cancer cells are actively dividing. One cancer cell actively trying to become two cancer cells at the time that sample was made. So it’s a way of measuring how rapidly is that growing.

We talk about adjuvant therapy in women who had stage I, II, or III disease who may have had their primary tumor and lymph nodes involved removed. But there is that possibility that some microscopic cells might have spread elsewhere in the body. And that’s why we often think about therapies that affect the whole body. And women who appear to have been diagnosed with disease localized to the breast or the lymph nodes. It’s that potential that disease has already spread elsewhere. And we call chemotherapy, or hormone therapy, or in this case the cyclin-dependent kinase inhibitors used in that situation adjuvant therapy.

It really kinda shows the bias of surgeons. It was considered an adjuvant or something you added to surgery.

Janine Guglielmino, MA (00:07:58):
Thank you so much for answering that, and we really appreciate those kinds of questions. We know that we’re using a lot of different kinds of terms here.

There’s a number of questions from people who have had early-stage breast cancer but didn’t qualify to get Verzenio for one reason or another. And a lot of these questions are around the number of lymph nodes that they had cancer in. And so there’s some questions about how you figure out how you judge when to offer either one or the other.

Kathy D. Miller, MD (00:08:31):
Yeah, so initially the FDA approval was very limited. And the reason for that is even though we talk about these trials enrolling a group of patients at higher risk of recurrence, when you look at their absolute risk of recurrence, it is quite true that most of those women would be fine and live to be healthy old women and never have a recurrence of their breast cancer if they didn’t receive any systemic therapy. So high is sometimes dependent on what you’re comparing it to.

But that means we need to pay particular attention to the side effects. And some side effects can be potentially life threatening. When the FDA took a look at the very early data, which is always hard because you don’t have as many events, so the results are a bit uncertain, they felt like the balance of benefit and risk was only favorable in patients who were at very high risk, which meant they had tumors involving four or more lymph nodes or tumors bigger than 5 centimeters involving one to three lymph nodes with this high measure of proliferation by Ki-67. We now have the benefit of having additional follow-up for from the abemaciclib trial. And as we have more follow-up and more events, our confidence in those results gets more certain, and we’re able to see that there was really a favorable balance of benefit and risk in women who had any lymph nodes involved. And it no longer needs to be restricted to patients who had this high proliferation measure of Ki-67.

Now in practice, these are individual decisions where we need to think carefully with our patients about: What is the risk of recurrence if we do nothing? How much can I reduce her risk of recurrence with hormone therapy? Does she also need chemotherapy? And once she’s had chemotherapy and hormone therapy, what is her remaining risk of recurrence? What benefit might there be from either abemaciclib or ribociclib? What are their toxicities? And what does that mean to that woman? Because our individual tolerance for side effects and where we think that balance of risk and benefit might tip can be very different from woman to woman, even though the pathology results might look the same.

Janine Guglielmino, MA (00:11:06):
Dr. Miller, I’m going to ask one follow-up question, and I promise everyone, we are going to talk about HER2-positive breast cancer and triple-negative breast cancer as well. But I want to ask this question just based on what you just said.

Someone is asking, how do you judge when you’re talking to someone, when is quality of life more important than taking an aromatase inhibitor? For example, this person’s really struggling with the side effects of hormonal therapy.

Kathy D. Miller, MD (00:11:34):
Well, first, you are not alone in struggling with the side effects of hormone therapy. That is an experience that varies dramatically from woman to woman, with some women finding this really not difficult at all and for others the side effects are really intolerable.

The good news is we have several options for hormone therapy. It is not uncommon, in my practice, for my patients and I to talk about those side effects and decide we may need to stop one agent, switch to a different drug or a different form of anti-estrogen therapy, and see if we can find one that that is a better match, a better tolerated agent for them.

While there are some small differences in the activity of those different hormone therapy agents, the bigger difference is not what hormone therapy you’re on, but your ability to continue hormone therapy for many years. So you would be better off taking a drug that in large randomized trials might have looked a teeny tiny bit less effective because it’s one that you can actually take and keep taking.

There are other non-hormonal things that we can do to minimize hot flashes, to help with joint stiffness, to help with vaginal dryness. But this requires having a treatment team that is willing to listen to your concerns and what side effects bother you and is willing to work with you to see how can we make this tolerable for you.

Janine Guglielmino, MA (00:13:05):
Thank you so much for answering that question, Dr. Miller.

I wanted to move on to a couple of other studies that we heard about in the hormone receptor-positive setting. There were a number of interesting ones. Would you like to talk for a moment about the ovarian function suppression study that was shared?

Kathy D. Miller, MD (00:13:26):
Sure. So, ovarian function suppression you can think of as actually the original systemic therapy for breast cancer, dating all the way back to 1895 when a surgeon first removed the ovaries of a young premenopausal woman who had metastatic breast cancer and saw that her tumor shrank. We didn’t understand the biology behind that. We didn’t understand about the estrogen receptor until in the 1970s and then developed other ways to inhibit estrogen.

And along the way, people started thinking about removing the ovaries or suppressing the function of the ovaries as a bit old school. And that we have moved on from that. As we’ve realized the power of hormone therapy we’ve also realized that many of our premenopausal women will continue to have ovarian function even through chemotherapy or their periods will resume. And that led to a couple of different questions.

Data we had seen over several years looking at adding ovarian function suppression to hormone therapy in premenopausal women who either didn’t need chemotherapy or in most cases received chemotherapy, not already completed chemotherapy. Those were trials known as the SOFT and TEXT trials, and we’ve just recently seen the 12 year follow-up of those studies. There was a significant overall survival advantage, particularly in women who were at higher risk. And that included women diagnosed with breast cancer at 35 or younger, women who had tumors bigger than 2 centimeters, or women who had tumors involving the lymph nodes.

But the other question, and one that I think you will see us revisiting is maybe some of those women don’t need chemotherapy at all. And if their tumors are very hormone sensitive, maybe if we maximize or optimize their hormone therapy with ovarian function suppression that may reduce their risk to such a degree that chemotherapy no longer makes sense and no longer provides benefit.

There’ve been some small studies comparing ovarian function suppression and hormone therapy to chemotherapy, really suggesting that chemo may not have a lot to add. Now, there will be a national study looking at that, specifically using some of the molecular profiling tests to really identify women who we think their tumors are very hormone sensitive and where chemotherapy just may not be needed.

Janine Guglielmino, MA (00:16:06):
Thank you so much for discussing that. And I’m wondering if there were studies that you heard about in the metastatic setting for people with hormone receptor-positive disease that you might want to share this evening with our listeners.

Kathy D. Miller, MD (00:16:23):
Lots of studies in the metastatic setting looking at some other ways of taking advantage of blocking estrogen or other things that we can add to blocking estrogen.

Probably the most exciting is a study known as the CAPItello study, I think is what the study was called. The drug is called capivasertib, depending on which syllable you want to emphasize. That is a drug that inhibits a pathway called the AKT pathway. You can think of that as one of the escape pathways that if you block estrogen then signaling through that AKT pathway may allow the [cancer] cells to survive. So blocking both could be more effective. And we’ve now seen the results of a phase III study looking really exciting that this combination gives us another option for patients with metastatic disease to really amplify and extend the benefits of hormone therapy.

That drug is not approved yet, but this large phase III study we all expect will be headed to the FDA for approval soon.

Janine Guglielmino, MA (00:17:33):
Excellent. Thank you.

I know there was there was a study that was looking at the timing of giving CDK 4/6 inhibitors, and there was this study showing that people could take it as their second treatment rather than their first and start with anti-estrogen therapy alone. And I’m just really curious about your input on that study.

Kathy D. Miller, MD (00:18:03):
I think it’s a difficult question. What we ultimately would like to do for all of our patients is help them to live as well as possible for as long as possible. And that always means maximizing control of the breast cancer as effectively and as long as we can but also minimizing the side effects, the toxicity, the inconvenience, and the cost and all of the bad things that come with our treatments.

Now, most new drugs are often tested first in people who’ve had other therapies, and that was true of the CDK 4/6 inhibitors. The first studies looked at adding them to second line hormone therapy, they then moved into the first line hormone therapy setting. But that gave a very practical question, do you get more benefit for more women if you use them first or if you use them second or does the order really matter?
So there was a trial looking at randomizing women to either hormone therapy alone — and then at progression, a different hormone therapy with a CDKi — or hormone therapy with a CDKi and at progression a different hormone therapy, in most cases by itself.

They looked at the period of time that both treatment 1 and treatment 2 together kept the disease under control. And it did not look like there was a big difference between those. But the period of time that when women were on a cyclin-dependent kinase inhibitor was shorter in the women who got the cyclin-dependent kinase inhibitor second, which meant the overall toxicity burden might have been less, and certainly the overall cost was less.

I think what we really need is a way to know which women benefit for from this very powerful drug that has some side effects and that cost a ridiculous amount of money, because that would really be the way to know how to best take advantage of it.

I think probably in the U.S. the study is not going to change practice very much, but it has big implications for regions of the world where healthcare spending is more limited and where it would be really hard to justify the increased cost to a health system for using these drugs upfront.

Janine Guglielmino, MA (00:20:32):
Thank you so much for answering that question.

I think we’re going to move into another area now and answer some other questions. Why don’t we turn to talking a little bit about triple-negative breast cancer and what we learned at ASCO there.

There was an interesting study that we reported on of a new potential agent for metastatic triple-negative breast cancer. And I honestly, I’m not sure I can pronounce it. So I’m wondering if you can share a little bit about that study and, and your thoughts about it and the name of the medication as well.

Kathy D. Miller, MD (00:21:11):
Oh, I’m going to have to look up the name of the medication.

Janine Guglielmino, MA (00:21:16):
I think it’s toripalimab.

Kathy D. Miller, MD (00:21:18):
Toripalimab, yes. It’s a new drug, but it’s not a new idea. So toripalimab, it is another antibody that is in the class of drugs called immunotherapies or immune checkpoint inhibitors. If you have metastatic breast cancer, it is not because your immune system is faulty, but the immune system has to be tightly controlled. And in particular, your body has to have a way of telling the immune system, these are healthy cells, leave them alone, don’t destroy them. And they do that with a lock-and-key system.

The healthy cells have a key that goes in a lock in the immune cells, and whenever the lock enters the key, those immune cells just sit there. They don’t attack. And many aggressive cancers, including about 40% or so of metastatic triple-negative breast cancers have hijacked that normal control — they express that same key. So if those immune cells are able to recognize the tumor, they don’t do anything to help chemotherapy be more effective or to help control it.

There was already a drug called pembrolizumab that blocks the lock-and-key. There are other drugs approved for other types of cancer — nivolumab, atezolizumab — that are commonly used for other types of cancer. They all work in roughly the same way. They’re antibodies that either recognize the key or that recognize the lock. Either way you stop them from getting together. So cells that recognize that cancer are able to help with that response.

This was a study of a new monoclonal antibody still in that same mechanism. First one to be approved in China, produced commercially and developed in in China, results that looked very similar to results that we’ve seen with pembrolizumab in breast cancer. We don’t have any studies directly comparing one of those immunotherapy approaches to the other. And looking across trials always gets a little bit sketchy. But certainly another trial suggesting that for at least someone with triple-negative disease, this is a really powerful component of their therapy.

Janine Guglielmino, MA (00:23:40):
Thank you. And we have a couple of questions from individuals who are asking about whether there was anything new focusing on HER2-low targeting for people with triple-negative breast cancer or other types of breast cancer.

Kathy D. Miller, MD (00:23:59):
Lots of discussion about HER2-low. Just so I don’t break into lingo again, HER2 is often tested with a pathology test called immunohistochemistry. It’s essentially a stain that turn cells that have that HER2 receptor brown and the pathologist grade that staining from 0, that we would call negative, to 3+, that we would call positive. And then 1+ and 2+ we either lumped together as calling them negative or we would do additional testing with a different sort of HER2 tests to determine if they should be considered positive or negative. And people have started calling that group that are 1+ and 2+ by that immunohistochemistry test, but negative by other HER2 tests, HER2-low.

Now we have a lot of biologic arguments as to whether that’s really a distinct subset or is this a categorization that’s kind of an artifact of how we do the testing. But we care about it because there is a drug called fam-trastuzumab deruxtecan [Enhertu], which is an antibody that recognizes HER2 attached to a chemotherapy. The goal of this drug is not in these tumors to shut down the function of that growth factor, it simply uses that growth factor as a mailbox and the antibody as an address label to deliver chemotherapy much more to the tumor cells than to the healthy cells of the body. And that’s now approved in this HER2-low category because it was much more effective than other naked chemotherapy options that were available.

So there are several other drugs in that same class, called antibody-drug conjugates. The antibody is what provides the specificity or the targeting, and then you can attach different chemotherapies onto those antibodies. And there are a couple of other early studies, so single-arm phase II studies, but in heavily pretreated patients with both HER2-positive disease and HER2-low disease, all of which had significant activity. And that always gets us very excited when we can see significant response rates in women who’ve had three, four, five, six previous therapies. That tells us this is likely to be a really active agent.

Those drugs are all moving forward into randomized trials very rapidly. So I think this is going to be a very exciting time for us in our ability to provide more options for those patients. Also really motivating for researchers to find other self-service proteins that you could target as a way of delivering drugs to the tumors.

Janine Guglielmino, MA (00:26:56):
Thank you. That’s very helpful.

Were there other studies that you saw at ASCO in the area of triple-negative breast cancer that you would want to share with our community?

Kathy D. Miller, MD (00:27:08):
So I think we are trying to learn more and more about triple-negative breast cancer and beginning to think about whether in some patients, particularly with early-stage disease, the immune system has had such an effect at recognizing their tumor that they might not need chemotherapy at all, or they might need less chemotherapy.

The very simple way that pathologists assess this is to look for something called tumor-infiltrating lymphocytes, simply to see when they look at your cancer on a microscope, how many of those lymphocytes, type of white blood cells, do they see at the edge of the tumor and integrated in the tumor. And the more of those white blood cells they see, the better the prognosis of those patients.

We are now starting to study whether some of those patients particularly, with stage I or early stage II disease, there might not be chemotherapy at all because their prognosis is so much better than we thought when you lumped everybody together or might need a much more abbreviated, shorter, less toxic form of chemotherapy. So I think that’s going to be where the field in triple-negative is headed.

Janine Guglielmino, MA (00:28:27):
Thank you. I have one more question before I promise that we will turn to HER2-positive breast cancer.

One of our participants is asking about PARP inhibitors that were prescribed to her because she has a BRCA mutation and she had early-stage breast cancer. Can you just explain when a PARP inhibitor is used in early-stage breast cancer and what it’s for?

Kathy D. Miller, MD (00:28:58):
Sure. PARP is an enzyme that’s important in the cell’s ability to repair DNA. So all of our cells are having damage to the DNA by living in the world. And that’s very important because if damage in your DNA doesn’t get fixed and gets perpetuated, that can lead to all sorts of problems including leading to cancer.

Now, the BRCA1 and BRCA2 gene mutations that increase the risk of cancer, those genes are important in the cell’s ability to repair DNA damage. And because repairing damage is so important to the cells, there’s a lot of redundancy. Different types of damage gets repaired in different ways, but there’s a lot of redundancy there so that you’re not dependent on one single repair pathway.

You can think of this as if you work in a large office, if somebody is sick, someone else can take over their function. But they’re probably not quite as efficient about it. They’re a little slower and they might make more mistakes. And that’s what happens when one repair pathway has to take over the function of the other.

But if you have someone out sick in your office and then you get a big rush of work coming in, it all starts to fall apart. And that’s sort of what happens with BRCA and PARP. They’re two partner pathways. If you’ve lost the function of one because you’ve inherited a mutation, you are now really dependent on the PARP pathway. So the PARP inhibitors are drugs that inhibit that pathway, and they’ve been particularly effective in women with a BRCA1 or BRCA2 mutation.

They were first studied and first approved in the metastatic setting, and we’ve now seen data looking at them in the adjuvant setting, also in women who had higher risk of recurrence. Now that was for women with triple-negative disease who either had stage II disease or higher, who had surgery first, or if they had chemotherapy before surgery, they still had residual disease. Because women who had chemotherapy before surgery who had complete disappearance of the tumor, what we would call a pathologic complete response rate, have a very good prognosis, they were not included in that trial. For women who had hormone sensitive disease, they needed to have involvement of at least four lymph nodes to be eligible for that trial.

And just like we talked about with the cyclin-dependent kinase inhibitors, that was because these are drugs that have side effects. It would be difficult to recommend those drugs to women who had very small tumors and a very low risk of recurrence even without them.

Janine Guglielmino, MA (00:31:50):
Wonderful. Thank you.

I’m going to move into talking about some of the studies that were presented for people with HER2-positive breast cancer. Before we jump into specific trials, there is a question about whether people who have both hormone receptor-positive and HER2-positive disease, whether there were studies presented that talked about their specific situation of having triple-positive breast cancer.

Kathy D. Miller, MD (00:32:22):
I’m sure there were, but I can’t think of any specific ones. There are a couple of studies in that population that, that I have not seen results for yet, but that I think are going to be particularly important. And a big question as to whether the cyclin-dependent kinase inhibitors might also be helpful in those women.

In the clinic, we often argue about should those women, particularly in the metastatic setting, be immediately treated with HER2-targeted therapy, but do they really need chemotherapy? Or could many of those women be treated first with HER2-targeted therapy and hormone therapy and only think about chemotherapy at time of progression? And that’s definitely a setting where the cyclin-dependent kinase inhibitors may be helpful in extending that period of time. So that’s being studied in one ongoing study.

It’s also fairly common in the community for those women to initially be treated with chemotherapy and HER2-targeted therapy. And then once their disease is under control, the chemotherapy is often discontinued and the HER2-targeted therapy then continues often with hormone therapy added at that point. And that’s another setting where the cyclin-dependent kinase inhibitors might be helpful. That’s also being addressed in an ongoing study, but I haven’t seen results of either of those efforts yet.

Janine Guglielmino, MA (00:33:50):
Thank you.

Of the studies that you saw focusing on HER2-positive breast cancer, which ones were the most interesting to you that you would want to share with our audience today?

Kathy D. Miller, MD (00:34:02):
So by far, my favorite is called the PHERGain Study. We have known for a few years that some women with HER2-positive disease are so sensitive to HER2 itself that if they’re treated with just HER2-targeted therapy, no chemotherapy of any sort before surgery at time of initial diagnosis, some of those women will have complete disappearance of their tumor. Now with two HER2-targeted antibodies in a tumor that was HER2-positive but estrogen negative, it was about 25%. And four women whose tumors were triple positive it was about 12% to 15%.

But there were a couple of questions. One is, What was their long-term outcome if they didn’t get chemotherapy at all? It was fantastic that you completely eliminated the tumor in the breast, but could we be certain that you completely eliminated any microscopic disease? And if we thought we were doing good by eliminating the side effects of chemotherapy upfront, might we actually be doing harm by exposing those women to a higher risk of recurrence?

And the other question was, how can we figure out who those women are so that we don’t have to give them chemotherapy? So those were the goals of the PHERGain study. It enrolled women with largely stage II and III HER2-positive disease. They were treated with two cycles of two HER2-targeted therapies, so trastuzumab and pertuzumab, the two antibodies, no chemotherapy, hormone therapy as well if the tumor was estrogen positive.

After those two cycles of therapy they had a PET scan to look at the metabolism of those tumors. And if there had been a significant decrease in the metabolism, they then continued just the HER2-targeted therapy for a total of six cycles. And then they went to surgery

If they did not have complete disappearance or a significant response by the PET scan after those two cycles, then chemotherapy was added and they got a standard course of six cycles of chemotherapy and HER2-targeted treatment and then went to surgery.

And they had several questions. One is how many of the women who had this PET response after two cycles had a pathologic complete response, complete disappearance of the tumor at surgery, with just a HER2-targeted therapy? And it was roughly a third of patients, about 35%. Not bad. More than if you lumped everybody together.

If women at surgery still had residual disease even though they had not gotten chemotherapy before surgery, they got chemotherapy then after surgery. It’s essentially a way, to say this nicely, making women prove they really need chemotherapy and not giving them chemo until you had some proof that they needed it, either because their tumor wasn’t responding by PET scan or it didn’t completely respond and there was still disease at surgery.

The important thing is they now looked at the three-year follow-up of those patients. So they were able to compare the outcome of women who did not appear to respond who got chemotherapy added early.

Those women had a slightly higher risk of recurrence. Among the women who appeared to respond, about a third of whom did not get chemotherapy at all, about two thirds got chemotherapy after surgery, their three-year recurrence survival was very low and it did not look any different in the patients who did not get chemotherapy at all.

I think that really gives us the ability to individualize treatment for patients in this sort of stepwise fashion. Starting with biologic therapy, if that appears to be working, sticking with that, rather than giving everyone chemotherapy up upfront. So for me, that was the most exciting study because that gives us a way to even more individualized treatment.

Janine Guglielmino, MA (00:38:38):
Thank you for sharing that. That could be really exciting.

Were there other studies in perhaps in the metastatic setting that caught your eye and that you might want to share?

Kathy D. Miller, MD (00:38:51):
Other studies in the metastatic setting, looking at other antibody-drug conjugates, I think that’s really where the field of HER2-targeted therapy is headed. There are several that where the antibody targets HER2 but they have attached a different chemotherapy — and in a second, the name of the one that’s farthest along will come to me — Dato-DXd. Similar to the fam-trastuzumab but a different chemotherapy with a very different mechanism of action attached to it. That drug also has significant activity, was very well tolerated moving into phase III trials that we hope will lead to its approval. Those have already started.

You will also now see us struggling with how to best use those antibody-drug conjugates and trying to understand when tumors become resistant to an antibody-drug conjugate do we need to change the antibody? Has the target changed? And you’re no longer delivering chemo. Or did the cells become resistant to the chemo? You need to change what’s being delivered. And there are now some studies just getting started looking at those sequencing questions.

Janine Guglielmino, MA (00:40:11):
Thank you. That’s really interesting and a really important question.

We have an interesting question from someone who’s asking about whether there were any studies that were presented about the potential in HER2-positive metastatic breast cancer of stopping treatment at any point.

Kathy D. Miller, MD (00:40:34):
So I didn’t see studies presented at that, looking at that, but it’s a question that we’ve been talking about and struggling with for some time. And I have several patients in my practice who have stopped their HER2-therapy in the metastatic setting. In one of our collaborative research groups we are about to start a trial that will be known as the STOP-HER trial that is asking exactly that question.

After a lot of discussion, we didn’t think that randomizing women with metastatic disease, who had had disease under control for several years and were doing well, to continuing HER2-therapy or stopping was going to be feasible. There are just too many opinions and fears and individual thoughts that impact those decisions. So this trial will not randomized, but it will enroll women who have had disease under control with HER2-targeted therapy alone, so without chemotherapy, for at least a couple of years. And those women and their doctors will decide to either continue or stop, and they will be followed over time to see does there appear to be any difference in the rate of recurrence, of problems that with those women’s disease over time.

I can tell you in the patients of mine who’ve stopped, they’ve usually stopped after us talking about it for several years and wondering, Do you still need this? What are we still treating? Is this worthwhile?

This will at least give us some data to help inform those discussions.

Janine Guglielmino, MA (00:42:25):
Thank you. There’s a similar question here about hormone receptor-positive metastatic breast cancer and whether that has been studied or is under study.

Kathy D. Miller, MD (00:42:40):
It’s a good question, and I have to say I don’t think that has been studied in the metastatic setting with hormone therapy. And I’m not aware of groups talking about studying discontinuing therapy entirely in women with metastatic hormone receptor-positive disease who’ve been stable for a very long time. That is perhaps a failing and shows the bias on our part as a medical community. As I think about my own practice, I certainly have patients who have been stable on the first hormone I gave them for their metastatic disease for more than a decade, and they’re still taking it. And she and I haven’t really talked about should we stop, what are we still do treating, do you still need this.

I think we are sometimes guilty of assuming that hormone therapy is easy and well tolerated and doesn’t have side effects and that we don’t need to think as carefully about those things as we do with IV therapies. But you have made me think about that differently.

Janine Guglielmino, MA (00:43:51):
I thank the person for her question.

Someone was just asking about the name of the trial that you mentioned in the HER2-positive setting about stopping treatment.

Kathy D. Miller, MD (00:44:03):
It’s going to be called the STOP-HER Trial. And it’ll be coordinated by the Translational Breast Cancer Research Consortium.

Janine Guglielmino, MA (00:44:10):
Great. Thank you.

We have a number of questions from folks who were asking whether there were any studies specific to lobular breast cancer that were presented at ASCO. Or in general, whether there’s newer research on lobular breast cancer.

Kathy D. Miller, MD (00:44:29):
Lobular breast cancer is a challenge in many ways. It accounts for only about 10% to 15% of breast cancers. We know that it has different growth patterns in the breast and a different pattern of metastasis. It’s much more likely to be hormone sensitive, much less likely to have HER2 than typical ductal cancers. Unlikely to have high-risk scores that would support the use of chemotherapy in an early-stage setting. And despite knowing those differences, lobular cancers are typically lumped in with ductal cancers and we study them all together. And what that has meant is that because the lobular cancers are only 10% to 15% of the whole group, our ability to then look separately at women with lobular cancers is very limited.

There’s been a lot of discussion and a lot of basic science trying to understand at a molecular and protein level what’s different with lobular cancers and whether that could point us to different treatments. There’s been discussion about trying to launch trials separately in women with lobular disease. But I don’t recall seeing any of those efforts that at this point are still fairly small actually having results yet.

Janine Guglielmino, MA (00:46:04):
Thank you for that update.

I have another question from someone with metastatic HER2 breast cancer, asking about any studies that may have looked at medications that penetrate the blood-brain barrier.

Kathy D. Miller, MD (00:46:22):
Absolutely. We know that many of our medicines actually penetrate the blood-brain barrier, get into the brain more than we initially thought they did. One thing we’ve learned is that the blood-brain barrier in areas of cancer is not as much of a barrier as we initially thought.

We’ve seen data with drugs like tucatinib [Tukysa], one of the oral HER2-inhibitors, where they were actually able in some small early studies to measure the amount of the drug in disease in the brain. And with tucatinib, we know that it gets into the brain just as well as it gets to the rest of the body.

Even really large drugs like the antibody-drug conjugates clearly get into the brain because we’ve seen patients with brain metastasis enter those early trials and have their brain metastasis shrink.

And we’ve seen fewer new brain metastasis in some of those earlier studies than what you might have predicted. I think there will be even more looking at patients with CNS [central nervous system] or brain involvement earlier. Now that we’ve learned that medications really can treat brain metastasis and that the need for surgery or radiation is not always an immediate need. Those are very powerful ways of controlling CNS disease. But many of our medicines can be helpful as well. And that’s something we would not have said 10 years ago. We would’ve said, “We have no role here.”

I think you will also see more trials not excluding patients who have brain metastasis, which was also very common a decade ago. But if you had ever had brain metastasis, you were excluded from any clinical trials. I think that will become very uncommon.

Janine Guglielmino, MA (00:48:21):
Well, that is very, very welcome news. So thank you for sharing that.

Before I jump into some more audience questions we’ve talked about some of the trials that you found most interesting in all the subtypes. Is there any trial we haven’t talked about that you would really like to discuss with, with our community?

Kathy D. Miller, MD (00:48:41):
Yeah. A new imaging agent that I think is going to be really helpful for women with ER-positive disease. You can think of this as called FES-PET, or if you want to be technical fluoroestradiol PET, essentially a way of labeling estrogen as a way of with imaging, seeing not only is the tumor estrogen positive, but is that estrogen receptor functioning? Is it actually binding estrogen?

We had seen some studies over the years in including a recent one that was much larger looking at the FES-PET imaging and patients whose tumors were positive by the FES-PET imaging were much more likely to benefit from hormone therapy, and the benefit of hormone therapy lasted for a much longer time. So this is another excellent new tool that we have to individualize treatment for our patients, and to really help us think in a little different way about which patients with hormone sensitive disease, particularly in the metastatic setting, is where this would be used, are best treated with hormone therapy. And might there be women who might be better treated with chemotherapy, either upfront or chemotherapy earlier.

The FES-PET tracer has just recently been approved. There’s a commercial supplier for it. So that is now something that is available. There are a couple of important things that people need to know about. The liver itself has a lot of the estrogen receptor, so this is not helpful for imaging disease in the liver. It’s also not helpful if you’ve been taking a drug like fulvestrant that works by decreasing the production or degrading the estrogen receptor. But particularly for women newly diagnosed with metastatic ER-positive disease or who had been on something like tamoxifen or an aromatase inhibitor this could be an additional helpful piece of information in thinking about their next treatment decisions.

Janine Guglielmino, MA (00:51:04):
Thank you for sharing that. There were a couple of questions about that test, so I appreciate that.

We have a number of other questions and I will jump into some of these. One person is asking whether there were any updates this year about the length of time to give anti-estrogen therapy.

Kathy D. Miller, MD (00:51:29):
I don’t recall seeing any updates on that. We, in the adjuvant setting, have looked at many different durations. Some looking at durations with the same drug, some looking at duration but switching from one drug to another at some point along the way. To summarize lots of data, longer is better, but it’s not better by a lot. It’s better by a little bit. Those studies have been very consistent going longer than five years, so to 10 years is about a 3% difference.

Now, it’s a 1% difference in recurrence elsewhere in the body, about a 2% difference in new breast cancers in remaining breast tissue. So that’s particularly important for women who needed or elected bilateral mastectomies. They have less to gain from longer duration of hormone therapy because a portion of the benefit is preventing new primaries.

There was data about a year ago from a study that looked at seven or eight years instead of 10. It also was better than five, and it was better than five by about the same amount as 10. So that has suggested to many of us that maybe 10 isn’t needed, maybe you’ve gotten all the benefit, almost all the benefit, at seven to eight. This is definitely a situation where we need to better able to risk stratify women and better identify who still has significant risk, who should continue longer and has a lot to gain, who has very little to gain.

So there are a couple of national studies that that will be starting very soon. Some smaller studies that have already started looking at that four-, five-, six-year mark as a second decision point with very similar discussions that we had when you were first diagnosed. What’s your risk? What are the options that, that we might have to reduce your risk? And where does that balance of benefit and risk tip for you?

Janine Guglielmino, MA (00:53:45):
If someone’s looking to have that conversation with their doctor and they’re not getting the information that they need, how would you suggest they bring it up? What question they ask to get the information that they need?

Kathy D. Miller, MD (00:53:59):
Yeah. Subtlety is not my strength. I would ask direct questions. This may be a time to ask about a referral for a second opinion at a larger referral center, at a university hospital, at a more dedicated breast center. These are complicated decisions, and these are often not quick discussions. In a busy practice with somebody who is going from room to room and they have to quickly turn off the lung cancer part of their brain and turn on the colon cancer part and then switch to the breast cancer part, and then the kidney cancer part. I think that’s a very difficult situation to give people the time that they need. And I think those are good uses of the academic resources and second opinions.

I would also hope that your treatment team is able to hear that you need more information. You need information and a discussion to really be their partner in making a decision. It may be that if you tried to have that conversation once, you just got them on a bad day, and they’re quite willing to have that conversation. I have certainly had to sit with patients of mine in a subsequent visit and say in your last visit, you just didn’t get me at my best. It had been a bad day, I was exhausted and frustrated and I did not have what you needed that day. And I’ve appreciated them being willing to give me another chance.

Janine Guglielmino, MA (00:55:44):
Thanks for sharing that experience, Dr. Miller.

We have a couple questions about oral SERDs. If you could explain what they are, were there any studies about new oral SERDs or about combating resistance by the ESR1 mutation?

Kathy D. Miller, MD (00:56:10):
So first the SERD stands for selective estrogen receptor down regulator. The classic SERD is fulvestrant [Faslodex] which works by degrading the estrogen receptor. So if the receptor’s not there that then estrogen can’t bind to it, and it can’t stimulate growth.

The challenge with fulvestrant is that it’s essentially a rock. We couldn’t get it into solution to get it into a pill that could be absorbed into the body. So it had to be given as a deep injection. And I know many of you have had it, it’s a deep, big injection that while not awful is not pleasant. And that has in some ways limited using the drug and has certainly limited thinking about using it in the early-stage setting.

So the oral SERDs are exactly that. We’ve found other drugs that work by the same way as fulvestrant, but they don’t have the same problems. We can get them in pill form, they’re absorbed, and they get into the body to have their activity. Now, there are several of them. Virtually all of the drug companies that work in the oncology space have an oral SERD in some form of development. There is at this point, one called elacestrant [Orserdu] that has been recently approved. There are others, several others in phase III trials. One called amcenestrant that we learned in a phase III trial wasn’t better than other available therapies. So I don’t think that one is going to continue in clinical trials. But there are others that look much more positive.

I think this will do several things. It will give us an option in pill form rather than fulvestrant for many patients who are just starting hormone therapy. Some of these drugs have had activity in women who had been on fulvestrant and their disease was progressing. So that may give those women another option to extend the benefits of hormone therapy. And this is also much more feasible to think about moving into the early-stage setting where there may be even greater benefits.

Janine Guglielmino, MA (00:58:34):
Thank you.

I have a couple of questions about NATALEE, the clinical trial that we were discussing at the top of the program.

One person is asking whether, in the study the way the characteristics of people who received the treatment, whether all of those characteristics need to be present in the cancer to recommend the treatment or just certain pieces. So if they had no cancer in the lymph nodes, but the cancer was grade II and had other traits do they need to have all those traits in order to have an effect?

Kathy D. Miller, MD (00:59:22):
Hmm. I’m afraid I don’t trust my memory on that level of detail. The majority of patients in NATALEE had tumors that were lymph node positive. But I honestly, at the moment, don’t remember if there was a small group that were lymph node negative.

Janine Guglielmino, MA (00:59:43):
Thank you. I’m not even sure. I apologize to the person if I didn’t get your question right.

Kathy D. Miller, MD (00:59:49):
No, I understand the question. I just, I don’t remember that level of detail with confidence, so I don’t want to misdirect them.

Janine Guglielmino, MA (00:59:59):
Sure. And I would assume that that study will be published in a peer reviewed journal at some time as well, and we may get more data.

Kathy D. Miller, MD (01:00:07):
Yes. So it will be published and those features, I’m sure, this study is headed to the FDA. So those features will also figure into the FDA label and their thoughts about the appropriate initial indication.

Janine Guglielmino, MA (01:00:23):
Thank you. There are many questions about the STOP-HER clinical trial and how to get involved in it and where people can learn more.

Where is the best place for people to learn about clinical trials that may be opening?

Kathy D. Miller, MD (01:00:46):
There are several clinical trial websites with various degrees of clunkiness and user unfriendliness. The one that is probably the most used by researchers is clinicaltrials.gov. The STOP-HER trial will be open at probably about six places around the country. It’s going to be led by Dr. Heather Parsons at Dana-Farber [Cancer Institute]. And it has just, I’m not sure it’s even opened at Dana-Farber yet, but it’s about to. It’s going to be open at IU [Indiana University]. We’ve just gotten the materials in the last month to start the local regulatory approval process. So it’s not open at IU yet, but it should be within the next couple of months. But it will be available at about six or so places around the country.

Janine Guglielmino, MA (01:01:42):
Thank you. And another place folks can look is at Metastatic Trial Search, which is based off of the clinicaltrials.gov. So that might be a place that you could learn, print something out, and bring it in to speak with your physician.

My next question is about whether having lower dosages of medications mean you will have fewer side effects and whether there were studies about this presented at ASCO?

Kathy D. Miller, MD (01:02:19):
Yeah, it’s a really good question, and it’s something the FDA has spoken about recently. When drugs are first developed, first move into the clinic, they often go through something called phase I studies, where the doses are gradually increased until we run into toxicity that is really not safe or [is] prohibitive. And then we often use a dose that’s just a smidgen below the dose that wasn’t tolerable. And particularly for some drugs that work by inhibiting a receptor, inhibiting a protein, that may be way more than you need. So the FDA is going to be requiring companies to look more at the optimal dose rather than the maximum dose.

Now, whether reducing the dose of a drug means you’ll have fewer side effects, or that you’ll have less benefit, really depends on the drug. For some drugs it may not make much difference. For some drugs, it really may be crucial. There are very few drugs that we would start therapy at something lower than the typical dose, but all of those clinical trials, even though they had a starting dose had allowances for people to reduce the dose because they had individual toxicities that required adjustments. And many of those clinical trials then have looked at the effectiveness of the drug in people who needed a dose reduction compared to those who were able to stay on the full initial dose. And when those analyses have been done, they have typically shown that the dose reduction did not impact the efficacy.

I explain this to my patients very simply. The starting dose is the dose for the average patient. You might not be average. We will learn that together. And if you need a dose reduction, then you need a dose reduction. And we need to take care of you, not the average woman who’s not in the room.

Janine Guglielmino, MA (01:04:37):
Well, I think you have a lot of fans out here, Dr. Miller, who are wishing that, that their physician would speak to them similarly about some of these issues. I can see from some of the comments that we are getting. So thank you.

Kathy D. Miller, MD (01:04:49):
So I know several of my own patients are on the line. I’m trusting you all to remain silent now.

Janine Guglielmino, MA (01:04:55):
<Laugh>. Unfortunately, we’re very close to the end of our program, and I’d like to just give you an opportunity to say some closing remarks and potentially share the things that you feel are most likely to be discussed with people who are on the call by their physicians.

Kathy D. Miller, MD (01:05:16):
So I think it’s tough for me to know what will be most likely discussed because the advances are so different depending on the type of disease and the setting. I think many more patients with higher risk ER-positive disease will hear about adjuvant, cyclin-dependent kinase inhibitors. Abemaciclib for many women is pretty difficult with significant GI side effects, much less GI side effects with ribociclib. So I think that will be an option that many physicians and many patients will welcome as an alternative.

I think we will also begin to hear more about individualizing therapy for patients, particularly with HER2-positive disease. And I think where we are headed in the field, is two parallel paths. For many of our women with ER-positive disease and triple-negative disease and HER2-positive disease, they have an excellent outcome with our current best therapies. And the question for those women is not what more can we do, but what don’t we need to do? What can we eliminate and still maintain that excellent outcome?

There’s a smaller but really important group of women whose disease is more aggressive, is resistant to our best therapies who don’t fare as well. And those women need very different research questions. We need to know what’s different about their tumors, what new therapies are on the horizon that can help them.

And for the women with metastatic disease I think it is constantly important for them to know that we know you’re there and that we are so sorry our best therapies of the day failed you and that you are in this situation. And we are committed to continuing to work to improve the quality and the quantity of your life. And that many women with metastatic disease have very different trajectories. And we need to understand that so that we can individualize their treatments as well.

Janine Guglielmino, MA (01:07:37):
Thank you so much Dr. Miller. Thank you for sharing your time and your expertise with us this evening.

Kathy D. Miller, MD (01:07:43):
Really, it was my pleasure.

Janine Guglielmino, MA (01:07:45):
And I’d also like to thank all of you for your questions. I really am so sorry we could not get to all of your questions. And as always, I’m just inspired by how many questions are asked and how much information that you have.

If we weren’t able to answer your question, I encourage you to go to LBBC.ORG and explore, and I hope that you’ll find a number of the answers to your questions there.

Before we wrap up, I just want to quickly again thank our sponsors for this program, for their support, our signature sponsors, AstraZeneca, Novartis, and our benefactor Merck. And I want to remind all of you to please fill out your evaluation after the program. Let us know how we did and what we can do better in next time. We will be posting a video of this presentation on LBBC.ORG, as well as a transcript. And that will be happening within the next few weeks. Please keep following us on our social channels so that you’ll be up to date on when we post that. And we’re here every day to help you with your emotional, practical and medical challenges of living with breast cancer. So thank you all for being with us tonight and for learning. And I hope you have a peaceful evening.