Recently approved therapies and promising approaches for the future with Nancy U. Lin, MD

Living Beyond Breast Cancer’s 17th annual Conference on Metastatic Breast Cancer was held April 28-30, 2023 as a hybrid conference in Philadelphia, PA in-person and virtually via our online conference platform. In this session, Nancy U. Lin, MD Hear discusses drugs that have been approved for metastatic breast cancer over the last 2 years and how they impact each subtype of breast cancer.

Watch the video or read the transcript below to learn how these latest approvals compare with previous standard-of-care therapies, what we know, and what we don’t, and hear about the exciting drugs and approaches in the pipeline for the next 3 to 5 years.

Transcript

Nancy U. Lin, MD (00:00:01):
Today the topic of my talk will be metastatic breast cancer, recently approved therapies, and promising approaches for the future. I’m going to try to pitch this at a number of different levels because many of you are relatively newly diagnosed and then there are patients who are very far out from their metastatic diagnosis. So hopefully there’ll be a little bit of something for everyone.

I wanted to start by just giving a background of breast cancer subtypes, because at the end of the day, this is how we think about breast cancer as oncologists, and how we think about what the right treatments would be to pair with specific patients.

In terms of breast cancer subtypes, we can classify breast cancer by looking at the appearance under the microscope. So we can divide cancers into ductile cancers — and on the top [image] is what a typical ductile breast cancer looks like — or lobular breast cancers. And lobular breast cancers tend to have these more kind of dotted appearance as opposed to mass-like appearance. And then there are a number of rarer tumor types like metaplastic and other types.

Then the other thing that we do is we look at the receptors. And the three most important receptors that we look at are estrogen receptor, which is ER, progesterone receptor, which is PR, and HER2. And you can see from the grid, we’re looking for these brown-stained cells, and that tells us that the cancer cell makes one of those receptors. Depending on the combination of stains, we’re able to tell you whether your cancer is estrogen receptor-positive and HER2-negative, whether it’s HER2-positive, or whether it’s so-called triple negative, meaning it’s negative for these three markers, estrogen, progesterone, and HER2.

In addition to this kind of standard pathology testing, there are other tests that can be helpful and the number of tests that can be helpful has been expanding. So I wanted to spend a minute discussing this. The first is what we call germline genetic testing. This is what we think of as kind of traditional genetic testing, looking for genes that are passed on from your parents and that you potentially could pass on to your children. This is generally done with either a blood sample or a cheek swab. And again, looking for changes that are inherited.

There’s also a type of genetic testing, which is called somatic or tumor testing, which is really looking at the changes in the genes that have happened in the cancer. So these are not changes that you can pass on to your children. And this can be done either from blood in what’s called a liquid biopsy or a blood biopsy, or it can be done from the tissue sample. From this we can get a lot of information, and this includes something called a tumor mutation burden, how mutated the cancer is; the estrogen receptor status, whether it’s mutated or not; a gene called PIK3CA, which we’ll talk about later on; HER2 mutations; and a whole range of other mutations, some of which can also make people eligible for specific clinical trials.

Finally, there’s another set of tests that we now run. We run something called PD-L1, and that we run that on patients who have triple-negative breast cancer for the purpose of identifying patients who could benefit from immunotherapy. And then for HER2, as we’ll talk about, we now have this new category, which is called HER2-low.

I wanted to just show the drugs that have been approved by the FDA [Food and Drug Administration] over the 20 year period of time from 1995 to 2015. And I chose these years because 1995 is the year that I started medical school. So the year before I started medical school, none of these drugs would’ve been available for patients outside of clinical trials. And if we look at this list, I mean, it’s really astounding, like thinking about how we would take care of patients with metastatic breast cancer, without hormonal therapy, without Herceptin [trastuzumab], without many of our common chemotherapies that we give without the targeted therapies that we give. And all of this had happened over that period of time.

Then between 2015 and now, here are the additional drug approvals that we’ve seen. They include elacestrant [Orserdu], which we’ll talk about in a minute, for patients with estrogen-positive breast cancer, pembrolizumab for patients who have triple-negative breast cancer, a number of new HER2 therapies, the whole class of antibody-drug conjugates, and then a number of new targeted therapies. And again, we’ll discuss each of these in turn.

What I’m hopeful about is that the pace of the approvals has accelerated in recent years, and I think that will continue to accelerate as we understand more about breast cancer.

So first I’m going to talk about estrogen receptor-positive, HER2-negative breast cancer, and just talk through how we currently think about treatment today, and then I’ll throw in along the way some of the exciting aspects. Then we’ll do this for each of the tumor subtypes in turn.

For patients who have estrogen-positive breast cancer, the first thing we typically will prescribe is some sort of hormonal therapy, whether it’s Faslodex [fulvestrant] injections or some sort of aromatase inhibitor pill, along with a CDK 4/6 inhibitor. There are three of them on the market. They’re palbociclib [Ibrance], ribociclib [Kisqali], and something called abemaciclib [Verzenio]. And many of you in the audience may be on one of these drugs or may have had them in the past.

When patients’ cancers become worse on these treatments, then we go potentially to another type of endocrine therapy. And here there are a number of different choices. It would be possible to combine hormonal therapy with a medicine called everolimus, or Afinitor. It would be possible to give elacestrant if a patient has developed a mutation in the estrogen receptor gene ESR1. It would be possible to give hormonal therapy with a targeted medicine alpelisib, or Piqray, if the tumor has a mutation in the gene, PIK3CA. And it also would be possible to just use our old standby Faslodex, or fulvestrant.

One of the things that’s coming down the pike is a medicine called capivasertib. And this is another type of targeted medicine. There was a positive phase III trial. We expect that the FDA will likely review this drug sometime this calendar year, and I think all of us are anticipating it will very likely be approved.

Just a few comments and some updates about what I’ve just shown you. The first is to talk about this study, which was called the RIGHT Choice study. If you’re newly diagnosed with estrogen receptor-positive metastatic breast cancer, one of the most frequent questions that I’m asked is, “Should I do chemotherapy first? I want to be aggressive. Hormonal therapy doesn’t sound like enough.” And this trial was really trying to address that specific question.

This trial enrolled patients with estrogen-positive, HER2-negative breast cancer. And importantly, these are patients who had to have aggressive disease, meaning disease in their liver or disease that was a significant tumor burden. Basically, the patients where historically we might have thought about giving chemotherapy.

The patients who were assigned either to get hormonal therapy and a CDK inhibitor, or they were assigned to get two chemotherapies given simultaneously, so really an aggressive chemotherapy approach. And it turns out that there were better outcomes in the patients who received the hormonal therapy and CDK inhibitor. The cancers actually stayed under control for significantly longer compared to chemotherapy.

And I think this was a really important and very practical study to answer a question that we get all the time in the clinic.

The next topic I want to talk about are these new hormonal therapies. And elacestrant is the most recent one to be approved. It’s an oral medicine. In a way it’s sort of, but not quite, like oral Faslodex, which is an injection as many of you know. What elacestrant does is it actually causes the estrogen receptor to break down. Normally in cancer cells that are estrogen driven, the estrogen receptor is pushing on the accelerating pedal, so if you take away the estrogen receptor, there’s nothing pushing anymore. What’s interesting about this particular drug is it also works in patients whose cancers have mutated the estrogen gene. About half of the time, if we follow patients long enough, the estrogen gene becomes mutated in response to medicines like aromatase inhibitor, hormonal medicines. And that’s a way that the cancers are able to become resistant to treatment. So the important aspect about this drug, it was actually shown to be particularly effective in patients whose cancers had become mutated in this way.

But there are many other hormonal therapies kind of down the pike in clinical trials. Again, elacestrant was recently approved, but there are many other drugs of similar class called, one is giredestrant, imlunestrant, camizestrant, they all have these kind of funny names. There’s also other categories of hormonal therapies including lasofoxifene, OP-1250, and a drug called ARV-471.

So there’s really quite a large range of hormonal therapies, and I think that in addition to testing these on their own, the trials are now testing them in combinations with other medications, so I think there’s a huge amount of activity in this space.

I want to talk about this pathway, which we call the PI3K/mTOR/AKT pathway. It’s a complicated diagram, but the point of the diagram is that the way that cancer cells send signals coming from the outside sets off this cascade of things that happens within the cancer cell that allow it to grow and survive. If we are able to shut off some of these pathways, we can hopefully basically handicap the cancer and make it unable to grow or divide in the way that it would ordinarily do.

Some of the medications that are in this category are alpelisib, or Piqray, everolimus, or Afinitor, and then this new medicine capivasertib, which again we think will likely get an approval sometime this calendar year. And one of the questions that we don’t know the answer to yet is, can you go from one to another to another, what’s the right order to go in. We’re not sure of these questions, but it’s good to have a lot of options.

After patients finish hormonal therapy. Not finish, but after the cancer doesn’t seem to respond anymore to hormonal therapy, we move on to chemotherapy. It used to be that that’s what it was. It was chemotherapy x, chemotherapy y, it was all different kinds of chemotherapy. But now there are some additional medications that we can try. And these include what’s called PARP inhibitors, and I’ll talk about those in a minute. They also include something called antibody-drug conjugates. And the two that we currently have approved for estrogen positive patients are trastuzumab deruxtecan, otherwise known as Enhertu and sacituzumab, which is otherwise known as Trodelvy.

What is an antibody drug conjugate? On the left is a picture of a normal antibody. An antibody can be made to identify any specific protein in your body. Your body makes them to fight infections, like viral infections, but we can generate antibodies to find specific targets on the surface of the cancer cell. And then the conjugate part of it is that there’s chemotherapy drugs or other drugs that can be attached to this antibody.

So the antibody will basically stick to the cancer cell, the cancer cell will swallow it, and then in the process of swallowing it, the drug is released at very high concentrations, higher than you would get in the normal bloodstream.

This is an example of a clinical trial that led to the approval of Enhertu for patients with HER2-low, estrogen-positive metastatic breast cancer. In this study, patients had to have what we traditionally would’ve called HER2-negative breast cancer, but it wasn’t like completely negative. So 3+ is positive, zero is negative, 1+ or 2+ is kind of in between — and now it’s become the so-called low category. Patients in this HER2-low category either got regular chemotherapy or they got Enhertu, and at the end of this phase III trial, it was very clear that patients who received Enhertu had a much higher rate of tumor shrinkage, they had longer cancer control duration, and they had better survival.

Similarly, there is a study called TROPiCS-02 and that studied the antibody-drug conjugate called Trodelvy. This study did not have any pre-selection. There wasn’t any extra special tumor testing. It was just if you had estrogen-positive metastatic breast cancer and had had chemotherapy already, a cancer had gotten worse on previous chemotherapy, then those patients were eligible to enter the trial. And in this trial, patients received either the Trodelvy, or they received a chemotherapy of physician patient choice and there were a number of different options that were allowed. And again, in this trial, what was seen is that the patients who received Trodelvy had more tumor shrinkage, longer cancer controlled duration, and better survival. This one is also now available for patients with this subtype.

I mentioned earlier the this type of medicine called PARP inhibitor. What PARP inhibitors do is that they work specifically in patients who have inherited mutations in the BRCA1 or BRCA2 genes. And there were two randomized phase III trials that compared a PARP inhibitor, which is an oral pill, versus chemotherapy in patients who had inherited BRCA1 or BRCA2 mutations, who had essentially HER2-negative breast cancer. And just one aspect of the trial I’m showing here on this slide is the so-called objective response rate, so that the chance the tumor would have a significant tumor shrinkage. And you can see in both trials it was 60 percent with the PARP inhibitor pill versus only about 30 percent with chemotherapy. So double the chance of tumor shrinkage.

Also in these trials, importantly, they ask patients to fill out quality of life questionnaires and the quality of life was better with a PARP inhibitor.

One of the messages here is that regardless of family history, regardless of ethnic background, it’s important to ask your doctor whether you should have germline testing to see whether you could be a candidate for one of these medications. And one of the important things that we’ve discovered over the years is that although the initial conventional thinking was that BRCA1 and BRCA2 mutations were most common in people of Ashkenazi Jewish ancestry, it turns out that there are a number of populations across the world who also are at higher risk of having BRCA mutations, including Caribbean Black populations, some South American populations. So we can’t just assume based on ethnicity who we should or should not test.

What’s on the horizon for patients who have estrogen-positive breast cancer? There are many, many new hormonal therapies and hormonal combinations. There are new medicines that are targeting this so-called PI3-kinase pathway. There are medicines to try to target resistance, there are antibody-drug conjugates, and there are a lot of things in clinical trials.

Now we’re going to move to HER2-positive breast cancer, nd again, a lot of change over the last couple of years.

Our first line treatment, the first treatment we generally give is some sort of taxane, whether Taxol [paclitaxel] or Taxotere [docetaxel], along with Herceptin and Perjeta [pertuzumab]. However, now in the second line setting, we now typically will offer Enhertu. And in some patients, based on the status of cancer in their brain, we might instead offer tucatinib [Tukysa], and I’ll show you those data in a minute.

Then whichever the patient didn’t receive second, they might receive third. Then fourth would be, again, one of those drugs or potentially one of our older drugs, T-DM1 [Kadcyla]. As patients go on to fifth line or beyond therapies, there are a number of different chemo combinations with Herceptin and there’s also a new drug called margetuximab [Margenza].

Now I want to show you the results of the phase III trial that led to Enhertu now being put as the second treatment that patients should receive. This was a study which took patients who had been on Taxol and Herceptin and then randomly assigned them to either Enhertu or T-DM1. Everybody got active treatment, the previous standard of care was T-DM1. In this trial there was again a very dramatically higher rate of tumor shrinkage, a very dramatic improvement in the duration of cancer control, and longer survival with the Enhertu.

Moving on to tucatinib. This study was looked at a little bit later. Patients in this study had to have previous Taxol, Herceptin, Perjeta, and T-DM1, which again, would have been the prior standard of care. Then after their cancer had gotten worse on those medicines, they could go onto the trial. On the trial everybody received Herceptin, everybody received chemotherapy in the form of capecitabine [Xeloda]. And then some people received tucatinib and others received a placebo.

So when I say placebo, it doesn’t mean patients got nothing. They all got Herceptin and chemotherapy.

In this study there was better rate of tumor shrinkage, not only in the body but also in the brain with this combination. There was a longer duration of cancer control, and there was better survival. In fact, in patients who had brain metastases, the two-year survival was doubled with the addition of this tucatinib pill.

I want to give you a sense of some of the HER2 trials to watch out for, either because of the potential to enroll but also because they may ultimately change our standard of care.

There is a trial which is called PATINA, where we’re just waiting for the results, and that’s for patients with estrogen-positive, HER2-positive breast cancer, where we’re trying to see whether adding or borrowing those CDK 4 inhibitors that we use for the other subtype of breast cancer, whether they help in HER2-positive breast cancer. We’re all sort of anxiously awaiting when the results of that study might come out.

There are also … three studies we improve on that first treatment that patients receive in the metastatic setting. And those trials are currently in enrolling patients.

Last point I want to make about HER2 before we go on to triple negative, is this really important question that we’ve come to, which is, Is HER2-positive metastatic breast cancer potentially curable? You’ve probably heard from your doctors that we don’t have for the vast majority of patients, we don’t really have curative intent treatments for metastatic breast cancer. We’re trying to control it as long as possible with good quality of life. And we hope that your survival will be measured in years. But we don’t promise people that we can cure their breast cancer.

But we all take care of, as oncologists, patients with HER2-positive breast cancer who have been alive 10 years, 15 years, sometimes 20 years, usually not longer than that because Herceptin, remember, was approved in 1999 or so.

And so we’ve always wondered could some of those patients actually stop treatment? Would they be OK if they stop treatment? And some patients have actually done it on their own, I mean, together with their doctor, and we know that they’ve done OK, but we don’t know what the chance of doing OK is. And so this trial called STOP-HER2 was just recently opened. It’s taking patients who have been at least three years on their HER2 treatment and they’re doing fine on that first HER2 treatment. And the patients themselves will choose within the trial whether they feel comfortable stopping or they would prefer continuing treatment. But everybody has scans at the same time points and there’s extra blood collections for research.

In addition, there’s a clinical trial that we hope will be launched by the end of this year, which is called SAPPHO (Sequential APProach to HER2-directed therapy for de nOvo MBC). And this trial is actually looking to see whether we can intensify treatment for patients upfront with HER2-positive breast cancer, in hopes that we might improve how people do in the long run.

Now I’m going to move to triple-negative breast cancer. And 10 years ago, or even five years ago, this is basically what the treatment algorithm would look like. Every line of therapy was chemotherapy and we didn’t know whether any particular chemo was better than another.

This is what it looks like now, and I don’t have fourth, fifth, etc. line on here, not because people don’t get to it, just to be clear, it’s because I didn’t have room on the slide. But in the first line setting we want to see whether patients have PD-L1 positive cancers because those patients who are positive would get chemotherapy plus immunotherapy. We want to understand who has a BRCA mutation because you might be able to receive a PARP inhibitor instead of chemotherapy. And then for the other patients, we generally would offer chemotherapy.

As the second treatment, we often are thinking about the antibody-drug conjugates, including Trodelvy, including Enhertu, and then again, if somebody had not previously had a PARP, they could receive a PARP at that time. Then third line, whichever the patient did not get previously or we’re thinking about chemotherapy.

I want to just take a moment to talk about what is immunotherapy, at least as we prescribe it now, and how does it work. The basic concept is that when your immune cells, they’re called T cells, they find a cancer, there’s a little handshake or switch that happens such that the cancer cell will actually be killed off by the T cell, by your immune cell. But cancer cells are very tricky and they basically find a way to turn off the switch and turn off the immune cell. So even though your body has done all the right things, the immune cells have been activated, they’re trained to find the cancer, they got to the cancer, they got next to the cancer, and the cancer just cell just turns off the switch. What immunotherapy does is it basically turns the switch back on so the immune cells can actually attack the cancer.

This is the trial that was done in patients who have metastatic triple-negative breast cancer. It’s called KEYNOTE-355. This study took patients as their first treatment for metastatic disease, and patients either get conventional chemotherapy or they got chemotherapy plus pembrolizumab, or Keytruda. One important point to highlight from this study is that this was the first treatment patients received for their metastatic disease. When we think about clinical trials, it’s definitely not just a last resort kind of approach. Patients in this trial volunteer to go on a trial as the very first treatment for their disease.

What was seen in this trial was that there was a longer length of tumor control and better survival with pembrolizumab in patients who have PD-L1 positive cancers and a higher proportion of patients who have what we call exceptional responses — those patients who do really well.

Once patients have received a couple of types of chemotherapy, we had been stuck for many years with just giving yet another kind of chemotherapy when the first two or three didn’t work. And obviously that has been very frustrating for both doctors, but especially for patients. That led to the discovery of these new drugs called antibody-drug conjugates. The ASCENT trial was a phase III trial that took patients with metastatic triple-negative breast cancer, who have been on previous chemotherapy, and patients either got sacituzumab — Trodelvy — or they got chemotherapy. And the trial showed that patients who got Trodelvy had a much higher rate of tumor shrinkage, better cancer control duration, and better survival.

In addition, a subset of patients with triple-negative breast cancer will also have what we call HER2-low cancers, meaning the cancer, although it’s HER2 negative, has a little bit of HER2. So this trial called DESTINY-Breast04, this is a phase III trial, patients either got Enhertu or they got conventional chemotherapy. And just like the previous trial we saw higher rates of tumor shrinkage, longer duration of cancer control, and better survival. The caveat is that this study mostly enrolled patients with hormone receptor-positive breast cancers only 60-some patients in this trial had triple-negative breast cancer. So you take it a little bit with a grain of salt, but it is an option available to patients and I think it’s a very effective option.

Before I close, I want to say a few words about clinical trials. All the data that I’ve shown you, all the new drug approvals, they all have happened as a result of patients volunteering to enroll on clinical trials.

Many of the trials I’ve shown you are not the last resort trials. Patients got lots of other treatments after they came off the trial. Phase I, II, or III trials may be appropriate depending on your situation and the therapy that’s being tested. Really importantly, if you’re interested in clinical trials or interested in learning about them or participating them, I can’t stress how important it is to express that interest to your oncology team. As doctors, we’re human. We have both conscious and unconscious biases. We might see somebody and say, “Oh, she has like a bunch of young kids and is so busy, I don’t think she would have time to participate in trial.” And you don’t want somebody to be making these assumptions without you really participating actively in that decision making.

You can consider a second opinion in an academic cancer center, or there are some private practices that are really focused on clinical trials, and then explore clinical trial matching resources.

So where are we now? I think we have a much better understanding of breast cancer subtypes. There are many more treatments available and the way that we treat people with metastatic cancer is so different than it was 5 or 10 years ago.

One thing that I didn’t spend a lot of time talking about today, because my focus was on new therapeutics, was that I hope that we’re paying better attention to your quality of life and symptom management.

And there have been also major improvements in symptom management, anti-nausea medicines, and other supportive care medications, as well as a better understanding of how integrative medicine can sort of integrate into our treatment of patients with metastatic cancer. And all of this, I think, has resulted in longer and better survival in many patients.

But I don’t want to sugarcoat things and I think all of you are here because you know that this metastatic cancer is a serious illness and we still don’t understand why some cancers metastasize and others can be cured. We only partially understand why some cancers become resistant to our treatments Although we have many different treatment options that we can run people through, it’s not an endless list, and we know that. With rare exceptions, we still can’t cure metastatic breast cancer.

I want to take a moment to acknowledge the people we’ve lost in the past year and years with metastatic breast cancer. People still die of breast cancer, so we know we need to do better.

Where are we headed? I think scientifically we are really trying to work hard to understand what causes metastatic spread and what causes treatment resistance. We are trying to develop better treatment options that can not only overcome established resistance but maybe prevent resistance from happening and extend survival. I think we’re getting better, but we still have a ways to go at better selecting the right therapy for the right patient at the right time.

Someday, I hope in my lifetime, we will get to a point where we can really honestly say that we can cure people with metastatic breast cancer. We’re not at that point yet, I know all of you know that, but I feel like really in the last couple years we can start to see that happening at some point, not a hundred years from now.

Thank you all for your attention and I look forward to the discussion.

Janine E. Guglielmino, MA (00:29:57):
Thank you so much Dr. Lin. That was an amazing presentation and really got through so much in a short period; we really appreciate it.

We’ve already got a number of questions so I’ll just go ahead and ask the first one.

One of our attendees is asking if you have both hormone receptor-positive and HER2-positive metastatic breast cancer and experience a progression, which of those would you target first?

Nancy U. Lin, MD (00:30:27):
For patients who have estrogen-positive and HER2-positive breast cancer, typically the HER2-positive part of it trumps everything, and we usually go down the HER2-positive sort of pathway. Some of the things are a little bit different, for example in patients who are getting chemotherapy plus Herceptin or chemotherapy plus Herceptin-Perjeta, eventually we switch people just the to the Herceptin or just the Herceptin-Perjeta. And there we will frequently add in hormonal therapy to target the estrogen receptor-positive part of things. But one of the things that I think is really interesting is this whole idea of whether those CDK 4 inhibitors that we use for estrogen-positive, HER2-negative breast cancer, whether we can pull them over to HER2-positive patients. And again, there’s this phase III trial called PATINA that has fully enrolled patients and really at this point just waiting to see what the results show. Maybe we’ll end up using CDK 4/6 inhibitors in this setting.

Jean Sachs, MSS, MLSP (00:31:27):
That’s exciting. The first I really heard of that. I love all that you shared about clinical trials, and as you know at Living Beyond Breast Cancer, that is something we talk about often.

A specific question someone has is, this person is considering Trodelvy alone or in conjunction with Keytruda and wants to know, what do you think the benefit is of both together?

And I just wanted to add, because I recently talked to someone where their insurance would not pay for the Keytruda, so wondering if you’ve had experienced that.

Nancy U. Lin, MD (00:32:00):
There are several clinical trials ongoing, including some that are being led at Dana-Farber, where I work, both for estrogen-positive as well as for triple-negative breast cancer patients where we’re looking at whether adding immunotherapy to antibody-drug conjugates like Trodelvy would be useful. The reason for that is because if you think about the way that immunotherapy works, it really depends on something for the immune system to react to. So the idea is that the antibody-drug conjugates actually cause more tumor breakup and tumor killing and that provides more sort of raw substrate for your immune system to see. Maybe that that would actually create more of a beneficial effect in combination with immunotherapy than just regular chemotherapy.

There are trials both for estrogen-positive and triple-negative breast cancer patients because we don’t know whether combining them is helpful, that’s why accessing these combinations at this point in time is really part of a clinical trial.

Related to the Keytruda question, at this point in time, the two ways that people can generally access Keytruda from an insurance standpoint related to the way it’s approved by the FDA, one is in combination with chemotherapy for patients who have triple-negative breast cancer whose cancers are PD-L1 positive. So that’s one group. And then the other group that I didn’t talk about in my talk out of interest for time is that patients we know from these gene panels that we run, some patients have what we call high tumor mutation burden. And those patients, regardless of whether it’s triple negative or estrogen positive might qualify for Keytruda if the tumor mutation burden is very high.

Outside of those situations, that can be difficult to get insurance reimbursement. But that’s really because we don’t have the evidence base right now for a lot of the situations outside of the two that I just mentioned.

Janine E. Guglielmino, MA (00:34:03):
Since we were talking about immunotherapy, someone is asking whether Keytruda and other immunotherapies can cause autoimmune conditions and whether that’s a concern for you.

Nancy U. Lin, MD (00:34:17):
Yes. So again, I could have spent even more time talking about all the side effects of these medicines, which I didn’t mean to downplay the fact that these medicines have side effects, it’s really out of the interest of trying to get through a lot of new therapies that have been approved.

Immunotherapy does have the potential to go too far and make your immune system too strong. And the most common place that that manifests itself is the thyroid gland, where it’s actually fairly common that people’s thyroids are affected by immunotherapies like Keytruda and need to be on some sort of hormone therapy for their thyroid, essentially for life even after they come off of the medication.

The other immune side effects fortunately are less common, but they can include attack on your bowel, attack on the skin, attack on other parts of the body. So these are things that we do monitor kind of on a regular basis and sometimes require us to stop the immunotherapy and actually suppress the immune system.

It’s a tricky balance because we don’t have like a perfect way to turn the immune system on exactly to where we want it.

Jean Sachs, MSS, MLSP (00:35:23):
I’m going to try to do some specific quick questions, there’s so much.

This person is asking why was Orserdu only approved for those with an ESR1 mutation and it was her understanding that the clinical trial also included those without.

Nancy U. Lin, MD (00:35:45):
It’s a good question. So Orserdu, or elacestrant, is this oral hormonal medicine. The study allowed patients on regardless of whether they had an ESR1 mutation or not, and patients were either assigned to regular hormonal therapy or the elacestrant, or Orserdu, medication.

The overall trial did show an improvement with elacestrant, but it was a very modest difference. However, if one looked specifically at the group of patients who had ESR1 mutations, it was a much more dramatic and meaningful difference. So I think the FDA, not unreasonably, decided to restrict to that patient population.

Now there are patients who had normal ESR1 spelling, without a mutation, who benefited from the elacestrant. I think there can be some controversy there about how the FDA should have made the approval, but the truth is that in the trial the biggest benefit was really seen in the ESR1 mutated patients.

Now the ongoing trials of elacestrant, where it’s being combined with other types of medicines are not restricted to patients with ESR1 mutations. So there may be opportunities in the future to receive this medication even with normal ESR1, but in combination as part of clinical trials.

Janine E. Guglielmino, MA (00:37:09):
That was a great question. thank you for that.

Jean Sachs, MSS, MLSP (00:37:12):
Yeah. And thanks for distinguishing the chemical name versus the brand name. I know that sometimes is really confusing.

Janine E. Guglielmino, MA (00:37:17):
It’s an alphabet soup. Exactly.

There are a number of questions about clinical trials in general and some people with triple-negative breast cancer feeling frustrated that there aren’t more clinical trials. How can they find out more about clinical trials? Do you need to live locally to access a clinical trial? Could you speak to that please?

Nancy U. Lin, MD (00:37:39):
Yeah, I mean I think that clinical trials there is some ebb and flow, and if you’re a patient, it’s very frustrating if we’re in the ebb. This had happened actually for estrogen receptor-positive breast cancer. We were waiting for the results of a lot of these trials that I showed you. There was like this gap where we’re just like waiting and waiting for the results to come out and there wasn’t a lot to replace them until those results came out. And when you’re in that kind of ebb period, it is very frustrating.

But there are definitely are trials available. I think one of the tricky parts is that every hospital, every center has access to a different set of trials. There are some national resources that you can find online, there’s like a metastatic breast cancer trial matcher that you can put in some information and how far you’re willing to travel and there will be trials that come out.

I think those trial matching algorithms still need or benefit from a doctor looking at them with you, because you might end up with 40 entries and you need to figure out which ones are really the ones that you should focus on.

My advice is that you really want like a clinical trial Sherpa. That you want somebody that when you want to know whether you qualify for a trial because your cancer’s getting worse, that you feel like you have somebody you can go to, who you trust, who will look for trials for you. Not only at their institution, but if you want the person to look at other institutions will do that for you as well.

Jean Sachs, MSS, MLSP (00:39:15):
Thank you.

This is a testing question but it comes up often. With all these changes, how often should metastatic patients be tested for mutations or other subtypes?

Nancy U. Lin, MD (00:39:27):
Yeah, great question. I do recommend that in most cases, unless the cancer’s not accessible by biopsy, that when somebody has their first diagnosis of metastatic breast cancer, that there is a biopsy. Because we want to be sure that A) it’s breast cancer B) was there estrogen, progesterone, HER2. We don’t have any other way to do it besides looking at tissue.

Over time cancers can change. And so the times that I am thinking about re-biopsying a patient are if the behavior changes, like originally it was mostly in the bone and now all of a sudden it seems very aggressive and it’s very much in the liver. I might want to consider a biopsy to understand if the cancer’s still estrogen positive, maybe it’s now triple negative, which happens. That affects eligibility for clinical trials, it affects eligibility for things like immunotherapy. There are a lot of things that can change based on the change of that estrogen receptor status.

The other way to do things over time is what’s called a liquid biopsy. At the beginning I might do one, I might not, because you have to have a tissue biopsy most of the time, but later on I might order a liquid biopsy. And especially in patients with estrogen-positive breast cancers, we can find things.

For example, that ESR1 mutation that we talked about that makes people qualify for elacestrant as part of standard of care. The ESR1 mutation, if you look at the original breast cancer from the left breast, for example, 10 years ago, less than 1 percent of the time will it have an ESR1 mutation.

But if you look at patients who have been on hormonal therapy like letrozole or Arimidex [anastrozole] or whatnot, and the cancer’s gotten worse, over time, up to half of patients will develop an ESR1 mutation in their cancer. So if you test the original cancer only, you’re going to miss half of patients who could qualify for this medication. Especially for the estrogen receptor-positive patients, I do periodically either a regular biopsy or a liquid biopsy depending on the situation because it does change our care.

Janine E. Guglielmino, MA (00:41:35):
Dr. Lin, if you do not have a hereditary gene mutation, but your tumor, the tissue in the tumor test positive for one, is there any evidence that a PARP inhibitor would be helpful in those situations?

Nancy U. Lin, MD (00:41:48):
Yeah, so that’s a really good question. I did have a slide and I took it out because there were too many slides.

The BRCA mutations, these BRCA genes are genes that increase the familial risk of breast cancer. But there are in rare situations, people who never inherited BRCA from their family members, but the tumor itself mutates the BRCA1 or the BRCA2 genes. My colleague Nadine Tung at the Beth Israel in Boston, along with Judy Garber at Dana-Farber actually led a clinical trial in what’s called a translational Breast Cancer Research Consortium, where they looked specifically for those pretty rare patients and found that actually with the PARP inhibitor Olaparib, half of the patients responded, which actually is very similar to what we see in patients with hereditary BRCA mutations. So again, it’s another example of one of the things that we can find either with a tissue biopsy or a liquid biopsy that we would not find if we tested somebody’s original cancer.

Janine E. Guglielmino, MA (00:42:50):
Thanks, Dr. Lin. Could you talk a little bit about what exactly a liquid biopsy is?

Nancy U. Lin, MD (00:42:55):
A liquid biopsy is basically a blood test, and from the blood we can actually find microscopic bits of DNA that the cancer has actually shed into the bloodstream. This test is essentially the same technology that is now used for prenatal testing to look for fetal DNA, you can look for tumor DNA. It used to be a very difficult problem — it’s like needle in a haystack, but now it’s actually very doable and there’s many commercial labs who offer this testing. And so we can test many, many different genes and look for mutations in those genes just from a blood test rather than doing a biopsy.

Now the blood test cannot do certain things. It can’t tell us the estrogen receptor status. It can’t tell us a PD-L1 status. It can’t tell us if it’s HER2 low. So there are definitely limitations of a blood biopsy, but it’s very good at telling us the mutational status and the tumor mutation burden. And for patients who, you don’t want to constantly be doing invasive biopsies, it can be a helpful add-on.

Jean Sachs, MSS, MLSP (00:44:01):
Great. So helpful for patients too.

This question is about, could you explain HER2 low? We get this a lot. This person’s is 1+, but does that mean it’s low?

Nancy U. Lin, MD (00:44:15):
Yeah, so HER2 is this classic thing that we test for in breast cancer. The classic definitions were HER2 positive means it’s 3+ staining — you remember the brown stain I showed you, 3+ means super strong staining and then zero was negative. And in the past, the in between category we did a second test to see if it was really negative or it was really positive.

But the point is that there’s this group of patients who by the traditional criteria we would’ve called HER2 negative. And in your notes from the doctor they say that you have HER2-negative breast cancer. But there’s a difference between people who have HER2 zero, meaning we don’t see any HER2 when we do the brown stain or there’s a little bit just not enough to call it positive.

In the past medicines like Herceptin were tested in patients with essentially HER2-low cancers and found not to be effective, so that’s why we don’t give Herceptin or T-DM1 or those kinds of medicines to HER2-low patients.

But the newer generation of medications, including Enhertu, they actually are powerful enough. They look like they work very well in patients who have HER2-low breast cancers. And there are a bunch of other antibody-drug conjugates in clinical trials that are targeting HER2 low. So Enhertu is not going to be the last one.

It’s about 60 percent of estrogen-positive breast cancers are HER2 low and about 40 percent of triple-negative breast cancer are HER2 low, so it’s really common. And if you had your original biopsy five years ago, your doctor might not have written down what it was, they may have just written down it was HER2-negative. And then we have to go chasing back these old path reports to figure out what it actually was.

Janine E. Guglielmino, MA (00:46:02):
So Enhertu has been studied in a number of different subtypes of metastatic breast cancer and one person is wondering whether it may ever become an option as a first treatment after diagnosis?

Nancy U. Lin, MD (00:46:15):
Yes. There are many clinical trials actually looking at both Enhertu as well as Trodelvy and not waiting until somebody’s gotten worse on something before going on. So for HER2-positive breast cancer, there’s a trial comparing chemo plus Herceptin-Perjeta versus Enhertu. For triple-negative breast cancer there are trials putting Trodelvy as the first treatment versus regular chemo. And then for estrogen receptor-positive breast cancer trials, not trying to replace or get rid of hormonal therapy because we usually go through those first, but basically once you move on to chemotherapy, should we just start straight away with an antibody-drug conjugate rather than doing regular chemo first.

Jean Sachs, MSS, MLSP (00:47:00):
Yeah, we have some good comments in here about what, what can’t Enhertu do.

There are several questions about as wonderful as these new drugs are, the financial toxicity and they can be upwards to $15,000 and there’s high copays with Medicare Part D. Any thoughts on that?

Nancy U. Lin, MD (00:47:21):
Yeah, I think that this is, unfortunately I don’t have direct control over how the pricing happens. I think that, and there also is as you probably have experienced a disconnect between how drugs are paid for if they’re given intravenously versus how drugs are paid for if they’re given as a prescription and you take a pill home. In particular the pills are really a big issue for patients as far as out-of-pocket costs, because oftentimes a prescription drug benefit is such that you might need to pay 20 perent of the cost. And that’s not so bad if it’s a hundred dollars for the medication for a month. It really is a problem if it costs $10,000 a month, which many of these newer medicines cost.

I do think that this is a place where patient advocates and us as the oncology community really need to come together.

There’s two issues. One has to do with the way insurance coverage is structured and prior authorizations and copays and just the logistics of that. And the other has to do with just the drug pricing in general, right. Because 20 percent of 10,000 is a lot different than 20 percent of 100. And I think we really do have to find ways to do this because as we develop more and more drugs that are very effective, it’s just not going to be sustainable financially either for individual people and also just for the healthcare system in general.

Janine E. Guglielmino, MA (00:48:51):
For patients that you’re seeing today in clinic who are really struggling with the financial costs of treatment, how do you guide them as a physician? Where can they get help?

Nancy U. Lin, MD (00:49:02):
That’s a great question. Every center has a way that they’ve tried to manage this and I work at Dana-Farber, we have a resource specialist and then we have a pharmacy office, and part of their charge is to help people find ways to cover the cost of the medications. Whether it’s programs through the drug companies that help subsidize or provide drug to patients, whether it’s other patient assistance programs that patients may qualify for, whether it’s actually other things like gas cards or parking or other things that may not directly pay for the drug but offset the out-of-pocket costs that people experience when they have a diagnosis of cancer.

I’m first to acknowledge it’s not enough. When you think about how much not only the drug cost is but the cost of getting in and out of clinic visits and the lost time and there’s a lot of costs that we don’t add up, so to speak. It’s very expensive to be living with a diagnosis of metastatic breast cancer. And again, I think this is where, as an oncology community, as advocacy with LBBC, it’s just such an important thing to try to keep on people’s radar screen, the legislators and our government officials because it’s a very, very important issue.

Jean Sachs, MSS, MLSP (00:50:29):
A couple people are curious. Do you find the circulating tumor tests Signatera useful at this time?

Nancy U. Lin, MD (00:50:40):
Yeah, so I don’t know if anyone from Signatera is here. I personally don’t order the Signatera assay for the purpose of monitoring the so-called tumor fraction or tumor burden. I think that it’s certainly a valid test in the sense that it measures what it says it measures. It’s not a quack test, it’s real test. I think that what we don’t know at this point is what is the value or not value of switching therapy or making therapeutic decisions based on the results of the test.

So let’s suppose the Signatera test says the tumor fractions going up. Well, do I change the patient’s therapy if the scans look fine and the tumor markers are OK and the patient feels OK, probably not. And so that’s, I think, the part that is to me less clear cut.

Janine E. Guglielmino, MA (00:51:34):
In general, what are the best tests or what are the tests that you feel most comfortable with monitoring the cancer’s response to treatment?.

Nancy U. Lin, MD (00:51:44):
It’s tricky and it depends from patient to patient. We definitely use scans some patients who have disease that’s measurable, it’s pretty straightforward on scans to figure out if the cancer is getting better or not better.

For patients who have disease primarily in the bone, it can be more difficult because CAT scans don’t usually become normal. And so you don’t know whether the change that you see is because the bone is healing, and it’s a good thing, or because there’s more cancer, which is a bad thing. And so there we often use other pieces of information, how patients are feeling, if they have new bone pain, the bone pain’s getting better. We might use the tumor markers to help guide us there. And I do think that, going back to the previous discussion, maybe that’s where some of these newer assays, like Signatera might end up being very helpful, is in these patients who we have a difficult time with our standard testing, always being fully sure if the cancer is responding or not.

Jean Sachs, MSS, MLSP (00:52:52):
We do have a question from a man with metastatic breast cancer who was excluded from a trial. So wondering …

Nancy U. Lin, MD (00:53:00):
Yes. I actually just coincidentally yesterday Tatiana Prowell, who is at the FDA and some of you are familiar with, gave a talk at Harvard, one of our conferences. She made the point that at this point in time, the FDA is scrutinizing all clinical trial protocols that come in. And if a sponsor wants to exclude men with metastatic breast cancer from a trial, they really push back.

So I think in general, we really shouldn’t be seeing that anymore. If this particular man is interested, if there’s a trial that was very recent that he was excluded from, he could send the details and I’m happy to run it up a flagpole, but it really shouldn’t be happening anymore.

Jean Sachs, MSS, MLSP
Thank you. I’m sure he’s listening, and that is good.

Janine E. Guglielmino, MA (00:53:49):
In general, Dr. Lin, what should we be doing as a community to help diversify participation in clinical trials?

Nancy U. Lin, MD (00:54:04):
Yeah, it’s a great question. I recently was asked by one of my patients who’s African American and was thinking about whether to participate in a trial, “How many other black individuals have gone on this trial before me?” And I said, I don’t know, I’ll find out. And I went back to the sponsor and I found out, and it was, not surprisingly, very, very few.

I think that clinical trials do require additional effort on the part of patients. They’re only available at certain centers, often large academic centers. Rural patients in addition to underrepresented minority patients can have difficulty accessing clinical trials for all sorts of structural factors.

I think that there is a little bit more attention paid and we’ll see how this goes over time of trying to reimburse some of the clinical trial costs to patients. So costs like transportation, like housing. Unfortunately, it’s not always possible to do studies that are designed, run, led by a drug company, a little bit more possible to do. Trials that are designed by like a U.S. cooperative group, where the budgets have always been very, very minimal to begin with, it’s not as possible. But I think a lot of centers are really trying to come up with creative ways to be able to help offset some of the financial cost of participating in trials, which I do think is still a very important barrier.

And then I think efforts by LBBC and other advocacy organizations and by some of you out in the audience, patient advocates are really, really important because I think people really respond to seeing other people who look like them and who have similar backgrounds, and to feel trust. Because participating in a clinical trial requires trust, and if you don’t have that, a patient is not going to be interested in being a guinea pig. I can understand that feeling entirely.

So I think it really starts with trust, but it also needs a lot of, I think, structural input as well to try to get some of these financial and other structural barriers to come down

Janine E. Guglielmino, MA (00:56:29):
Our next question is about dosing and your opinion on starting at the highest dose versus a lower dose. And there were a couple of specific questions about if you’re on a medication for a period of time at a particular dose and NEAD, so the cancer’s not growing, there’s no evidence of active disease, could you lower the dose?

Nancy U. Lin, MD (00:56:55):
Dosing is a really great question. Historically, the way we’ve, in oncology, described the starting dose of medications is in the phase I trials, patients are given escalating doses of medications. And then when you get to a point where too many people have side effects, that’s then one step below that is considered the maximum tolerated dose.

That dose is often what’s taken forward into phase II and III clinical trials. And sometimes those phase I trials where the dose was found are relatively small studies and the side effects that were being measured to sort out the dose were the side effects in the first cycle of therapy, where obviously we all know that side effects can be accumulative over time. Then what ends up happening is the phase III trial tests a certain way and then you don’t really know, maybe you really did need to have that first dose being a bigger dose before reducing. You can’t tell from the way the trials are designed.

There is definitely an effort in phase I studies now to explore multiple doses. Not every possible dose, but at least to explore more than one dose, to do like what’s called an expansion, where after the dose is sort of identified that you might take a couple different doses forward and have patients on them for longer, and then decide what dose based on that should go into the phase III.

It does complicate the phase I development. It does slow things down a little bit in terms of getting that dosing sorted out a little bit better. But I do think in the long run that that is the right approach because otherwise we end up subjecting patients to a lot of toxicity and we don’t even know if it’s necessary for patients to have that toxicity.

Janine E. Guglielmino, MA (00:58:42):
Thank you. And this is definitely an area where patient advocates have been doing a lot of work.

Nancy U. Lin, MD (00:58:46):
Yes, absolutely.

So I will say again, like now I’m quoting Tatiana Prowell again, hopefully she’s OK with that, but yesterday when she gave the remarks from the FDA perspective, she stated that so much of the impetus for the dosing initiatives in phase I have come from the advocacy community and specifically from the breast cancer advocacy community. So I think what you guys do makes a big difference.

Jean Sachs, MSS, MLSP (00:59:15):
And a lot of those people are in the room today, so thank you.

I know we’re really close to the end of time, but there are several questions about taking treatment breaks, and I know you can’t answer specific personal questions but this person is thinking about taking a break from Trodelvy, it’s working well. In general, like how long can people take a break and what is the guidance on that?

Nancy U. Lin, MD (00:59:42):
I think of treatment breaks in a couple different ways. One is, Can I take a break to go on vacation and skip a week or two or three of medication? Generally the answer is yes. There might be some rare exceptions — patients who have like a super aggressive cancer and they just recently started therapy — but generally the answer to that question is yes.

Sometimes people want to take kind of a scheduled break but go back. So I want to take like a six-week break because I’m feeling really beat up, and then I’ll come back. Generally, again, unless their situation was that they had a very aggressive cancer, oftentimes the answer is yes.

I think the trickier part is like a real break. Like I want to come off treatment and just be scanned, and then when the scan looks worse, I want to go back on. That I think is really hard to give a general answer to, that’s very case by case. As I said, for HER2-positive patients, we’ve just launched a trial to actually do that on purpose, but the reason it needs to be a trial is because, I can’t quote somebody right now, if you do that, what’s the chance that it’s going to be OK? I don’t know. And so I think it’s very much an individual discussion with your doctor.

It also depends on whether there’s any maintenance strategy that’s less toxic that’s possible. So for patients who have estrogen-positive breast cancer, it might be that somebody has a lot of side effects on Trodelvy. They’ve had a good run on it, cancer’s in response. and maybe they want to go on hormonal therapy back again. And that would feel, I think, more comfortable than going on nothing. And so I do think it’s very case by case. I wouldn’t say that it’s never, but it is very much individualized to the individual situation.

Janine E. Guglielmino, MA (01:01:30):
Thanks Dr. Lin. So I guess I get the last question. You talked a lot about HER2-positive breast cancer and the potential for a cure. How close do you think we are overall in finding cures for metastatic breast cancer?

Nancy U. Lin, MD (01:01:46):
Yeah, I think probably the one that we’ll figure it out first is HER2. I don’t know whether this trial is going to do it or not, but I think the drugs are good enough and we see enough people with what we call exceptional response 10 years, 20 years, on the same treatment that we feel like it’s just got to be possible.

But these things take time. This trial that I talked with you about, that’s going to start this year, it’s probably going to take two years to enroll and then patients are going to have to be followed for a few years after that. So even if everything goes exactly to plan, that’s like five years from now when we’ll know the results of that study.

I think that for triple negative, we’re not quite there in terms of having enough really effective therapies to really think that we can cure people today. But it only takes like one or a few breakthrough medications before we might get to the point where we say, “Yeah, maybe it’s time now to try.” And that’s very hard to predict when that would be.

For estrogen-positive breast cancer. I think that that might end up being the last one we cure in the sense of if you define cure as you get a certain amount of treatment and then you stop. Because I think for estrogen-positive breast cancer, as we know in the early-stage setting, people get recurrences 10 years later. It’s a really sneaky kind of cancer, and so maybe it won’t be cured but maybe it’ll be like sustained hormonal therapy or some sort of maintenance therapy that’s indefinite. And we might not call people cured, but they won’t die breast cancer. I don’t know when that will be, but I am very optimistic.

I just think about what was available to people with breast cancer when I started medical school and it’s just practically nothing. When you think about what my oncology colleagues, senior colleagues, were doing and how they were treating patients. They didn’t have any of these tools that we have now, and it’s so amazing. It is getting faster. I know it’s not fast enough, but it is getting faster. So I hope that we’ll see a time when people don’t die of breast cancer.