Session 3: Navigating ESR1-Mutated Breast Cancer: Biomarkers, Targeting Mechanisms, and Treatment Decisions

Kelly McCann, MD, PhD, reviews relevant clinical evidence, guidance on estrogen receptor 1 (ESR1) mutation testing, and practical considerations for patient selection, safety monitoring, and dose management in ESR1-mutated breast cancer management.

Hello. Welcome to this Oncology Learning Network webinar. This is the Community Connect Webinar Series. Today we're talking about estrogen receptor biomarker testing, targeting mechanisms, and treatment decisions in breast cancer care. I'm Kelly McCann. I am a breast medical oncologist. I was recently at UCLA for 12 years. I just moved down to UC San Diego. And I do a lot of clinical trials and treat all types of breast cancer.

Today, we're going to talk about the clinical relevance of ESR1 mutations and distinguish testing-at-progression guidance from the label requirements for the FDA-authorized plasma test. We're going to talk about SERDs and differentiate them from PROTAC-mediated estrogen receptor degradation and other ER-targeted approaches. And we'll talk about a case that we can use as a patient example. And then we're going to apply the label-based patient selection, dosing, adverse event monitoring, dose modification, and counseling in practice.

So ESR1 biology is very interesting because this is a mutation that develops in response to estrogen deprivation therapy. So if your premenopausal patients on ovarian function suppression and an aromatase inhibitor, they can eventually develop this kind of mutation. Your postmenopausal patients can develop this mutation as well. So you only see it after somebody's been exposed to an aromatase inhibitor. This isn't something that is there from the very beginning of the cancer; it's purely a resistance mutation.

This is in contrast to some of our other mutations, like the PI3-kinase mutations. That happens in about 40% of patients with estrogen receptor–positive, HER2-negative breast cancer. The estrogen receptor-activated mutations lock the estrogen receptor into this active conformation, and that estrogen receptor no longer needs estrogen in order to become active. So that's an important aspect of trying to identify these mutations and then use a medication that can bind both the active conformation and the inactive conformation.

Usually, what we recommend is that people look for these after exposure to an aromatase inhibitor by doing liquid biopsies. The reason for that is because it's a resistance mutation; if a patient has a lot of different areas that are evolving independently, you might biopsy one or another and miss that mutation entirely. It might just be present in one or more of those different areas of metastasis. But if you do a liquid biopsy, you're more likely to find it because the ctDNA will be shed. So this is a preferred way to look for ESR1 is by ctDNA liquid biopsy.

On the other hand, if you have someone who has a PI3-kinase mutation, you expect that, because it's been there since the beginning, you expect that to be present on a liquid biopsy if there is enough disease burden, or you would see that also if you did a tissue. So that's a very important distinguishing feature.

Another thing that I think is important to note is that sometimes there's not enough of a disease burden in order to turn a ctDNA test positive. So this is why we recommend that there be testing at every progression because you just might not see it immediately. It might show up later. It's still in response to that early aromatase inhibitor exposure, but you might not be able to see it. So if you get a liquid biopsy and you don't see any targetable mutations, it might just be a false negative because there just wasn't enough ctDNA shed to turn that test positive.

We have a lot of tools in our toolbox for targeting the estrogen receptor. The aromatase inhibitors, of course, are very successful as a strategy until an ESR1 mutation develops, and that can happen in up to 40% of patients. The SERMs can target the estrogen receptor by binding estrogen receptor and it changes how the transcription of estrogen-modulated genes are expressed. So that can be tamoxifen. There's another drug that's in development in the ELAINE trials called lasofoxifene, which is also a very exciting drug.

And then we get to the SERDs. So SERDs are selective estrogen receptor degraders. They bind to the estrogen receptor and often they will cause a conformation that is recognized by the proteasome-ubiquitination system, and so there's a degradation of that estrogen receptor.

Finally, we get to the PROTACs. So vepdegestrant was recently approved only for patients with ESR1 mutations. And the way that works is by bringing together the target, which is estrogen receptor, with a ubiquitin ligase through a single molecule. The estrogen receptor gets ubiquitinated, and then the drug is actually released to go do it again in order to hit as many estrogen receptors as possible. And that protein is also degraded in the proteasome system. So the CERD and the PROTAC, they're both estrogen degraders, but the PROTAC is a little bit more direct way, and it can be something that can be kind of recycled in the cell to go on and hit additional estrogen receptors.

Right now, by the NCCN guidelines, if a patient is not in visceral crisis with estrogen receptor-positive, HER2-negative disease and they've been on endocrine therapy plus usually a CDK4/6 inhibitor as a first-line therapy, then at the time of progression, the next line therapy depends on what other mutations do we have. So there are a lot of different strategies.

One of them is from the MAINTAIN and postMONARCH trials, which is to switch out from the aromatase inhibitor to fulvestrant and use either ribociclib or abemaciclib and keep going for as long as the patient doesn't progress. Because there is about a 40% rate of PI3-kinase mutations, we also have a lot of strategies that utilize fulvestrant in addition to inavolisib, or there's alpelisib, there's capivasertib, and even everolimus. There's also data that was presented recently on the PAM pathway inhibitor, PAM being PI3-kinase/AKT/mTOR pathway with gedatolisib. Right now, that medication is only approved for hormone receptor-positive, HER2-negative without a PI3-kinase mutation. So that's an excellent strategy as well.

Finally, we get to if a patient has an ESR1 mutations, we've got a lot of options. So we've got imlunestrant's approved, elacestrant's approved, camizestrant was recently approved, and then we also have vepdegestrant. So there's a lot of different options there.

Finally, if someone has a lot of visceral disease and their disease is moving very quickly, and maybe it wasn't in the liver, now it's in the liver, and you biopsy it, and the estrogen receptor is no longer there, that's when we start turning to our cytotoxic therapy. So some of the art of treating ER-positive/HER2-negative breast cancer is trying to figure out when do we stop using our endocrine therapies and switch over to a chemotherapy strategy? So that is something that I think we all struggle with when we're treating patients in the clinic.

So right now, the approvals, imlunestrant plus or minus abemaciclib, elacestrant, vepdegestrant, camizestrant plus a CDK4/6 inhibitor, they are all approved only in the ESR1-mutated patients. That might change in the future. I think that giredestrant and its pending approval in the adjuvant setting is hopefully going to reset the thinking a little bit on the fact that these drugs, oral SERDs, also work on the wild-type estrogen receptor.

So to talk about the imlunestrant approval, let's focus on EMBER-3, which was a global, open-label, phase 3 trial. Patients were estrogen-receptor positive/HER2-negative. They had to have had prior exposure to an aromatase inhibitor. It was not mandated that they have a CDK4/6 inhibitor. And about 70% of patients in this trial ultimately did have that kind of exposure. They couldn't have had any chemotherapy. They could have 1 additional endocrine therapy.

They were randomized 1:1 to imlunestrant 400 milligrams once daily, or the standard-of-care arm, was fulvestrant or exemestane, with the majority of patients getting fulvestrant. The primary endpoints were investigator-assessed progression-free survival in patients with ESR1 mutations and in all patients. The secondary endpoints, overall survival, overall response rate, and safety.

This is the demographic information. The most important thing to point out here is that the line of therapy in the advanced setting for the vast majority of patients, this was second line, so almost 80% of the patients. And then the previous CDK4/6 inhibitor exposure was about 70%.

Some of our other clinical trials, like with EMERALD trial that looked at elacestrant, they mandated that a CDK4/6 inhibitor be given before they went on to that oral SERD. So it's very important that we not make cross-trial comparisons, especially in light of the fact that the patient populations were so different.

This is the efficacy for EMBER-3. We see imlunestrant in the blue line, with a median progression-free survival of 5.5 months versus the standard of care, which was 3.8 months. So that gives a hazard ratio of 0.62.  

Clinical benefit rate, which is also a win. It includes overall, like a response, a partial response, complete response, and also includes those patients who have stable disease. With imlunestrant in the patients with an ESR1 mutation [clinical benefit] was almost 50%, and that's in comparison to the fulvestrant or exemestane arm, which was 36%.

The adverse reactions are pretty minimal. They're very, very, very few grade 3 or 4 events in imlunestrant or fulvestrant or exemestane. There can be some musculoskeletal pain, which we expect from anything that depletes estrogen exposures, including just going into menopause. I hear that all the time from my patients coming in the door. It's just they already have the joint stiffness and it's from menopause. So that is also something to be aware of here. And the best treatment for that is to get up, move, and just keep trying to exercise.

Some patients did report fatigue and there can be some GI side effects. I think some of the oral SERDs, to one extent or another, can have those GI side effects. And in my practice, when patients experience those, it usually gets better after about a month. So just help them to stay in there.

There were some lab abnormalities. The biggest one to watch out for in any of these drugs is AST/ALT because anything that's metabolized through the liver can cause elevations in [inaudible].

Also, there was a potential for increase in lipids, especially triglycerides. So that's always important to watch out for in our patients because they need to have a healthy heart in addition to keeping their breast cancer under control.

The VERITAC-2 trial was a global, open-label, phase 3 trial looking at vepdegestrant. So this is our oral PROTAC agent. In this clinical trial, patients were ER-positive/HER2-negative. They were stratified by ESR1 mutation just like they were in EMBER-3 and EMERALD and SERENA-6, which mandated that they have an ESR1 mutation. So in the trial, these patients were randomized 1:1 vepdegestrant and the control arm was fulvestrant.  

I think in designing clinical trials with these agents in the future, it's getting harder and harder to figure out what the control arm should be. Fulvestrant as a monotherapy right now is just not considered to be an ethical control arm. We use fulvestrant doublets in our patients. So this field is quite difficult to design trials for in the future.

These patients did have to have a CDK4/6 inhibitor, so that differentiates it from the EMBER-3 in which 70% had a CDK4/6 inhibitor. They could have up to 1 additional endocrine therapy, and they had to have had their prior therapy progression without disease of at least 6 months. So sometimes when we're trying to figure out is it time to pull out chemotherapy in our patients, it's because we figured that they progressed so quickly in their last endocrine therapy that they are considered endocrine therapy resistant. So this mandated most recent endocrine therapy had to be 6 months or longer.

The primary endpoint here was progression-free survival by resist criteria with select secondary endpoints, including overall survival, overall response rate, clinical benefit rate, and safety as well.

The demographics were quite similar to with EMBER-3. Here, the 80% of the patients or so had had 1 prior line of endocrine therapy, and so they're going on this trial as a second line. There were about 20% of patients who had had 2 prior lines of endocrine therapy before enrollment on this clinical trial. CDK4/6 inhibitor mandated, so 100% of patients had had this.

And it's important in these clinical trials also to look at what percentage of patients had visceral disease. I think a lot of these trials don't show the median progression-free survival that we see in the real world because the RECIST criteria, there has to be something to measure, and bone-only disease patients are often excluded from those trials. So we all have those patients who have been on 1 of these therapies for many, many years with bone-only disease. They often wouldn't be excluded from these kinds of trials. So that's very important in explaining to your patients what the median progression-free survival is. If you've got a bone-only patient, they might get a lot longer on their therapy than that patient who has liver metastases, for example.  

The efficacy here in the ESR1-mutated population was a median progression-free survival of 5 months with vepdegestrant versus 2.1 months with fulvestrant. Clinical benefit rate, meaning they had stable disease or they had a response, was 42% with vepdegestrant versus 20% with fulvestrant. So that is a win when patients can have stable disease.

There were no complete responses. There were a pretty equivalent amount of partial responses to the EMBER-3 data. Overall survival right now is immature.

Safety data, again, you see the musculoskeletal pain from the decrease in estrogen signaling, see fatigue, some GI side effects. And then importantly, there was QTC prolongation. It was considered mild by the FDA, with very, very few grade-3 events, 1.6%, but it is something to keep in mind when you are prescribing other medications that can prolong the QT.

In laboratory abnormalities, again, we see some elevations in AST/ALT, but very, very few grade 3/4 events in vepdegestrant versus fulvestrant.

So to kind of focus on a patient case and think about what types of therapies could we give someone, let's go with a 65-year-old woman. She has medical history, hypertension, hyperlipidemia. She's diagnosed with de novo metastatic hormone receptor-positive/HER2-negative breast cancer with bone disease and 2 liver lesions, but normal LFTs. Her baseline ctDNA is negative for any actionable mutations, and she is treated with first-line aromatase inhibitor plus ribociclib times 3 years. So that's a nice long response on her first-line therapy.

When she progresses, she has new bone lesions and 3 liver lesions. She's asymptomatic and her labs remain normal. Her repeat ctDNA at this point, after exposure to an aromatase inhibitor for 3 years, shows an ESR1 mutation, D538G.

So this is a typical patient that we might see, and she has a lot of options. So imlunestrant is 1 option. Imlunestrant plus abemaciclib was recently approved by the FDA. Not showing that data. It was very, very recent. We also saw camizestrant approved with any of the 3 CDK4/6 inhibitors that are currently available, palbociclib, ribociclib, and abemaciclib. Eventually, we'll also have hopefully approvals for giredestrant plus everolimus per the evERA trial. This patient could be treated with gedatolisib plus fulvestrant plus palbo as well. So she has numerous options that you could use, and how we're going to choose between these is actually going to be pretty difficult.

So kind of an overall summary of the ESR1 mutation treatment decision making. So patients who have progression of disease should have ESR1 mutations assessed, and the preferred way to assess that is by liquid biopsy because that is kind of a global overview of what mutations might be evolving in the cancer. And then we review our previous therapies to assess exposures, confirm eligibility for an ESR1-directed therapy, evaluate comorbidities, concurrent therapies, and then assess patient disease-specific factors that might influence the estrogen therapy treatment selection.

The key takeaways are that ESR1 mutations are a resistance mutation that has driven development of new estrogen receptor-targeted approaches that can address the persistent estrogen receptor signaling in the absence of estrogen. So with aromatase inhibitor-resistance mutations, you have to switch to something else. And we have a number of drugs that will treat that by degrading the receptor.

Routine testing for ESR1 mutations that recurrence or progression can help identify patients who might benefit from the newer estrogen receptor-targeted treatment approaches. I think sometimes even if a patient has an ESR1 mutation though, it's also important to look at the overall view. ESR1 mutations, the liquid biopsies don't replace imaging, and they don't replace tissue biopsies if those are needed.

So for example, if you've had a patient with bone-only disease for a very long time, she has an ESR1 mutation detected in the blood, but then she has new liver metastases, that is an indication that maybe her disease has shifted into something more aggressive, and you might want to biopsy the liver to see if she still retaining that estrogen receptor in the liver? Because sometimes what happens is you detect an ESR1 mutation in the blood, you biopsy the liver and estrogen receptor is totally gone. It's shifted into more of a triple-negative phenotype. So if you put that patient on an oral SERD, you'll treat her disease that still has estrogen receptor, but you're not doing anything that addresses the liver, and that might be a time to switch over to chemo.

And then finally, we differentiated between the SERD-mediated estrogen receptor degradation from PROTAC-mediated. Ultimately, they're both degraders and they haven't been directly compared, but they are slightly different in that the PROTAC-mediated cell drug will bring together ubiquitin ligase with the estrogen receptor and more directly cause its degradation.

And with that, I'd like to take questions. Thank you very much for listening.

So one question, “In your practice, what is the most important trigger for repeating ESR1 testing? And how do you operationalize retesting at progression?”

So it's a great question. I think that if somebody is really early on in their endocrine therapy AI plus CDK4/6 inhibitor, of course I'm going to test them at the first progression right after. But if that test comes back negative, then it might just be that they don't have a high enough burden of disease to detect that ESR1 mutation. So that to me is sometimes frustrating when you know that the oral SERDs can treat patients who have estrogen receptor wild type or with an activating mutation. So I do tend to repeat the ESR1 testing at other progressions as long as I think the patient actually has endocrine therapy-sensitive disease. So when that patient kind of switches over into getting very minimal time on their therapy, then that's when I start looking for other things or might consider a re-biopsy.

“How do visceral disease burden, pace of progression, symptoms in the absence or presence of visceral crisis affect your treatment decision-making?”

So visceral disease indicates a poor prognosis. So the patient who gets 10 years on an aromatase inhibitor plus CDK4/6 inhibitor with bone-only disease and maybe something pops up in the bone, you radiate it and keep going. That's fundamentally different from the patient who has, like our patient case here, liver metastasis from the very beginning. In general, if someone has visceral disease, then I'm going to have kind of a shorter leash on that patient. I'm going to want to know whether or not she's responding to therapy pretty quickly.

And I explain this to patients by just noting that my priorities in her body are going to be brain, liver, lung, and then bone and lymph nodes. So just calling out that if someone has liver metastases, then the liver is what I'm primarily concerned with, and that's what I want to monitor and make sure that she's responding to that.

“When considering an ESR1 mutated patient, which clinical or disease features most influence my choice among the ER-directed therapies?”

This is a great question. So I usually in the first line setting use an aromatase inhibitor plus either ribo or abema, depending on patient preference. I like to give my patients a menu of options, "Would you rather have diarrhea or EKG monitoring?" So the patients are on that.

postMONARCH and MAINTAIN studies were primarily studies looking at ribociclib or abemaciclib after progression on palbociclib. That's not what a lot of us are doing in practice anymore. So my second-line therapy is usually not to go onto a CDK4/6 inhibitor. I usually switch it up into something that's targeting the PI3-kinase pathway. And if I don't have anything like a PI3-kinase-activating mutation or AKT mutation, which would lead me to use capivasertib, for example, then I'll use everolimus or now we have gedatolisib available. So my preferred second-line therapy is to do that kind of strategy.

In the future, we will have hopefully giredestrant plus everolimus in that setting. There's also data that was just published in the ELEVATE trial, which was a phase 2 safety trial looking at elacestrant plus numerous other types of combinations. So they looked at ribociclib, abemaciclib. They also looked at everolimus and then looked at capivasertib. The dosing for the everolimus and capivasertib are slightly different. They're lower than you would give as the standard dose. So for example, the everolimus was 7.5 and capivasertib was 1 notch below what you would usually dose it, which I think was 320 milligrams. So usually that's what I'm doing in the next line therapy. Yeah.

“What practical counseling points do you prioritize to help patients understand dosing adherence, adverse event monitoring, and when to contact the care team?”

That's a great question, and that's something that we're constantly updating our patients with. It's very helpful when there's a whole team and a nurse might be involved, an APP, a pharmacist, so that there's somebody else who's also there. Some of these drugs have blister packs, so that aids in adherence, and some don't.

In general, the adverse events that we see with the oral SERDs have been related to estrogen deprivation, musculoskeletal pain, for example. I have had patients who have had GI toxicities, and I think that just telling them upfront, "You might be a little nauseated or have some other changes in your bowel movements." Just telling them that that can get better with time is really important. It's when we start combining these with things that target the PI3-kinase pathway that things get a little bit more toxic, when you start getting stomatitis, for example, and hyperglycemia.

I think that is maybe the end of the questions.

Thank you for attending this webinar. We're going to wrap it up. No additional questions, so thank you very much.