Dr. Erika Hamilton: Welcome to Shared Decisions, Better Outcome: Collaboration in Managing Targeted Therapy for Hormone Receptor Positive HER2-negative Breast Cancer, a JADPRO Virtual Roundtable. I'm Dr. Erika Hamilton, I’m the Chief Development Officer, Late Phase, and Director of the Breast Cancer Research Program at Sarah Cannon Research Institute in Nashville, Tennessee, and I’m joined by two fantastic colleagues. I'll let Heather introduce herself first.
Heather Moore: Hi, my name is Heather Moore. I'm a clinical oncology pharmacist in breast oncology at the Duke Cancer Institute. I've been there for about eight years and I’m happy to be here.
Dr. Erika Hamilton: Fantastic, thanks for joining us. And Melissa?
Melissa Rikal: Hi, I'm Melissa Rikal. I'm a nurse practitioner at Sarah Cannon Research Institute Oncology Partners and I've been here for 12 years now, working primarily with breast and gynecologic cancer patients in our research program.
Dr. Erika Hamilton: Fantastic. So, this is part one of a three-part series on team-based care in breast cancer. Our first case will focus on the nuances of treatment selection and shared decision-making when managing a patient with hormone receptor positive HER2-negative breast cancer whose disease has progressed on endocrine therapy in combination with a CDK4/6 inhibitor. I'm going to present this case.
AH is a 44-year-old white female who was diagnosed with de novo metastatic ER/PR-positive HER2 1+ but non-amplified breast cancer. And this was back in 2021. At that time, she had disease in her liver and her lymph nodes as well as in bone. She was initially started on leuprolide for ovarian suppression in combination with letrozole and palbociclib in 2021. She ended up having a total abdominal hysterectomy and bilateral salpingo-oophorectomy to be able to get off of the leuprolide shots in 2022. And then she stayed on letrozole and palbociclib.
She ended up undergoing one dose reduction of palbociclib, but tolerates this well with only Grade 1 fatigue. She presents to us with worsened right hip pain and increasing right upper quadrant fullness, which she really describes as an aching-type pain. Imaging reveals progression in her bones and two new liver lesions that are about a centimeter and a half. She's had good disease control now for 5 years on endocrine therapy in combination with a CDK4/6 inhibitor.
So, what would we want to know about her cancer now? Melissa, what are you thinking?
Melissa Rikal: So, moving on to second-line therapy, I think the key in our ER-positive breast cancer patients, particularly when we know they've had good disease control and they're still endocrine sensitive, we're thinking about what endocrine pathway we can do next. We're looking at a mutational analysis ideally. Often we're doing those with liquid biopsies now because of the fast turnaround time. And generally those show us the mutations that we're looking for. So maybe an ESR1, maybe a PI3 kinase mutation, PTEN, AKT, BRCA, all those are pathways we can utilize to target the mutation in their cancer and most effectively treat with next-line therapy.
Dr. Erika Hamilton: Fantastic. Heather, anything to add there? Do you see most often tissue being sent for profiling or liquid biopsies?
Heather Moore: That's a great question. I would completely echo everything that Melissa mentioned. I think at this point, just because they're less invasive, more convenient, we think about the time that it takes for them to come back, we also tend to defer to a blood biopsy at that point so we can send it off. And usually we can have those back within about a week where if you think about the time to schedule and get a tissue biopsy, by the time you're sending that off and getting that back, it does tend to be a little bit of a lag. I would completely agree.
Dr. Erika Hamilton: Yes, I agree with you guys as well. The other advantage of a liquid biopsy is it gives us a little bit better snapshot of what's occurring in the body as a whole, as opposed to putting in a needle in one discrete lesion where that lesion may not have a particular mutation, but other lesions had we biopsied, those do. I think the data really shows that we get a better snapshot of all mutations that patient may have by using blood-based testing as well.
So, our options here, we get this back and her liquid NGS returns with the p53 mutation, very common to see that in cancer, as well as an ESR1 mutation. She does not have a PI3 alteration. So Melissa, what options would you be thinking about now for treatment? There are a lot of options here in the second-line setting for ER-positive disease.
Melissa Rikal: So probably thinking about maybe elacestrant or imlunestrant next line. And Erika, I might let you talk a little bit about maybe some new news that we could use for this patient as of today.
Dr. Erika Hamilton: Yes. So, we are recording this on May the 1st of 2026. Hot off the presses today was approval of a third agent for ESR1 mutant breast cancer, vepdegestrant. This is a little bit of a different drug because it's a PROTAC or a proteolysis targeting chimera. You can functionally think about it as a degrader, but it really degrades in a different way by using the E3 ubiquitin proteasome system. This data was presented at ASCO last year. Again, it's oral, very similar to elacestrant and imlunestrant, but really great safety data with this compound. Very infrequent for patients to discontinue this due to side effects, 3%, and very infrequent for any reductions, 2%, in the VERITAC-2 trial. So it’s very well tolerated. And in this trial, we saw more than a doubling in progression-free survival among patients that had ESR1 mutations. So I completely agree with you, Melissa.
In terms of single agent endocrine therapies, we have imlunestrant, we have elacestrant, and now we also have vepdegestrant. Heather, any other therapies you see in this setting?
Heather Moore: I think what we're all hoping for maybe now in the upcoming time is maybe combination therapies. I don't know about you guys, thinking about EMBER-3 and a combination with CDK, but I think in this space, that's kind of where we are. I think often is when we have, especially now having three options, is really thinking, is there one that you may choose over another? I think that side effects are pretty similar, maybe a little bit of variance in terms of the trial. Something I often think about is elacestrant with EMERALD, 30% of those patients had prior fulvestrant, whereas when we think about EMBER-3 and imlunestrant, they excluded patients with prior fulvestrant, so that’s something to think about. I think side effects between imlunestrant and elacestrant are otherwise very similar. In clinical practice, I think we've seen that they're overall tolerated very well, very excited about vepdegestrant coming to clinical practice.
So I don't have any experience with that one yet, but otherwise I tend to think more about side effect profile access for patients and kind of more along that line for patient-specific factors.
Dr. Erika Hamilton: Yes, fantastic. The other options that we can think about, I think for a patient that has an ESR1 mutation, are options for combinations that don't require a mutation. So we have fulvestrant and abemaciclib approved based on postMONARCH. We also have an oldie but goody endocrine therapy in combination with everolimus, which particularly after the SWISH study is much better tolerated and we see that being given a lot. Melissa, we participated obviously in the clinical trials for VERITAC-2 and have treated a lot of patients on vepdegestrant. Any pearls? What's your experience? How do patients tolerate vepdegestrant?
Melissa Rikal: Honestly, I feel like it's similar to our other SERD-type drugs, really well tolerated in our patients. Easy dosing, well tolerated. We saw good responses, so it’s really exciting to have this additional option.
Dr. Erika Hamilton: Fantastic. So, in this case, this particular patient had elected to start single-agent imlunestrant. Our pharmacy provides handouts, increased patient education, and we also have a nursing callback system where nursing called the patient one week into treatment, and she reported that she was tolerating this quite well.
Heather, I might come to you. In terms of monitoring for imlunestrant, we certainly think about monitoring liver function tests, lipid profile, and then drug interactions we want to look at. But in terms of symptoms, what do you counsel patients on the common symptoms they might experience in terms of education for that?
Heather Moore: Great question. I think that generally when I see patients, we discuss nausea being probably one of the biggest ones. I will say that when we think about nausea that was reported within clinical trial, and I'm not sure about you guys, but what we've seen anecdotally in clinical practice is that patients have actually tolerated this very well. I haven't really seen the nausea translate from clinical trial into clinical practice, but I do think that is something that we focus on. So, strategies in terms of if they're having nausea, if they could schedule antiemetics beforehand or making sure that they're taking it with food. I think the other thing is fatigue, knowing that sometimes you may notice some increased fatigue initially as patients adjust to therapy. So, over the first or second cycle, it does tend to improve over time. And then often side effects that we think about with these types of therapies in terms of hot flashes, bone aches.
Though, I mean, again, I don't know about you guys, but I found that with the oral SERDs that anecdotally we've seen that they're tolerated much better than what we think about with our aromatase inhibitors. It's something that I mentioned, but honestly I find that within the real-world space, those symptoms are often improved. I think sometimes it can also be helpful just from a drug interaction perspective. So, we talked about lipids, making sure that you have lipids at baseline, but then just also making sure if there are other medications. These are CYP3A4 substrates. So, if there's anything that could increase concentrations, and being mindful of labs at baseline in case there are any dose modifications that are required, or also medications that may bump liver function test and being mindful of that with our monitoring.
Dr. Erika Hamilton: Fantastic. So for case one, let's leave you with a few key clinical takeaways. Patients who have benefited for at least 12 months on first-line endocrine therapy in combination with CDK4/6 are really the patients that we think about as being appropriate for further lines of endocrine therapy in the metastatic setting. Many options exist in second-line ER-positive metastatic breast cancer, and the choice between these agents really is driven by mutational status in these patients—ESR1, PIK3CA, AKT, PTEN, and even BRCA alterations. Education around options for treatment and the importance of mutational testing requires a team-based approach. And now there are three FDA-approved options in this space, two oral SERDs and one PROTAC for patients with ESR1 mutations.
Thanks so much for a great discussion. This brings us to the end of this case. Please see our other two videos for further discussion about the latest research in breast cancer at JADPRO.com.
