Patient Case 1: Mutated ESR1 in HR+/HER2- Metastatic Breast Cancer
Centering discussion on the first patient case, panelists reflect on the importance of ESR1 mutation in the setting of HR+/HER2- metastatic breast cancer.
Transcript:
Joyce O'Shaughnessy, MD: Thank you, thank you, guys. I think that really sets the stage really very nicely. We can get into the first case of a patient that we're going to really make some potential recommendations based on the genomic alterations in her cancer. This is a hormone receptor positive, HER2-negative metastatic breast cancer patient. So, she is 57 years old, postmenopausal with a personal history of breast cancer., presenting with sternal pain on a follow up appointment. So, she was initially diagnosed at age 49 with stage one HR-positive, HER2-negative breast cancer. And she was treated…she only needed at that time adjuvant tamoxifen. So, she received 5 years of adjuvant tamoxifen and then she stopped, and she finished up the therapy approximately going on 3 years ago. So, she has had a fairly long disease-free interval. She hasn't recurred early, kind of medium; this is kind of medium, isn't it? But she comes in with some midsternal tenderness with an elevated alkaline phosphatase and bone scan indeed shows uptake in sternum, scapula, lumbar spine, iliac crest. And then additionally, CT scans show bone and liver metastases and she has a biopsy of the liver metastasis, and it's shown that it is estrogen receptor positive, HER2-negative metastatic disease in her liver and presumably bone. And NGS is sent on that liver biopsy and it comes back negative for actionable mutations. And so, she's in the first-line setting now. Not sure an actionable mutation would change things for her right now, but still, nonetheless, nothing was really obvious there for targeting later on. Good performance status, a PS [performance status] of 1. So, she's treated with ribociclib and letrozole as first-line therapy, and she gets about 16 months of benefit, which is a little bit on the short side, and CT scan shows progression in her liver and bones. She's got a new lesion in her liver, but also the bone is progressing. So now she has ctDNA testing, which now reveals an ESR1 mutation that wasn't present, apparently, in at least that part of the liver biopsy that was initially biopsied. So, she is then started on the new oral SERD, selective estrogen receptor degrader, elacestrant, which is a once-a-day drug. And so let's talk about ESR1 mutations. What are they? Why are they important? Why do we test for them? How do we test? When do we test for them? Do we test by themselves, go looking for it, or are they part of a panel? And what's kind of like the prognosis? What's the clinical implication? So Komal, what do you think about, tell us your thinking about ESR1 mutations.
Komal Jhaveri, MD, FACP: Yeah, absolutely. So, I think one thing that we learned about ESR1 mutations is that when we test the primary tissue, they are not very prevalent. They are very, very rare, about 1% to 2% at best. These are actually occurring under the selective pressure of therapies in the metastatic setting, so this is why we've seen that under the selective pressure of aromatase inhibitors specifically, we've seen these mutations develop, which then leads to ligand-independent but estrogen-dependent pathway activation. And another way of saying that is that the tumor is ER-dependent, just ligand-independent. And so that happens under the selective pressure of aromatase inhibitors. So when we looked at trials such as the MONALEESA-2 [NCT01958021] trial, which was a first-line ribociclib study in postmenopausal women, and we looked at baseline cell-free DNA, we saw that these alterations were about 4%. When we then tested many other data sets, which was in the pretreated setting, so in the second/third-line metastatic settings, we're seeing that with cell-free DNA, we had about 40% to 50%. So. this is not a trivial alteration to find in our patient population with ER-positive breast cancer. In fact, using our own in-house, next-generation sequencing assay in the tumor, MSK-IMPACT at Memorial, when we looked at the tumor tissue, it's 20%. I think the point here is that these are subclonal mutations, so if you do just a single biopsy from 1 site of the tissue, you might miss distinct metastatic sites that might harbor these mutations, which you might be able to capture in cell-free DNA, because that's a reflection of your tumor burden, all metastatic sites, and not necessarily a reflection of one site. And so, you want to test them in the path. And now we have a therapy which is specifically approved. So elacestrant, based on the EMERALD [NCT03778931] trial, got approved specifically in ESR1-mutant tumors. And the reason it got approved in ESR1-mutant tumors was because the differential benefit or the delta of benefit here was stronger or more pronounced than the all-comer patient population. So, if you identify an ER-sensitive tumor or an ER-dependent tumor, and this is one of the surrogates of ER dependency, especially because post-CDK4/6 it is so heterogeneous and there's so much happening in the tumor biology that we don't necessarily completely understand yet. And this is one way of identifying an ER-dependent tumor. You identify that in the plasma. Guardant360 is the approved companion diagnostic for it. So post-CDK4/6, I do tend to test for ESR1 mutations, so I can either assign them to a clinical trial if I have a combination trial for a novel endocrine agent such as an oral SERD [selective estrogen receptor degrader] or others, or single agent or combination, or offer them elacestrant. And that would be applicable for the case that you just were discussing, who after 16 months, which is rather short, as you pointed out, but perhaps still OK and appropriate given the exploratory analysis that was presented from the EMERALD trial, kind of suggesting that those patients who stayed on the first-line CDK4/6 for 12 months or longer, had a PFS of slightly longer than 8 months with single-agent elacestrant, which is well tolerated. So I think that's where I think about ESR1 mutations. In terms of prognosis, I think we know that they carry a prognostic significance. So tumors that harbor this mutation have a slightly worse prognosis. If you have more than one ESR1 mutation, it's worse prognosis than somebody who has only 1 ESR1 mutation. So that's relevant. And as we would imagine, it has predictive implications as well, meaning we know it happens under the selective pressure of aromatase inhibitors. So you're not going to necessarily benefit from, say, exemestane, a steroidal AI, upon progression on a nonsteroidal AI. And that's why you think about SERDs. And while fulvestrant can be active, some of these alterations, for example Y537S, is 1 example where fulvestrant might not have the best activity. But we've seen activity with novel SERDs and novel endocrine agents that are in clinic in late-phase developments. And elacestrant is one of them that is already approved. I think there are many benefits to identifying these alterations. They're common. They're prognostic. They have predictive capabilities, and this can really help assign the right therapy to a given patient in clinic.
Transcript is AI-generated and edited for clarity and readability.
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