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My name is Seth Wander, and we'll be talking today about personalizing therapy and estrogen receptor positive, HER2 negative metastatic breast cancer via biomarkers and evidence-based decision making. Here are my disclosures. And so the objectives for today's session will be to interpret biomarker results, for example, ESR-1, PPIC3CA, and HER2 status in the context of therapy eligibility, to determine when to perform molecular testing in the metastatic setting, and to integrate biomarker data into treatment decisions using real-world examples and clinical trial evidence. Let's start with a clinical case. This is a 65-year-old patient with hypertension and poorly controlled insulin-dependent diabetes. The performance status is one. She presents with back pain and a breast mass. Diagnostic imaging reveals a 3.5 centimeter right breast mass and regional adenopathy. The PET CT has multiple bony lesions. The bone biopsy confirms metastatic breast cancer. Estrogen and progesterone receptors are positive. HER2IHC is 1+. Baseline CTDNA testing reveals a PIC3CA H1047R mutation. So, this patient presents with de novo metastatic hormone receptor-positive, HER2 low breast cancer. She receives first-line therapy with letrozole and ribocyclib and has an excellent response lasting more than 4 years. She then has new progression in the bone with several new liver lesions, but liver function tests are normal. Repeat CTDNA at the time of progression confirms the original PICC3CA mutation as well as a newly acquired ESR1D538G mutation. Which of the following would be the best second-line therapy for this patient? Folulvestrant, Fulvestrant with alpeliib, Elisestrant, or trastuzumabdoxican. And we'll revisit this later on and we'll be able to uh approach the data and answer to this question. So, this is the outline for our discussion today. I wanna start by talking about new therapeutic options for endocrine resistant breast cancer. So we'll start with resistance to anti-estrogens and CDK46 inhibitors. As we saw in the case a moment ago, PICC3CA mutations tend to be early events. They're often there at the time of diagnosis or metastatic progression. So, regardless of how you test the patient, whether it's a solid tumor biopsy or a circulating tumor DNA assay, we tend to find these alterations and we call them truncal because they're there at the trunk of the tree. ESR1 mutations, on the other hand, are very rare in untreated or primary breast cancer, typically with a frequency of less than 5%. They tend to arise under selective pressure on an aromatase inhibitor. And so we call these alterations acquired, and they can reach up to 25 to 40% frequency in the 2nd and 3rd line metastatic setting. Here on the right-hand side, the color coding is off a little bit, but you can see all of the different shades, uh, uh, are different genetic alterations identified in, in this patient. This patient at the time of meta metastatic diagnosis, uh, she had a PICC3CA alteration but no ESR1 mutation. She did well for uh two years on aromatase inhibitor therapy and then had a number of new acquired alterations that you can see on the right, including an ESR1D538G mutation. On the bottom, we see a schematic of the uh ESR1 gene, which encodes the estrogen receptor. Most of the mutations that we'll be discussing today occur in the ligand binding domain of the protein. These mutations result in constitutive activation of the estrogen receptor in the absence of ligand. So it's quite a clever evolutionary tool that the cancers use to find their way around aromatase inhibitors. Remember, the aromatase inhibitors deprive the body of estrogen. These mutations then allow the receptor to turn on even in the absence of estrogen. And so that's why they tend to occur after AI therapy. Now, we also have done a lot of work, our team and many others, looking at molecular drivers of resistance to both anti-estrogens and CDK 46 inhibitors. And the take-home message here is that there's no single, um, uh, particularly common alteration that drives resistance to CDK 46 blockade. Here, we see a number of alterations in pathways that regulate cell cycle progression. For example, um, uh, amplification of cyclin E, activation of CDK2, loss of RB, activation of aurora kinase, upregulation of CDK6 expression, all of which can provoke resistance to CDK46 inhibitors. We also see activation of various oncogenic signaling pathways, including the RASMA kinase and the AKTMTOR pathway. So here we see a number of different potential targets to overcome CDK 46 blockade. Next generation CDK-2 inhibitors, next generation aurora kinase inhibitors, uh, MC and ERC inhibitors, RAS inhibitors, AKT inhibitors, FGFR inhibitors, and Um, all of these are under various stages of, of clinical development for patients with, uh, CDK 46 refractory ER positive metastatic breast cancer. Many of these alterations also convey resistance to the anti-estrogen component of the regimen, uh, in addition to the ESR-1 that we were just speaking about. So let's talk about some of these new anti-estrogen agents, some of which have already entered uh clinical practice and others are, are well on their way. This is a really nice review that was published a couple of years ago, highlighting the different classes of, of, um, estrogen blockers and estrogen down regulators uh that are in clinical development phase 1 through phase 3. On the left-hand side, you see the drugs that we've been used to using over the last 20 years, the aromatase inhibitors, which we just spoke about, the selective estrogen receptor modulators like tamoxifen and the emerging drug lasafoxopen. These bind the receptor and modulate their uh the receptor activity in a tissue-specific manner. We have the selective. Estrogen receptor degraders that bind the receptor and help target for degradation. We have the proteolysis targeting chimeraveptgestrin, which we'll talk about in a moment, that also recruits the degradation machinery of the cell in a slightly different way than the SERDS. We have the complete ER antagonists, the serans and the selective ER covalent antagonists, the circas, that are also moving along in various stages of clinical development. Today we're going to primarily focus on the next generation oral SEDS and the Protac. Now, here's data from the EMERILD trial. Uh, this was a phase 3 prospective study for postmenopausal women and men who had had up to 1 prior line of chemotherapy, 1 to 2 prior lines of endocrine therapy. They had to have progression on the CDK 46 inhibitor. Now, we're gonna, uh, commit the, the that we tell all of our fellows never to do, uh, which is to compare across phase 3 clinical trials because unfortunately, we have to do that in clinic when we're making these decisions. And when we're looking at the data over the next couple of minutes, I, I want you to just keep in mind some of these criteria. Did the trial allow prior chemotherapy? How many lines of prior endocrine therapy were allowed? Did the trial require or simply allow prior CDK 46 resistance? And what you'll see is there are some important differences between these trials. And in my opinion, the Emerald trial was actually the most heavily pre-treated of all of the phase 3 next generation anti-estrogen trials that we're going to review. Almost 20 to 25% of these patients had prior chemotherapy. Nearly half of them had an ESR1 mutation, and 40 to 50% of them had two prior lines of endocrine therapy. So, uh, quite heavily pre-treated. Almost 500 patients were randomized to endocrine therapy of clinician choice, either an aromatase inhibitor or fulvestrant, or the oral SERD eliestrant. The primary endpoint was progression-free survival. And here you can see the curves. Now, the other The thing I want you to remember as we're moving through these trials is the shape of these curves. You can see there's a steep drop, somewhere between 30 and 40% of patients, regardless of which line they're on, uh, have really complete, um, refractoriness to endocrine therapy in this setting. Then the curves begin to separate, and then we see a little bit of a tail where there's a small number of patients who are actually doing really well for years on endocrine monotherapy. And we'll start to dissect these populations in a moment. What you can see here is in the overall study population, there was a very small difference between the two curves, an improvement from about 1.9 months to just under 3 months with Eliestrant. But on the right-hand side, if you look at the subpopulation of patients who have ESR1 mutations, the curve uh separates a bit further from 1.9. 9 to almost 4 months of benefit. And again, here, the hazard ratio dropped from 0.7 to 0.55 with a highly significant P value. Based upon this data in the United States, Elisestrin was approved in patients who had had a prior endocrine therapy and harbored ESR1 alterations in the metastatic setting. Now, the authors went on to look at specific subgroups, not just whether or not they had ESR1 alterations, but how long uh they had benefit from the first-line endocrine and CDK46 inhibitor therapy. And here again, you can see these are ESR1 um altered uh patients with at least 6 months, at least 12 or at least 18 months of prior CDK46 inhibitor therapy. When you enrich the population for those patients who had at least a year on their first line. Endocrine and CDK therapy, the curves separate even further, uh, now from about 1.9 up to almost 9 months. And so, in clinical practice right now, most of us are thinking about deploying Eliestrant monotherapy for patients who have progression on a prior endocrine and CDK 46 inhibitor, who have ESR1 alterations, and who had a prolonged uh prior benefit on that first-line CDK inhibitor of at least 1 to 2 years, based on this data. Now, these oral surgeons are generally well-tolerated. I'm not gonna spend too much time, but I will include these tables just for your reference. Um, here, Eliestrin, very few grade 34 toxicities, as you can see. In my anecdotal experience in clinic, I find these drugs actually to, to be better tolerated, for example, in terms of hot flashes, joint pain. Many of the menopausal type symptoms that we experience. They do um have maybe a signal for slightly more GI toxicity. Here you can see some nausea, um, decreased appetite, uh, a little bit of low-grade diarrhea. Um, but again, uh, most patients are, are tolerating these pills quite, quite well with, with low-grade toxicity, if at all.