Case Study: Metastatic Breast Cancer in the Second-Line Setting

Melissa Rikal

Now we are going to discuss a patient with second-line metastatic ER+ breast cancer. Let's look at a patient case and talk through how we make treatment decisions for this patient.  

Mary is a 61-year-old female with a past medical history of hypertension and type 2 diabetes. She presented to the hospital in June 2024 with pain and possible infection after hip arthroplasty. Imaging showed concern for widely metastatic disease, including a large left breast mass and left axillary lymphadenopathy. Her initial biopsy of the left axilla showed an invasive lobular carcinoma. This was ER+ 95%, PR+ at 5%. HER2 was 1+ by immunohistochemistry (IHC), and fluorescence in situ hybridization was non-amplified with a Ki-67 of 55%.  

So, Mary was started on first-line therapy with a CDK4/6 inhibitor and letrozole; she initially tolerated this and had a great response. However, after about 9 months, she had scans that showed progressive disease, including new liver metastasis. She underwent a liver biopsy showing metastatic adenocarcinoma consistent with her breast primary. ER+ was now 100%, PR+ at 30%. Her HER2 was 1+ by IHC. Ki-67 1% to 5%, and she had a Guardant 360 test that showed multiple ESR1 mutations, a BRAF mutation, MEK amplification, and a high tumor mutational burden. So how would you approach a treatment decision for this patient?  

Kelsey Martin

I think after we see these biopsy and Guardant results, it would make a lot of sense to put her on a second-line treatment of elacestrant. Elacestrant is a second-generation SERD, or selective estrogen receptor degrader. These drugs work by binding to the estrogen receptor and inducing the degradation; it reduces the activity of the estrogen receptors themselves. So these drugs can be really beneficial because they can overcome the resistance mechanisms that some of those cancer cells have built to aromatase inhibitors and to treatments like tamoxifen. Anyone who's had a little resistance to some other endocrine-based therapies can still have a great response to something like elacestrant.  

Fulvestrant is a first-generation SERD, so this is one that's been around for 20 years or so, and it still works great for a number of patients, but there is a little bit of a barrier of having to come in every 28 days for these injections. And so these second-generation SERDs are being developed as oral therapies, which really helps with our patient adherence and tolerance of the drug as it is a new and improved way of delivering the same type of drug, but doing it in an easy way for those patients. Elacestrant is taken once daily and this dosing simplicity really optimizes adherence for our patients. 

Melissa Rikal

That's great that she would be able to continue on an oral therapy. So how would you say a patient like this would tolerate something like elacestrant?  

Kelsey Martin

Well, this patient has really tolerated it well. She had minimal side effects, which is typically what we would see and expect for patients on elacestrant. If patients do have side effects, they're generally pretty mild, but they can range from nausea, fatigue, vomiting, decreased appetite, increased blood triglycerides or cholesterol, to even some muscle pains or myalgias. But both in our clinic and in the studies, the side effects were generally very mild, low grade and not needing a lot of interventions for those patients.  

The study that helped gain elacestrant’s approval was called the EMERALD trial.¹That was a phase III trial that had patients on elacestrant vs. standard-of-care endocrine monotherapy, with a couple different options of physician's choice. The study showed that most side effects with elacestrant were grade 1 to grade 1, so the drug was very well tolerated. And we also saw that progression-free survival was prolonged in all patients, particularly those that had an ESR1 mutation, which is what is required in the standard setting today based on the FDA approval. So it was not required on the study, but it's required now in the post-approval setting. And so those patients certainly had an increased progression-free survival, and the timeline was about 3.8 months of progression-free survival vs. 1.9 months on the fulvestrant/aromatase inhibitor arm. The hazard ratio was 0.55 so we saw a 45% reduced risk of progression of disease. So patients certainly got a little bit longer time on that drug.  

Melissa Rikal

You also mentioned hyperlipidemia as a possible side effect with elacestrant. How often do you monitor this in a patient like Mary? 

Kelsey Martin

Typically, we monitor lipids by conducting a whole lipid panel about every 3 months. And though we can see some mild elevations, we rarely have to intervene with something like a statin. If we can, we avoid adding a statin just because of the side effects with that class of drugs itself. It could be that a patient already has hyperlipidemia and so they're on a statin. We might choose to increase the dose. That certainly could happen, or just encouraging a diet change to keep their lipid panel pretty stable. But generally, every-3-month monitoring is adequate.  

One thing that we will keep in mind though, is if we see the elacestrant get approval in the adjuvant setting, as was studied in the ELEGANT trial, we may get a little bit more aggressive in treating hyperlipidemia because our adjuvant patients and patients with early breast cancer would typically have a much longer life expectancy than our metastatic patients. So we may want to be a little bit more aggressive with making sure that their blood triglycerides and cholesterol are at much more manageable levels.  

Melissa Rikal

Thank you for sharing those management strategies, Kelsey. Are there other drugs that we should be on the lookout for in this class, or other oral SERDs that are on the horizon?  

Kelsey Martin

That's a great question. The exciting thing about this patient population is that there are a lot of treatments in development now that hopefully will have some FDA approval in the coming years. So elacestrant was approved in 2022, but there are still a number of other second-generation SERDs and trials at various stages across the country. And so there could be other approvals here in the coming years. And then there's also a number of trials that are enrolling that have different combination therapies with SERDs, so those might be beneficial with different medications like CDK4/6 inhibitors, or things like everolimus.  

There are potentially going to be other options where patients can receive these oral SERDs but have them in different combinations or in different varieties so that they could stay on these oral therapies and hopefully elongate their time on endocrine therapy instead of having to move over to something like chemotherapy for those patients. So it really opens the doors to a few more options for our patients, which is certainly exciting for us.  Are there any of these next-generation oral SERDs that you are particularly excited about Melissa?  

Melissa Rikal

We have certainly seen great tolerance with some of these SERDs in our own clinic. We have had multiple trials with camizestrant and have seen great tolerance with this SERD, too, thus far. Phase III SERENA-6 study data were released earlier this year showing positive results for camizestrant in combination with a CDK4/6 inhibitor first line with a statistically significant improval in progression-free survival. The progression-free survival was 16.0 months witih camizestrant vs. 9.2 months with an aromatase inhibitor, with a 56% reduction in the risk of disease progression or death. ² Some other SERDs that are in clinical trials and we will likely see FDA approvals for in coming years include imlunestrant, amcenestrant, and giredestrant. I am so excited for our patients to have more oral SERDs available to them due to the ease of dosing for these agents, improved progression-free survival, and the opportunity to extend our patients’ endocrine options for longer.  

Kelsey Martin

That’s a great look ahead, Melissa, and a bright future for our patients. New, easy-to-use treatment options are always greatly appreciated to be able to offer our patients more options.