Case Study: Weighing Treatment Options for Co-Mutated Metastatic Breast Cancer

Kelsey Martin

Melissa, let’s discuss what we might do if we saw a patient that had a co-mutation in the second line and we needed to weigh a few options for picking that patient's next treatment.  

Let's say you had a patient with ER+ metastatic breast cancer who had progressed on first-line treatment with a CDK4/6 inhibitor and an aromatase inhibitor, and we sent a liquid biopsy test to pathology before choosing a new treatment plan. That patient had both a PIK3CA and an ESR1 mutation. How would we go about deciding what we would give next to someone like that?  

Melissa Rikal

In the second-line setting, we have a multitude of options for patients with ER-positive metastatic breast cancer. We have monotherapies and combination therapies, particularly for patients with mutations. I think for a patient with a co-mutation with a PI3 kinase and an ESR1, we would want to target one of those next.  

We actually have several options when looking at both of these mutations. The one that we've had approval for longest would be alpelisib with fulvestrant. We are using this a bit less now since capivasertib was approved, just because we do tend to see more rash and hyperglycemia with alpelisib than we do with capivasertib. Capivasertib was approved within the past couple of years in combination with fulvestrant, making that now an option for patients with a PI3 kinase mutation.  

Capivasertib is an AKT inhibitor, so it targets any mutation in the AKT/PI3 kinase or PTEN pathway. We do tend to see a similar side effect profile to alpelisib, but the rash and hyperglycemia are in a much smaller cohort of patients than with alpelisib. Diarrhea, rash, and hyperglycemia are the most common side effects notable with this combination strategy.  

Then, elacestrant is another option for a patient with these co-mutations, which would be targeting her ESR1 mutation specifically. Elacestrant is approved as a monotherapy; it is a single-agent oral therapy that's actually quite well tolerated. We can see some mild nausea, skeletal pain, hyperlipidemia, and fatigue, but generally all very low grade and manageable side effects.  

I think we have great monotherapy and combination therapies that we could look at and we're going to have to weigh in several different factors when choosing which one would be best in the second line for this co-mutated patient.  

Kelsey, of these treatment options that I discussed, capivasertib has the more unique side effect profile. How have we managed that in our clinic?  

Kelsey Martin

I think that hyperglycemia is something we have to monitor for these patients. Not all therapies that we give in our clinic cause this, so it's certainly a different problem to address. We start by watching it closely at the clinic visits. There are some patients that will require some at-home blood sugar monitoring with finger glucose sticks—so some patients may need to keep a closer eye on their sugars in that way. If we do need to intervene with their blood sugar, typically we can manage that with metformin and increase the dose if we're not seeing an improvement. If it becomes a big problem and we're still having issues, we can send them to endocrinology and get their opinion as well. But that's been pretty rare in our patients. Something else to keep in mind, though, is if we put someone on metformin to help control their blood sugar, that can also contribute to diarrhea, which capivasertib can contribute to, too. That may be another reason why we keep someone on a lower dose of metformin or reach out to endocrinology sooner to get their opinion because we need to manage both the blood sugar and the diarrhea for those patients.  

In general, when we're making these treatment decisions, we're weighing all the side effects as well as the patient's comorbidities as a whole. We don't have head-to-head trials to know which therapy needs to come first in our algorithm as we're deciding what's best for the patient. Each patient is going to have to be looked at individually to decide what's best for them.  

In a patient that might have diabetes, for example, maybe one of the AKT or PI3K inhibitors is not best for them because their blood sugar may already be an issue that is not well controlled. If they have a malabsorptive gastrointestinal disorder—Crohn's disease or irritable bowel syndrome, something like that—again, they might want to avoid a PI3K or AKT inhibitor because of the diarrhea. Alternatively, someone that already had poorly controlled hyperlipidemia may not be the best fit for elacestrant because of the possibility of having elevated triglycerides and cholesterol. We discuss these considerations with our patients as we're deciding what we think is best for their next line of treatment.  

Melissa, what other things are we considering when choosing these therapies, apart from the side effects and the patient comorbidities?  

Melissa Rikal

Another major consideration would be perceived patient adherence. This would potentially be based on the patient's age, limitations, proximity to the clinic, maybe their health literacy, or their level of past compliance. For example, an elderly patient who may have some mild dementia or age-limiting factors preventing their ability to come in frequently for monitoring, taking multiple doses a day, or having an altered dosing schedule may not be the best fit for an AKT inhibitor like capivasertib that has more of a unique dosing strategy.  

Proximity to the clinic is something we're going to consider, too. If they live hours away, they may not be able to come in monthly for glucose monitoring and their fulvestrant injection. Having more spaced-out visits on something like elacestrant might be easier for these patients.  

Their health literacy is a factor we would consider because we need them to be able to report adverse effects, take their medication properly, and manage dosing holds properly if they're having those higher-grade symptoms. If there's somebody that hasn't been compliant with visits in the past and we know they don't show up regularly for their scheduled visits, then something like monthly fulvestrant, which we want to give on time, might be a lesser consideration than something that they can take at home.  

Kelsey Martin

With so many factors limiting treatment choices, what kinds of treatments and dosing schedules would be recommended for such patients? 

Melissa Rikal

Elacestrant is a little bit of an easier dosing schedule as a once-daily oral agent, dosing continuously. There's no extra lab monitoring required other than ensuring we check their lipid panel every few months, and, obviously, regular labs since this is a patient with metastatic cancer.  

With capivasertib, the dosing schedule is a bit more complicated—twice daily, dosing 4 days on and 3 days off, as well as the monthly injections with the fulvestrant combination. We are going to require more frequent labs with this regimen of regular glucose monitoring, lipid monitoring, etc., every month.  

Another factor we would consider is whether this patient has reliable transportation. Do they have the resources to get back and forth to the clinic? What is their distance from the clinic, and what type of job do they have? Are they traveling regularly where they may not be able to get to the clinic every 28 days because of their work schedule?  

While we are looking at all of these factors in our treatment decisions—patient adherence, side effect profile, and their comorbidities—we also know that some patients would factor in the efficacy data of these treatments when they're making their treatment decisions alongside their oncology team. Kelsey, can you share some of the data from the trials of elacestrant and capivasertib?  

Kelsey Martin

It's true that a lot of our patients might weigh a lot of their decisions based on how this medicine makes them feel, and what the ease of administration is. But there's also just as many who care a lot about how long they can be on this treatment before having to change.

The EMERALD trial was the trial that gained the U.S. Food and Drug Administration (FDA) approval for elacestrant.¹ That showed a 3.8-month progression-free survival for elacestrant vs. 1.9 months for the fulvestrant/aromatase inhibitor arm for patients with ESR1 mutations. This about doubled the progression-free survival for those patients, and then they actually saw, in a subgroup analysis, that in patients who were treated with a CDK4/6 inhibitor and endocrine therapy in the first line for over 12 months, the progression-free survival was even longer at 8.61 months vs. 1.9 months.  

Then there’s the CAPItello-291 trial, which is the trial that led to the FDA approval of capivasertib^.2 It showed capivasertib plus fulvestrant had a 7.3-month progression-free survival vs. 3.1 months in the fulvestrant monotherapy arm for patients with AKT pathway alterations. Again, quite a few months longer for those patients.

Like you said, Melissa, there's some patients who will value those data as they're making their decisions. And then there's others who will ask us, our oncologists, and our team what we think might be best. And so, again, weighing all of these options for these patients is going to be important because there's no one trial or one data fact that helps us decide. It's looking at the whole picture and trying to determine what might be best for this patient and how we sequence their treatments.  

Melissa Rikal

I think in a co-mutated patient, we're using the art of medicine. There's not necessarily a right or wrong answer. It's talking with the patient and collectively deciding what would be the next best second-line strategy. But this personalized approach is how we can aim to give each patient the best possible outcome.  

Kelsey Martin

Agreed. Thank you for discussing these patient cases and treatment considerations with me, Melissa.