Neil M. Iyengar, MD, on Co-Occurring Mutations in Advanced Breast Cancer: Management Strategies

I'm now going to move to case two. Let's start with another case that again, I think presents a common situation that we need to address in clinic. And these are patients who are found to have more than one mutation in their next generation sequencing. So in this particular case, this was a 67-year-old postmenopausal female who presented with de novo hormone receptor positive HER2-null metastatic breast cancer, and she had bone predominant metastatic disease with some low volume small liver metastasis as well. She was otherwise healthy, mild hypertension, no diabetes, and a biopsy of one of the liver lesions demonstrated invasive mammary carcinoma that was estrogen and progesterone receptor positive and HER2-null. She had a good performance status, ECOG of one, and initially her molecular testing revealed no actionable biomarkers. Now, in the first line setting, she went on to get aromatase inhibition plus ribociclib, the current standard of care in the first line setting, and she did well with that. She had a clinical benefit for 22 months. Unfortunately then, imaging demonstrated progression in the bone and in the liver. She had growth of some of the preexisting lesions, and she underwent liquid ctDNA testing, which now revealed an ESR1 mutation, but it also revealed a PIK3CA mutation as well. I use this case as an opportunity to point out that sometimes, although we think of PIK3CA alterations as truncal alterations and that are present as oncogenic drivers typically in the primary breast tumor, sometimes we pick up PIK3CA alterations later down the road, and this might be due to tumor or clonal heterogeneity, but we've also seen in some of the frontline CDK4/6 inhibitor trials that a higher proportion of patients, around 10%, are found to have a PIK3CA, a new PIK3CA alteration after their first line CDK4/6 inhibition, and that's what happened in this particular case. And so now in the setting of co-mutations in PIK3CA and in ESR1, we're faced with the question of do we target one of these mutations? Do we target both of these mutations? So I want to start by reviewing some of the resistance mechanisms in hormone receptor positive HER2-negative metastatic breast cancer. And of course, there are several mechanisms that are summarized here on this slide, but certainly we know that ESR1 mutations do develop under the pressure of aromatase inhibition as a resistance mechanism to aromatase inhibition. But in addition to ESR1 mutations, we also know that alterations in the so-called PAM pathway, that's the PI3K/AKT/mTOR signaling pathway, can also confer resistance. And here you can see some of the frequencies of these alterations. This is typically in the upfront setting, so that ESR1 frequency of 16% is lower than what we would see in patients who've been on an aromatase inhibitor for a longer period of time. But you can see there that PIK3CA alteration is about 40%, and again, that's because the alterations in PIK3CA tend to be stable and detected at the time of diagnosis. And so these alterations, again, raise the question of do we need to be targeting all of these alterations at once if we have co-mutations or can we use a sequencing strategy? Well, we certainly have an explosion of novel ER targeting agents, and the oral SERDs represent a really exciting class, not only in terms of the mode of delivery, oral rather than intramuscular, but also their superior activity in the setting of an ESR1 mutation. And this slide is really summarizing some of our legacy and novel ER targeting agents, and certainly the oral SERDs you can see listed there with elacestrant as our first approved oral SERD in this space is really an exciting and progressive area of therapeutic targeting in metastatic breast cancer. Now, we've also seen more approvals and ongoing trials that are testing agents that target the PAM pathway and specifically PI3-kinase inhibitors, AKT inhibitors, and so forth. And so on this slide, you can see a summary of some of the key trials that have tested PAM pathway inhibitors, including PI3-kinase inhibitors, AKT inhibitors, and so forth. And what I'd like to point out here is that there is a heterogeneity of patient population. In some of these earlier trials, like SOLAR-1, for example, there were only a few or a handful of patients, if any, who received CDK4/6 inhibitors in the first-line setting, and so you have to keep that in mind, of course, as you interpret the progression-free survival data. And as we look at this median PFS, again, being cautious about comparing patient populations here, I think it's important that we also balance the toxicity profile of PI3-kinase and PAM pathway inhibitors. This next slide summarizes some of that, again, across the key trials in this space, and certainly we know that hyperglycemia can be an issue with some of the earlier generation PI3-kinase and AKT inhibitors, but so too can be diarrhea, mucositis, and rash, and there are some strict inclusion criteria with regard to hemoglobin A1C and other considerations. And so when thinking about patients who have co-mutations in ESR1 and in PI3-kinase, I think one of the key questions is the risk-benefit ratio of exposing patients to PAM pathway inhibitors. We have seen some subgroup analyses in the oral SERD trials that have tried to address this co-mutation question and assess the efficacy of monotherapy with an ESR1 targeting agent such as an oral SERD in the setting of co-mutations in ESR1 and PI3-kinase. This next slide is showing a subgroup analysis from the phase three EMERALD trial, which of course was the trial that led to the registration of elacestrant, the oral SERD in hormone receptor positive metastatic breast cancer. And this subgroup analysis looked at patients with mutations in ESR1 and PIK3CA, and you can see the median progression-free survivals listed here. Certainly, we still see a benefit with elacestrant over standard of care therapy, even in the setting of co-mutations in ESR1 and PIK3CA. But I think it's also important to keep in mind as a benchmark, the median PFS here, for example, of 5.45 months in the elacestrant group for patients that had an ESR1 mutation and PIK3CA mutation, as we think about the PI3-kinase inhibitors that have demonstrated a similar range of progression-free survival, perhaps at the expense of greater toxicity. And so there may be a subset of patients who we wish to spare that toxicity and present an oral SERD monotherapy option as a way to balance efficacy with toxicity. Of course, there are ongoing trials that are testing combination strategies with the SERDs, and we've seen data, for example, phase two data from the ELEVATE trial, which is testing elacestrant with various molecular therapy partners. And so the treatment landscape continues to evolve, and we will likely see more and more combinations in the setting of co-mutations. And so here is a current snapshot of what the treatment landscape currently looks like in hormone receptor-positive metastatic breast cancer. And again, this is rapidly evolving, but it's really a biomarker-driven approach, and we're seeing a lot of single agent as well as combination therapy options, particularly in the second-line setting. And again, I think we really have to ask the question of how do we balance therapeutic efficacy with toxicity and adverse effects as well as on target off tumor effects, for example, of PI3-kinase inhibitors for treatment selection. And I think ultimately, it really comes down to a shared decision-making model with our patients. We, as oncologists, certainly need to make a treatment recommendation, but we also need to take into mind what matters for our patients, what works in their lifestyle, and what doesn't work in their lifestyle to ultimately select the most appropriate and individualized treatment for that patient.