Neil M. Iyengar, MD, on Testing for ESR1 Mutations in ER-Positive Breast Cancer

Hi, I'm Neil Iyengar. I'm breast medical oncologist at the Winship Cancer Institute of Emory University in Atlanta, Georgia. And in this series, we'll be talking about ESR1 mutations, both in terms of testing strategies as well as treatment targeting as well as therapeutic selection for our patients with hormone receptor positive metastatic breast cancer. Now, this is certainly an evolving, a rapidly evolving space, and we're learning new data, I would say, by the week. So the treatment landscape is certainly changing, but I do think that there are some key principles that we can keep in mind as we embark on treatment selection for our patients. Let's start with a case, which I think is a frequent situation that we commonly see in clinic. This particular case was a 55-year-old postmenopausal female with de novo hormone receptor positive metastatic breast cancer. She was found to have multiple hepatic lesions and a biopsy of one of those liver masses showed invasive mammary carcinoma that was hormone receptor positive with an ER percentage of 85%, PR at 25%, and HER2-IHC 0, in other words, HER2-null. Now she had a good performance status, ECOG performance status of one and otherwise pretty healthy, some mild hypertension, no history of diabetes. Next generation sequencing was also performed on the liver mass biopsy and it was negative for any actionable mutation. So this patient was started in the first line setting with our current standard of care, and that was endocrine therapy with an aromatase inhibitor plus a CDK4/6 inhibitor, specifically ribociclib. So she did well on this treatment. She had a clinical benefit for about 20 months, but her subsequent scan unfortunately showed enlargement of several of the preexisting liver lesions as well as a new lesion in the lung. Now at this time, she also had a liquid ctDNA assay that was measured, and this revealed a new mutation in ESR1. So now she comes in to discuss the treatment recommendations for her next line of therapy. So this of course highlights what we do in terms of treatment selection for patients who are found to have an emergent or new ESR1 mutation. And I'll start by saying that the landscape for endocrine targeted therapies in ER-positive metastatic breast cancer continues to evolve. And certainly in the first line setting, our standard of care remains CDK4/6 inhibition with endocrine therapy. And now with the caveat that we're using a biomarker-driven approach even in the first-line setting for a subset of patients with aggressive disease with a PIK3CA alteration. And so this really drives our biomarker testing strategy. Typically, we're testing for molecular alterations at the time of metastatic diagnosis, and the paradigm really has been to test again at the time of progression or when you're trying to decide on treatment selection for subsequent lines of therapy. And so in terms of our available endocrine-based therapies, of course we have our legacy treatments with aromatase inhibitors and injectable SERDs such as fulvestrant, but we're of course now seeing novel SERDs, oral SERDs, even novel SERMs and other anti-estrogen therapies such as PROTACs and CERANs. And these all, of course, work to modulate estrogen signaling in the breast cancer cell. In addition to this, we have molecular therapeutics. I mentioned PI3-kinase targeting, we have AKT targeting, and we have PAM, PAM pathway targets now as well, as well as several molecular therapies in the pipeline. But let's focus on ESR1 here because this is really one of the most common drivers of endocrine therapy resistance. In fact, it's estimated that up to 50% of endocrine therapy resistance is due to the development of an ESR1 mutation. Now we know that ESR1 mutations typically develop under the selective pressure of endocrine therapy with an aromatase inhibitor. And the implications of this mutation is that it really then transforms the confirmation of the estrogen receptor into a constitutively activated confirmation that then turns on downstream proliferative signaling. And so targeting the ESR1 mutation from a molecular standpoint makes sense as a potential opportunity to overcome treatment resistance. We also know that ESR1 mutations are associated with poor prognosis, and there have now been several studies which have looked at either completed phase three trials or registry data indicating worse outcomes for patients who are found to have an ESR1 mutation in the tumor cell as opposed to those that are ESR1 wild type. And so for example, if we look across several of the completed trials in metastatic ER-positive breast cancer, we see that patients with an ESR1 mutation have shortened progression-free survival and overall survival compared to those without ESR1 mutations. And this again highlights the need to identify the ESR1 mutation and certainly to target the ESR1 mutation. Now, in terms of methods for testing, molecular testing to identify the ESR1 alteration, of course there's liquid testing, as I mentioned, through circulating tumor DNA as well as tissue testing, next generation sequencing on the tumor sample as well. We've seen several studies such as this one which have demonstrated excellent concordance between tissue testing as well as ctDNA testing. And in fact, ctDNA testing may pick up a higher proportion of patients with molecular alterations than tissue testing. I think this is likely due to tumor heterogeneity as well as metastatic site heterogeneity. And certainly for a dynamic mutation such as the ESR1 mutation, liquid testing offers us the opportunity not only for more frequent testing, but to identify mutations that may be heterogeneous across clones or metastatic site. And so this study here is demonstrating not only good concordance for mutations like ESR1 and others between tissue and circulating tumor DNA, but it also suggests that we may be able to detect more actionable variants in the metastatic setting if we do tissue and liquid testing concurrently. Now, we also know, as I mentioned, that mechanisms of resistance evolve based on the therapies that patients are exposed to, and certainly this is the case for ESR1 mutations here. And this is why a liquid assay such as ctDNA offers the opportunity to identify clonal evolution in real time. And that's the essence of what this slide is showing you here is that with selective pressure over time of aromatase inhibition, a subset of the tumor clone or cancer clone can develop the ESR1 mutation and then that becomes the dominant clone. And so our historic paradigm really is to test for these alterations at the time of progression because certainly at the time of progression, the dominant clone should identify which mutations are really driving the resistance. However, more recently, we of course have seen a new approach to monitoring for the emergence of ESR1 mutations, and this was tested in the seminal SERENA-6 trial where liquid assays for identifying emergent ESR1 mutations were conducted every two to three months in patients who were on their first line therapy for hormone receptor positive metastatic breast cancer. This was after being stable on that first line therapy for at least six months. And what you can see here is that a large number of patients underwent surveillance in the SERENA-6 trial, over 3,000 patients, and of those patients, 548 were found to have an ESR1 mutation. Half of those patients were found to be positive for the ESR1 mutation on the first test. And so I think that this raises the question of who should we be doing serial ESR1 mutation testing in circulating tumor DNA versus who are those patients where we can do testing only at the time of progression? And I think this really requires individualized decision making with our patients and a degree of shared decision making as well because certainly frequent testing may lead to increased anxiety and other considerations from the patient perspective that is important in this decision making. And so in this new paradigm of monitoring for the emergence of resistance mutations, circulating tumor DNA assays certainly make this feasible. But I think what we really need to do is ask ourselves which population of patients should we be monitoring and which population of patients can we get away with just assessing for molecular alterations at the time of progression? I would submit to you that those patients who have been stable on their first line treatment for at least six months, this was the eligible population for screening in SRENA-6, are certainly candidates for serial testing. However, we may also consider those patients that have been stable on first-line treatment for two or more years to be perhaps exempt from this type of testing because they are doing well on treatment and perhaps we can wait until the time of progression for molecular testing. Again, I think this really depends on the conversation with the patient and what the patient's wishes are for monitoring and when they want this information.