Erin Frances Cobain, MD: Hello everyone. Thank you very much for joining us. My name is Dr. Erin Cobain, and I am a breast cancer medical oncologist at the University of Michigan Rogel Cancer Center. I'm joined by two of my colleagues, Dr. Manali Bhave and Dr. Stephanie Graff. And I'd like to just pause to let the two of them introduce themselves, as well. Dr. Bhave?
Manali Bhave, MD: Great, thank you, Erin. Hi there, I'm Dr. Manali Bhave. I'm also a breast medical oncologist and director of our phase 1 clinical trials unit at Emory University in Atlanta. Great to be here.
Dr. Cobain: Thank you. Dr. Graff?
Stephanie Graff, MD: And I'm Dr. Stephanie Graff, director of breast oncology and associate professor at Legorreta Cancer Center in Brown University in Providence, Rhode Island.
Dr. Cobain: Wonderful. Thanks so much to both of you for joining. Today, we're going to be starting off by having a discussion about the use of next-generation sequencing in the care of patients with breast cancer. And I think where we'll begin this discussion is to talk about our use of this testing specifically in the care of patients with metastatic breast cancer, where we have the most established evidence for its use and clinical benefit. To start us off, let's think a little bit about patients particularly with hormone receptor–positive HER2-negative or [HER2]-low metastatic breast cancer. I think one of the things that we now have come to recognize is that, particularly in the second-line endocrine therapy treatment setting, there are many targeted therapies based on the identification of a genomic alteration that we are administering in conjunction with endocrine therapy. I think we're seeing a lot of questions about what the best timing is to do for next-generation sequencing, either via tumor or a liquid biopsy test, in order to best select therapy for patients.
I'm going to actually start off with Dr. Graff and just pose the question to you. When you see a patient newly diagnosed with hormone receptor–positive HER2-negative or [HER2]-low metastatic breast cancer at their original diagnosis, do you think about doing next-generation sequencing? Do you prefer to wait until after progression on initial endocrine therapy and a CDK4/6 inhibitor? Maybe you could just walk us through your approach and your thoughts.
Dr. Graff: This is such a great topic that comes up all the time, obviously, in clinic. So for me, when a patient has a new diagnosis of metastatic hormone receptor–positive breast cancer, I am confirming their diagnosis of metastatic disease. So I'm often getting a biopsy of a metastatic site to confirm it is what we know, or think, it is. And then that is able to confirm HER2-low or HER2-0 status for future treatment planning, confirm estrogen receptor/progesterone receptor (ER/PR) status, and finalize a diagnosis. On that tissue, I will normally send a tissue-based next-generation sequence. I think we know – and we'll talk about – how blood-based sequences are fantastic, especially for things like ESR1 mutations, but at that initial diagnosis, I think that I've got fresh tissue. I normally have enough tissue to send. So I'm sending that off. There are some limitations sometimes with bone biopsy. And so sometimes, in that situation, I would still send a blood-based assay. But normally, I can get what I need from a tissue assay.
I think that with the PIK3CA drugs that we'll talk about, knowing ahead of time that the patient will be a candidate for PIK3CA targeting gives us an opportunity to intervene early to help maximize their lead-in time. If an average patient is on a CDK4/6 inhibitor, which is my standard first-line therapy for months to years, that gives me a long time [during which] I'm able to maximize that patient's experience for future exposure to a medicine that's going to cause hyperglycemia. I can send them to physical therapy. I can partner with a nutritionist. I can get them connected with an endocrinologist to just dial back any insulin resistance that's going to help that patient tolerate a future PIK3CA drug. I'm trying to identify those patients as early as possible.
Then I know your next question is going to be, "Then what [about] progression?" On progression is really when I'm thinking about sending blood-based assays at that time, looking for ESR1. I'm doing that probably numerous times after progression on CDK4/6 inhibitors, and even after progression on the next line of therapy or the line after that, if I haven't already detected an ESR1, because that's such an easy, well-tolerated targeted therapy that we can reach for. It's important just to keep rescreening and checking to see if that's developed. Given the patients on the EMERALD trial, where 30% of them were previously treated with fulvestrant, I don't necessarily check for ESR1 on patients who are having metastatic recurrence on an aromatase inhibitor, because I'm still probably going to give them fulvestrant plus the CDK4/6 inhibitor. But I think that that's another question: How [will] that information impact us there at diagnosis? Dr. Bhave?
Dr. Bhave: Dr. Graff, I completely agree with your decision-making and your thought process. I also similarly get tissue-based next-generation sequencing done on patients at the time of recurrent disease or at the time of de novo metastatic disease, both to confirm what the diagnosis is, but then also to send off the tissue-based sequencing. And that's really to check for those inherent mutations like PIK3.
And now we do have some early data that perhaps in patients who have a PIK3 mutation that's detected, a drug that targets that in combination with a CDK4/6 and an endocrine agent at the time of first-line treatment might actually improve progression-free survival in that patient population. It's a high-risk population with endocrine resistance, and we're really trying to see how we can maximize use of targeted agents like PIK3 agents, but also in combination with CDK4/6 inhibitors in that patient population. And then similarly, at the time of progression on first-line [therapy] and subsequent progressions, I do end up sending off for plasma-based testing to check for ESR1.
And I've been surprised at times when I don't see it immediately after first-line treatment. I've caught that ESR1 mutation after, for example, fulvestrant or second- or third-line [treatment]. And given the fact that we did see some promising results with elacestrant on EMERALD in a more heavily pretreated population, I do sometimes go back to utilizing elacestrant in patients who have already seen two lines of endocrine therapy. We now also have the approval for capivasertib in combination with fulvestrant. And so now we're looking not just for PIK3, but AKT and PTEN alterations as well. So I think utilizing something as easy as blood-based plasma testing is something that we should integrate more frequently – I would say – into our treatment schema.
Dr. Cobain: Wonderful. Thank you both. I think that was really an excellent overview. Just have a few quick thoughts to add there. I think that one of the things to note with the approval of capivasertib is that, as Dr. Bhave just stated, it is not only based on the presence of an activating PI3 kinase mutation, but also if a patient has an activating AKT1 alteration or PTEN loss. And I think it's important that we are actually cognizant of what the capabilities are of the next-generation sequencing test that we are sending. And I say that with particular reference actually to detecting PTEN loss. That is a molecular alteration that is not as straightforward to identify as these other sort of hotspot mutations that occur in ESR1 or in PI3 kinase or in AKT1, where they're often isolated to regions of the gene that are readily picked up and the bioinformatics pipeline of the next-generation sequencing assay is well geared to identify those alterations.
PTEN loss can actually occur by a variety of molecular mechanisms, and the heterogeneity of the molecular mechanisms that can lead to PTEN loss sometimes makes some assays not able to detect all mechanisms of PTEN loss. Because of that, we've had conversations at our institution about whether or not there's actually a role for PTEN immunohistochemistry to sort of come back into the fold. And we've also just talked about the fact that maybe liquid biopsy, which technically has a little bit lower coverage than a tumor-based test, just because of tumor content, may make it a little bit more challenging to identify when PTEN loss is present. I don't think we have a perfect answer to that clinical issue, but I just like to put it out there that detecting PTEN loss may not be the most straightforward thing.
Dr. Bhave: On that note, though, when do you consider rebiopsy? At what point in lines of therapy, let's say for hormone-positive HER2-low or [HER2]-negative breast cancer, would you rebiopsy tissue?
Dr. Cobain: Yeah, I generally rebiopsy tissue when patients are endocrine refractory, largely because I am looking for the potential to match a patient with a targeted therapy clinical trial, generally when they're in the setting where I would typically – as a standard of care – consider chemotherapy-type treatment. But if you identify something that allows them to receive an endocrine agent along with a targeted inhibitor that you weren't otherwise aware that they qualified for, you always could go back to that kind of treatment.
Dr. Graff: And again, let me just add, we throw around phrases like "endocrine resistant" and "endocrine refractory" all the time, or an "endocrine refractory" patient. We've all seen those curves from trials like EMERALD or all the CDK4/6 receptors, CDK4/6 inhibitor, and all the sort of second-line trials where there's the sharp drop. Those are our "endocrine refractory" patients, right? Those patients who are falling quickly with whatever you're trying second. And yes, those may be patients who you're thinking about moving to more traditional cytotoxics or antibody drug conjugates (ADCs) because they've progressed so rapidly through your second-line therapy. But do that biopsy and send that tissue. It doesn't mean that if you identify something actionable, that you can't go back and offer that targeted therapy after that. It's going to take a little bit of time to get that genomic profile back. And so keep that in your list of options because the data for ADC after ADC still aren't very exciting or compelling. I think just making sure that we use all of the options available to target our patients' individual cancers remains paramount in the way that we approach cancer care.
Dr. Cobain: Great point. So let me transition us now to another topic just briefly here about the use of tests, particularly circulating tumor DNA (ctDNA) in patients with early-stage disease, in an effort to identify early recurrence. I think we're all aware that there is Centers for Medicare and Medicaid Services (CMS) coverage for some of these assays that utilize ctDNA to detect minimal residual disease that may not yet be evident on a CT scan, a bone scan, or a positron emission tomography (PET) scan. And I'm going to begin, I'll just ask Dr. Bhave, maybe you can share with us just what your thoughts are in general. Is this something that you're utilizing at all in your clinical practice, or [are you] seeing patients who have had this testing, and how you are advising them?
Dr. Bhave: That's a really great question. I think that's so relevant now that we have CMS coverage. And I'm sure I'll get questions related to utilizing that test in patients who have early-stage breast cancer and who have completed their curative-intent treatment. Right now, what we know so far, is that certainly, having detectable ctDNA puts those patients at high risk of developing radiographic progression. And we have a lead time that's on the order of three to maybe even nine months, depending on the subtype of breast cancer. The question, though, is: How do we utilize that information in a way that will extend patient survival? And that we don't have the answer to quite yet. I have not been utilizing that assay per CMS recommendations yet, but I have been utilizing it in clinical trial settings. And I would encourage patients who have high-risk early-stage breast cancer to potentially consider enrollment on one of those trials where we are utilizing ctDNA at regular intervals, so at their surveillance visits between four to six months on a clinical trial.
And if they have detectable ctDNA, then obtaining imaging to ensure that patients don't have radiographic progression yet. If they do, then those patients are considered metastatic and would go on to standard-of-care treatment for that disease. If not, then those patients on a clinical trial would be randomized to escalation of that treatment to more of a metastatic regimen versus continuation of their care drugs. And we do have the DARE clinical trial open at Emory and around the country to really understand the utility and the clinical benefit of ctDNA testing in that early-stage, high-risk, curable setting. So right now, I would say I'm not using it as part of standard of care. I'm definitely encouraging patients with high-risk disease to consider the use of that assay as part of a clinical trial, so we get a better understanding really of how to utilize that information and how best we can improve patient outcomes.
Dr. Graff: I guess I'll add that payer approval or test approval are very different metrics than drug approval. And I really think we need to stand by National Comprehensive Cancer Center guidelines and national guidelines. I am not ordering ctDNA on patients treated with curative-intent early-stage breast cancer. It is not a part of the national guidelines. We saw, as reported at the San Antonio Breast Cancer Symposium in 2023, the ctDNA feasibility cohort from the monarchE trial – so early use of abemaciclib in early-stage high-risk breast cancer. And in that, I think, I mean just a snapshot of the data, we saw that out of 10 patients who were initially ctDNA positive, three of them cleared their ctDNA. So 30% had this clearance of ctDNA and did not develop a recurrence on this study. And 21% of patients who were persistently ctDNA-negative had disease recurrence anyway.
I would say when we have 30% of patients who are positive and then clear and don't recur, and 20% of patients who are persistently negative and recurring anyway, we have a test that's just not very good yet. And when it comes with such overwhelming anxiety and confusion about how to interpret the results, [how to] act, potential lead time bias, and toxicity to the patient, it's important that we are continuing to evaluate this in clinical trials but not yet in our day-to-day patient decisions.
Dr. Cobain: Thank you both. I couldn't agree more. I think this is not something that I view as quite ready for prime time but also completely agree that looking at this in the context of a clinical trial is important. We here at the University of Michigan participated in the ZEST clinical trial, which – similar to what Dr. Bhave was referencing – was a trial aimed at delivering a novel therapy to patients who were ctDNA positive and had high-risk triple-negative disease but did not have overt evidence of metastatic disease. The treatment was actually a PARP inhibitor for those patients with positive ctDNA but no evidence of clear metastatic disease on scans. And that trial ended up closing early because, of the patients who were ctDNA positive, many of them already had clear evidence of metastatic disease on scans at the time we detected the ctDNA positivity.
And one of the lessons learned from that clinical trial was that monitoring was approximately every six months on study. And that if we are going to utilize ctDNA in the context of a trial to intervene early, perhaps the monitoring needs to be more frequently than every six months, which is challenging for patients and a potential logistical barrier. So a number of issues, I think, with this biomarker, to continue to work out.
I agree with you both, and I think our summary is in the context of a clinical trial [it is] very important to better understand how we can utilize it but not something we are utilizing in our routine everyday practice at present.
Excellent. Well, I think this was a wonderful discussion on a broad range of uses of next-generation sequencing in the care of patients with breast cancer. And we thank you all for listening. And thank you to Bhave and Dr. Graff for their excellent insights.
Dr. Bhave: Thank you.
This transcript has been lightly edited for clarity.
