COMMENTARY

FES PET for ER-Positive Breast Cancer: How Can It Help?

Kathy D. Miller, MD; Hannah M. Linden, MD

Disclosures

July 18, 2023

This transcript has been edited for clarity.

Kathy D. Miller, MD: I'm Dr Kathy Miller. I'm professor of medicine at the Indiana University, where I also am associate director of clinical research for the Simon Cancer Center and leader of the Breast Cancer Program.

Joining me today is Dr Hannah Linden, professor of medicine at the University of Washington. Dr Linden is also the director of the Breast Cancer Program at the Fred Hutchinson Cancer Center.

Dr Linden joined me today at the 2023 ASCO Annual Meeting in Chicago. It's been a good year for breast cancer.

Hannah M. Linden, MD: A very good year.

Miller: Thank you for joining me to talk about a topic that I know has been a passion of yours for years: thinking about how molecular imaging might help us make better decisions in treatment of our patients. In particular, I wanted you to talk to our listeners about fluoroestradiol (FES) imaging.

Linden: Or as the Europeans say, FES PET.

Miller: I like FES PET better.

Linden: We've been working on this for a long time. When I say "we," I mean the broader community. We've done a large amount of work at the University of Washington program project in molecular imaging, but really it's your neighbor, John Katzenellenbogen, who started this whole thing.

Mercifully, he is still alive to see it be successful because it's really, I think, progress for patients. You order a biopsy all the time, right? You look at the estrogen receptor (ER) stain, and that has meaning to you in terms of what you're going to do for a patient.

FES PET tells us what the body burden of cancer is doing and whether or not there's a molecular signal at each tumor site that shows there's a significant concentration of ER binding ability.

Miller: I want to make sure our listeners understand. What this allows you to do is, with imaging, see whether this tumor expresses ER and whether it binds ER? Instead of looking at just a little piece that happened to get sucked in the biopsy needle, it lets you look at the entire body's burden of disease. One question: If the tumor doesn't bind estrogen or some portions of disease don't bind estrogen, you don't see it. How do you know that's because there's nothing there or because it doesn't bind estrogen?

Linden: That's the problem of a negative study. The study won't be "negative" totally. The liver is where the tracers clear to, so you're going to see the liver. If the patient has a uterus, if the uterus is intact, that's your internal control.

I think what you're asking is, if you know the patient has 10 bone metastases by whatever imaging tool you used initially and none of them light up on the FES PET, what does that mean? That means that tumor isn't capable of concentrating and binding estradiol. It means that something's wrong and there isn't any ER there now.

It could mean that the patient now has triple-negative breast cancer. It could mean that the patient has myeloma or some other non-breast cancer–related disease.

Miller: I know this tracer has just been recently approved, and many in our audience have not yet had a chance to use this. Like any new tool, understanding how to use it — and maybe even more importantly, how not to use it — becomes really important. It's a great new tool for understanding not just whether ER is present, but at least whether it is functional and can bind to estrogen.

How do we use this to make decisions?

Linden: One thing that is mortifying to me is that every patient doesn't get a biopsy. You and I know, and we train people that if you think they have metastatic cancer, tissue is the issue, right? That's what we were taught. The truth is that many patients don't ever get that biopsy. They just have a radiologist and an oncologist say, "Oh, it looks like it's metastatic disease."

I don't think that's a good thing. I still think a biopsy is indicated. Sometimes I think the reason people aren't getting the biopsy is that actually it's a tough site to get to or the interventional radiologist wasn't very comfortable putting a needle into that bone.

Miller: It's a deep lung lesion. It's in the dome of the liver, or it's in a bone that looks like you it's about to break.

Linden: Or it's in a rib. You don't biopsy ribs. We don't do that. That would be an opportunity for you to get, frankly, a virtual biopsy.

Miller: That would be helpful if the initial tumor was hormone sensitive.

Linden: Correct.

Miller: And not appropriate if you already knew that the initial tumor was ER negative.

Linden: Right. Completely inappropriate to consider this for the HER2-positive or ER-negative tumor and the triple-negative tumor because yes, we see heterogeneity, but we don't usually see it go from unfavorable to favorable. If you have some strong suspicion — like maybe the patient had a lobular tumor on the left and something else on the right and you want to know which it is — this is going to tell you whether that strongly ER-positive lobular tumor has now metastasized elsewhere. It's not going to tell you about whether the triple-negative tumor has.

Negative results are always difficult to interpret, so you need to have a high positive predictive value in order to order the test.

Miller: Another way people have thought about using this is to decide if this is someone who ought to be treated with hormone therapy or someone who's better suited to chemotherapy. Is that an appropriate use?

Linden: Absolutely. I think that's a great use. You and I have many tools in our tool kit and we could achieve a response with many drugs, but you don't want to give them side effects. We would lean toward trying to give them endocrine therapy if it's at all appropriate. This is a good tool to use for that.

However, if you have the patient on adjuvant tamoxifen, you're not going to be able to see it because tamoxifen is going to block the binding of the tracer. There are caveats. The liver is the site where the tracer is cleared, so it's tricky to read.

Miller: You're a bit blinded in the liver because of all of the uptake.

Linden: If it's liver-only disease, I don't know that I would order the test, but it's great for bone, lung, and lymph nodes.

The other big question we get asked about is the gut. That's a really problematic site for us to manage.

Miller: It's a particular problem for people with lobular disease who are frequently ER positive.

Linden: Unfortunately, like every other imaging tool we have, the FES doesn't help us here because you do have some biliary clearance and there's nonspecific gastrointestinal uptake. It doesn't get us around that problem, which is unfortunate. That's a subset of patients that we're very familiar with because they're really challenging to manage and you'd really like to know what the tumor is doing there. I don't have an out for you there.

Miller: The other way we think about imaging very commonly is evaluating someone's response. If I've gotten the biopsy, and we've gotten the FES PET — I'm going to try to use that term from now on just because I like it — if we've gotten that and that's positive, they've now been on hormone therapy for several months and we want to know, are we on the right path, is this useful in that setting?

Linden: No. It is interesting. We have had the opportunity to study it, as have many other groups, and have published this a couple of times that if you want to see if your oral selective estrogen receptor degrader (SERD) is really blocking. In drug development, we have done this to show complete blockade and to help with pharmacodynamic imaging, such as peak of drug in the system, you should be fully blocked at all sites. That's our research indication.

We don't recommend people doing that in practice, in part because you and I don't know that that's necessary. Maybe you just need to modulate it. We don't recommend that at all. It hasn't been proven to be effective in that setting.

I think people get confused between FES PET and FDG PET. FDG PET is a great way to show whether the bone is responding. You've got a high standardized uptake value, you have lytic lesions that were hard to find initially by CT, and you want to know how the patient is doing without restaging. I find FDG PET to be helpful there. That's what EA1183 is looking at.

Miller: That's being studied in a group we all struggle with: the patients who have bone-only or bone-predominant disease. Bone scans don't change very quickly in the short term, and they sometimes get worse with healing. Symptoms hopefully are getting better because we're managing symptoms better. They are a tricky group, right?

Linden: I think FDG PET is very helpful there because you can see what's happening. You can see whether the metabolic activity has gone up or down. The most common sign of progression for many of our patients is that they have a new lesion, and you can find that new small lytic lesion in the other bone by using FDG PET.

FES PET won't help you there. It's just showing you where the ER expression is. If you're on a blocking therapy, you block the tracer. If you're on an aromatase inhibitor, it's not going to block the tracer so you can see it, but you're probably going to see the same thing that you saw before because ER-positive tumors don't all just disappear.

We don't have a metric to demonstrate that you were really strongly ER positive and now you're less positive. Is that the tumor or is that the drug? We don't recommend you get it at that point. Where you want it is when you think they're progressing and you're deciding whether to stick with the endocrine-based therapy or to now go off and give them some other great drug.

Miller: If your treatment was a blocker, an ER degrader, it's not going to help you.

Linden: Right. The novel oral SERDs, most of them have a shorter half-life. We have a little bit of a problem with both tamoxifen and fulvestrant because they have long half-lives. When you think you've stopped it and you switch the patient to another therapy, there's an overlap where they're still on it.

With the modern therapies, I think they'll come off quicker, and we've actually seen published data showing that., But most of us don't have the luxury of the modern SERDs yet. We're stuck with the tried-and-true fulvestrant and tamoxifen, and they stick around a long time.

There's an odd label for FES PET that [says tamoxifen and fulvestrant may block ER for up to 8 and 28 weeks, respectively],and I think that's an exaggeration. That has not been our practice in clinical trials. It's really just been 60 days, but that is the label.

Miller: It's like any new tool. I'm really excited to see this research of well over a decade come to fruition. Like any new tool, it's really important to understand where it can be helpful, where it might not be helpful, or might even lead you astray.

Linden: I think patients have a large amount of hope, and you don't want to hype something and use it the wrong way.

Miller: Thank you, Hannah. I know this has been a passion of yours for a long time. It's really exciting to see that tracer become available, and particularly to help us make better decisions for patients with ER-positive disease.

Linden: The precision medicine aspect is so important. This way, we can get the patient on the right therapy for their tumor at this time.

Miller: Thank you for joining me, and thank you for joining me as well. This is Dr Kathy Miller, coming to you from the 2023 ASCO Annual Meeting in Chicago.

Kathy D. Miller, MD, is associate director of clinical research and co-director of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University. Her career has combined both laboratory and clinical research in breast cancer.

Hannah M. Linden, MD, is associate program director of the Medical Oncology and Hematology Fellowship Program at Fred Hutchinson Cancer Center and UW Medicine. She is a breast cancer specialist who studies new molecular imaging techniques.

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