Author(s)Ashling Wahner
Fact checked by: Riley Kandel
Close collaboration with nuclear medicine colleagues enables breast cancer treatment teams to overcome imaging limitations in lobular disease and make informed treatment decisions using 18F-fluorodeoxyglucose (FDG)–PET/CT and estrogen receptor (ER)–targeted 18F-fluoroestradiol (FES)–PET/CT, according to Sophia O’Brien, MD.
“[FES-PET/CT] is helpful at the initial diagnosis of metastatic, ER-positive breast cancer, or at progression before the next line of therapy to help decide what the next line of therapy should be,” O’Brien said in an interview with OncLive®.
In the interview, O’Brien discussed the role of nuclear medical physicians in breast cancer diagnosis and staging, appropriate-use criteria for FES-PET/CT in lobular breast cancer, and why collaboration with multidisciplinary teams is essential for accurate diagnosis and management.
O’Brien is an assistant professor of clinical radiology in the Divisions of Nuclear Medicine and Breast Imaging, as well as the associate program director of the Diagnostic Radiology Residency, at Penn Medicine in Philadelphia, Pennsylvania.
Further reading: To see more of OncLive’s recent coverage of FES-PET/CT in lobular breast cancer, check out the insights we highlighted from a conversation with Jason Aboudi Mouabbi, MD, of The University of Texas MD Anderson Cancer Center in Houston.1
How do nuclear medical physicians work alongside medical oncologists and other specialists regarding the breast cancer staging and diagnosis? Why is this collaboration important for patients with suspected lobular breast cancer?
O’Brien: Nuclear medicine physicians work alongside the whole team of multidisciplinary physicians who take care of patients with breast cancer. We work with medical, surgical, and radiation oncologists, as well as interventional radiologists. We are often on tumor boards talking about complicated cases and helping inform management.
One of the radiology studies that nuclear medicine and nuclear radiology physicians read that is relevant to patients with breast cancer is FDG-PET/CT. FDG is a radionuclide, so it emits radiation. We can image where it goes in the body. It’s a glucose analog, so it’s a sugar molecule, and it goes to places that use sugar. Most cancers, including many breast cancers, love sugar. [FDG can] show breast cancers nicely on PET imaging. FDG-PET/CT stages breast cancers.
Not all patients who have breast cancer will undergo systemic staging. Many women and men might develop breast cancer that’s local. If there’s something abnormal in their breast or the lymph nodes near their breast, typically in the axilla or the armpit, but no signs or symptoms anywhere else, they continue with treatment based on breast imaging only.
However, if they have high-risk features—if the breast tumor is large, if it seems like it’s invading the chest wall, if they have inflammatory breast cancer in which the skin is involved, or if they have concerning signs or symptoms like back pain that makes their team worried that they have disease outside the breast or axilla—they undergo staging studies. FDG-PET/CT is an excellent staging study for patients with breast cancer. It allows us to see whether the breast cancer has gone outside the breast, lymph nodes, and axilla, as well as where it is.
Another staging study that can be done with PET/CT or without is a CT scan—typically a CT of the chest, abdomen, and pelvis, which is paired with a bone scan. The bone scan is the nuclear medicine study. It uses a different radionuclide, and it is specifically looking at bony metastases only if they’re osteoblastic, meaning the cancer cells and bone response are building more bone. The bones start looking brighter on imaging, and we can see that osteoblastic response on the bone scan. [The bone scan cannot] see lytic bone metastases, when the cancer eats the bone away. That we can only see well on FDG-PET/CT. Even though sometimes bone scan and CTs are done on their own, if there’s suspicion of lytic disease or tiny disease, FDG-PET/CT is a more powerful staging tool.
We help stage patients when they’re initially diagnosed with breast cancer. We also help restage patients if there’s concern for recurrence. If a patient has recurrent breast cancer, we want to see whether it only recurred in the breast, or elsewhere as well. That’s going to change their treatment. If a patient has disease outside the breast, they are typically not going to go straight to surgery, because that’s not going to solve the whole problem. They need to receive more systemic therapy to deal with the disease in multiple places.
FDG-PET/CT is sometimes used to assess treatment response. Studies have shown that we can see response earlier on PET. We can see the change in how [the cancer is] using glucose before we can see changes in [tumor] size. We use FDG-PET/CT frequently [to assess] response in other diseases, such as lymphoma. How, when, and where [to use FDG-PET/CT] to assess response in breast cancer hasn’t fully been fleshed out, but that’s something we’re sorting out.
The other study we can use as nuclear medicine physicians, specifically in patients with breast cancer, is a different type of PET/CT: FES-PET/CT. [FES-PET/CT uses] the same radionuclide, F18, which is radioactive fluoride, but it’s attached to an estrogen analog, and this estrogen analog binds to the ER. It’s specific for the ER in normal cells, such as in the uterus, but also in breast cancers and other cancers like uterine cancer that express the ER. That’s where FES-PET/CT comes in for patients who have invasive lobular carcinoma, due to the way invasive lobular carcinoma grows.
Pathology describes it as a single-file growth; the cells are crawling along tissue planes instead of forming big balls of cancer. That growth is hard to see on almost all imaging modalities: mammogram, ultrasound, breast MRI, and FDG-PET/CT. It tends to be mildly avid with FDG, if not avid at all, and sometimes totally invisible.
However, the invasive lobular carcinomas tend to be ER positive, so FES-PET/CT can swoop in, and that is often the test that can see the lobular cancers better than any other study. That gives us an assessment of the burden of disease. FES also characterizes the disease and makes sure FES binds to the ER that we know is there from biopsy, so we know it’s binding and that the patient might be a good candidate for endocrine therapy, which uses therapy that binds to the ER.
How is FES-PET/CT currently being used within clinical practice patients with suspected lobular breast cancer or suspected disease? What factors help inform whether you should use FDG-PET/CT or FES-PET/CT?
That is a question that comes up frequently in our tumor boards when we’re coming together as a group to decide what’s the next best step in a patient. The Society of Nuclear Medicine and Molecular Imaging has created appropriate use criteria.2 They looked at all the data and asked: What is the right time to use FES-PET/CT? There are 4 time points in a patient’s potential treatment history that would be good indications for an FES-PET/CT.
The first is characterizing disease when a patient has biopsy-proven ER-positive, metastatic, presumed metastatic, or recurrent—because we have a high suspicion of metastases at that time—breast cancer. A patient can get FES-PET/CT at the first point of metastasis or if they’re progressing on first-line therapies. This is a characterization of whether the disease is still binding to estrogen. It’s to determine whether this patient is a possible good candidate for endocrine therapies that target the ER.
Sometimes patients start receiving an aromatase inhibitor, which reduces the amount of circulating estrogen, but it doesn’t bind to the ER itself. [These patients] can get an FES-PET/CT if they progress on the aromatase inhibitor and their team decides to bump [treatment] up to a selective estrogen modulator or downregulator. They want to see: Are the ERs binding?
Sometimes patients will have ER positivity on tissue sampling, but their disease might not have functional ERs, or they might have heterogeneous disease. They might have sites that bind to the ER and sites that aren’t. If [the disease sites are] not binding FES anywhere, or if they’re only heterogeneously binding to FES, that tells the team that this might not be a patient who’s going to respond well to endocrine therapy. Or maybe the patient can’t be treated with endocrine therapy alone. We could image them during aromatase inhibitor therapy.
We cannot image patients when they’re already receiving an ER modulator or downregulator because those bind and block. What we are constantly telling our teammates in these tumor boards is, remember that FES-PET/CT is characterization at a treatment decision point before you start the next treatment. This is a great way to get a bird’s-eye view of the disease. Is the disease still binding estrogen everywhere? Once a patient starts tamoxifen or fulvestrant [Faslodex], it’s weeks before those can be washed out and before we can use the tracer. We don’t want to stop therapy just for the purpose of looking at a study.
The third indication for FES-PET/CT is for sites that are difficult to biopsy, or for which we think the prior biopsy was discordant. If a site of possible disease is sitting next to the aorta, we can’t get a needle into it safely. But we can get an FES-PET/CT to see if it’s binding the FES tracer. If it’s positive on FES-PET/CT, it is definitely ER-positive metastatic disease, because it is a specific tracer. If it’s negative on FES-PET/CT, we don’t know whether we’re looking at a site of ER-negative disease or a site that is not metastatic breast cancer.
[Regarding] discordant biopsy, a biopsy [may be] either indeterminate or one we think is incorrect; every test can have false negatives, specifically bone biopsies. Bone is a place where breast cancer likes to something with the processing of the bone biopsy sample that can sometimes lead to falsely negative ER receptor [disease]. [Imaging will say] it’s an ER-negative sample, but in truth, it is an ER-positive site of metastasis.
Sometimes the team says: We know this patient has ER-positive metastatic disease elsewhere, so we are assuming that in the bone is also ER-positive metastatic disease. The bone biopsy tells us it’s ER-negative disease. Let’s get an FES-PET/CT, and if that is wildly avid in all the bony sites, then we can say it was a false negative on the biopsy and that this is truly ER-positive metastatic disease. That can drastically change the patient’s care.
The fourth indication is clarifying questionable, suspicious, or indeterminate findings on other studies. Oftentimes, if a patient gets a staging FDG-PET/CT, and there’s a suspicious [finding] that’s not super obvious—because invasive lobular carcinoma tends to not be very avid on FDG-PET/CT—that can prompt an FES-PET/CT. The nuclear radiologist reading the FDG-PET/CT can say there’s an area or lymph node that looks a little suspicious. They can’t confidently call that disease based on [the results], but they [suspect] this patient has ER-positive invasive lobular carcinoma. The FES-PET/CT will clarify whether this and other sites that are suspicious on imaging are truly ER-positive metastatic disease.
There are also some maybe appropriate indications. Staging invasive lobular carcinoma is listed as a maybe appropriate indication. It’s not one of those [definite indications], but there are enough data here that we think maybe we should consider staging patients with invasive lobular carcinoma.
We don’t know which patients with invasive lobular carcinoma would require staging because we don’t use FDG-PET/CT to stage patients who have local disease. If it’s just in their breast and axilla, they’re not going to undergo a PET for systemic staging because there’s a higher risk of false positives than uncovering metastatic disease. But we don’t know what the indication for full-body staging should be in patients with invasive lobular carcinoma.
We have seen quite a few patients who end up coming either for research or for some other questionable reason, getting an FES-PET/CT, and having drastically more disease than they realized on breast imaging alone. More often than you would think, patients with invasive lobular carcinoma can have small, normal-appearing lymph nodes that are FES avid. Sometimes they’re bilateral axillae, sometimes they are in their chest, sometimes they are in their groin. We can follow those with biopsy to confirm disease there. That’s shown us that maybe we should be staging patients with invasive lobular carcinoma more often than we think, and maybe we should be staging them with FES-PET/CT.
What is your message to medical oncology colleagues about the importance of considering FES-PET/CT and consulting with nuclear medicine specialists to make sure the right imaging and diagnoses occur?
This is an evolving answer. Whenever we have a patient with invasive lobular carcinoma, we should be on high alert that maybe an FES-PET/CT might be useful in them, because it has been uncovering additional disease that totally changes their treatment. From local disease to metastatic disease, there are totally different management [strategies].
Any [medical oncologists] with [patients with] invasive lobular carcinoma should be at the ready to think, if we have a question on another imaging study, or if we are unsure about this biopsy, maybe get an FES-PET/CT to clarify what’s going on. The clarification is that sometimes the high-grade invasive lobular carcinomas act more like invasive ductal disease on imaging, and they might be better seen on FDG-PET/CT. [There should be] nuanced conversations between the whole treatment team to figure out what would be the right study when.
But on the whole, specifically for patients with invasive lobular carcinoma, but also for any patients with ER-positive, metastatic, presumed metastatic, or recurrent breast cancer, characterizing their disease is an easy way to get an FES-PET/CT as a baseline to make sure every site of disease is ER positive and functionally binding the ER. That can help you manage it. If there’s ever a question that comes up, FES-PET/CT can possibly help you answer that question.
We have to make sure the patient is not receiving an ER-blocking agent. Additionally, FES-PET/CT has not really been studied as surveillance. If you have a patient who has disease, and then they’re treated, usually we try to follow that with FDG-PET/CT because that has a lot of data [to support it]. I’ve seen a patient who underwent FDG-PET/CT and FES-PET/CT at about the same time, to identify all the sites of disease on FDG-PET/CT and to characterize them as ER positive on FES-PET/CT. Then they underwent treatment, and their follow-up was an FDG-PET/CT, which showed complete metabolic response.
If you have a patient who doesn’t have disease that’s avid on FDG-PET/CT, and it’s only well seen on FES-PET/CT, how do you follow them? If they’re receiving an aromatase inhibitor that’s not blocking the ER, [they may] undergo multiple FES-PET/CT scans as a bird’s-eye view, knowing that if there’s disease change or a hormone profile shift to ER-negative disease, that’s going to be invisible. That’s a big caveat. Also, FES-PET/CT is not good for looking at disease in the liver, which is a place that breast cancer, unfortunately, likes to go. It’s not comprehensive. We should consider FES-PET/CT a powerful tool that is part of a larger imaging program.
References
- Wahner A. FES-PET/CT guides staging and endocrine therapy decision-making in lobular breast cancer. February 17, 2026. Accessed February 23, 2026. https://www.onclive.com/view/fes-pet-ct-guides-staging-and-endocrine-therapy-decision-making-in-lobular-breast-cancer
- GA, Mankoff DA, Clark AS, et al. Appropriate use criteria for estrogen receptor-targeted PET Imaging with 16α18F-fluoro-17β-fluoroestradiol. Society of Nuclear Medicine and Molecular Imaging. Accessed February 23, 2026. https://snmmi.org/common/Uploaded%20files/Web/Clinical%20Practice/Appropriate%20Use%20Criteria/FES%20AUC%20revised%20-%202022-10-05%20Final%20BOD%20Approval.pdf
Originally published on OncLive: https://www.onclive.com/view/fes-pet-ct-imaging-can-clarify-lobular-breast-cancer-extent-and-biology