FES-PET/CT Expands Precision Imaging Potential in ER-Positive Breast Cancer

As conventional imaging defines anatomy and fluorodeoxyglucose (FDG)–PET/CT assesses metabolic activity, ¹⁸F-fluoroestradiol (FES; Cerianna)–PET/CT adds receptor-specific insight that can clarify equivocal findings and refine management in estrogen receptor (ER)-positive breast cancer, according to Igor Makhlin, MD.

“It’s sometimes easy to forget all the different [imaging] tools we have, because there are so many nowadays,” Makhlin said in an interview with OncLive. “Keep [FES-PET/CT] in your back pocket for those difficult situations where you’re not sure whether what you’re seeing on scans is truly ER-positive disease. That’s where FES-PET/CT can be helpful. Know what the limitations of the test are, and remember that it can be helpful for patients with lobular disease, as well as those with difficult-to-image, ER-positive disease. Use it as a troubleshooting tool to decipher [other imaging results], especially when there’s difficulty with getting a biopsy.”

In the interview, Makhlin discussed the current imaging modalities used for metastatic breast cancer diagnosis and highlighted FES-PET/CT as a newer, specific modality for ER-positive breast cancer, noting its high sensitivity and specificity in predicting response to endocrine therapy. He also mentioned potential future applications for FES-PET/CT, including combining this modality with liquid biopsy and expanding its use in early-stage settings.

Makhlin is an assistant professor of clinical medicine in the Division of Hematology-Oncology in the Department of Medicine at the University of Pennsylvania Perelman School of Medicine, as well as clinical leader of Flatiron Assist Breast Pathways and director of the Metastatic Tumor Board at Penn Medicine in Philadelphia.

Want to dive deeper? Watch Makhlin outline clinical evidence supporting the use of FES-PET/CT in breast cancer management.¹ You can also listen to a podcast conversation between Megan Kruse, MD, of Cleveland Clinic in Ohio, and Sophia O’Brien, MD, of Penn Medicine, about how medical oncologists and nuclear medicine physicians can collaborate to optimize the use of FES-PET/CT and other imaging modalities in clinical practice.²

OncLive: What imaging modalities are typically used in clinical practice for the diagnosis and management of breast cancer?

Makhlin: In the diagnosis and staging of metastatic breast cancer, we have several great imaging modalities. We have CTs and bone scans, which have been standard cross-sectional imaging modalities for a long time. In addition, we have FDG-PET/CT, which is good [at identifying] and following response for bone metastases.

We also have MRIs, which include MRIs of the brain when looking for brain metastases, as well as MRIs of certain organs like the liver, when we sometimes run into issues with imaging. There are certain types of breast cancers, like lobular breast cancer, where MRIs can be helpful. FES-PET/CT is a newer imaging modality that has specific uses.

What differentiates FES-PET/CT from other breast cancer imaging methods?

CTs are anatomic; they tell us information about whether [we can see something that] looks like a tumor and, if you’re comparing [new imaging with] prior CT results, whether [the tumors] have been there [previously] and whether they’ve gotten smaller or larger. FDG-PET/CT is now getting into the realm of functional imaging. It’s not specific for breast cancer, but the increase or decrease of the avidity of FDG is a functional assessment of the activity of whatever [disease] you’re following. However, it’s not specific [to] cancer.

FES-PET/CT is taking that to the next level. Unlike FDG-PET/CT, which uses a radiolabeled glucose molecule, fludeoxyglucose, FES-PET/CT uses a fluorescent probe attached to estradiol, and this is specific for ER-positive breast cancer. This is functional imaging of a specific subtype of breast cancer.

What evidence has helped support the integration of FES-PET/CT into the breast cancer imaging roster?

There have been several studies showing high sensitivity and specificity for ER-positive breast cancer with FES-PET/CT compared with standard-of-care histology through biopsy. Furthermore, there have been several studies showing the prediction of response to endocrine therapy with FES-PET/CT. Importantly, those studies show that a lack of FES uptake on a scan predicts poor response to endocrine therapy, which brings in a clinical element.

When you are deciding on an imaging modality in clinical practice, what factors may influence the use of FES-PET/CT over or in addition to other tools?

Right now, the most common use for FES-PET/CT is as a troubleshooting tool. There are [common] scenarios where [a patient has] a new lesion that may be difficult to biopsy. Particularly when you have a concern for new metastatic breast cancer, the spot is not [always] easily accessible for tissue biopsy. FES-PET/CT can be helpful [in this situation]; if it’s positive, you essentially see a diagnosis of ER-positive breast cancer. Additionally, it can be helpful when there is discordance between FDG-PET/CT and your suspicion.

Certain cancers, like lobular breast cancers, may be difficult to follow with any imaging modality, including CTs or FDG-PET/CT. Approximately 20% to 30% of those patients will not have FDG avidity on FDG-PET/CT. If there is a new finding on either CT or FDG-PET/CT that you’re following and you’re not sure if it truly represents disease, you can follow that up with an FES-PET/CT. Also, if you’re concerned that the amount of disease is higher than what you’re seeing on scan, that’s another great opportunity to use FES-PET/CT to try to better characterize the extent of disease.

Is there a role for FES-PET/CT to guide treatment decision-making in breast cancer management?

One of the scenarios I’ve run into is in early-stage workup, where there are suspicious features on a standard scan that are not accessible [via biopsy]. An FES-PET/CT that is positive for a distant lesion can completely change the paradigm of treatment from curative-intent surgery or radiation to a more metastatic paradigm, helping the patient forego invasive procedures and move right to systemic therapy. As you’re following patients in the metastatic setting who have proven disease and are on treatment, if there is a change in activity, either through blood work or through symptoms that are not being well picked up on scans, that’s a time when FES-PET/CT can be helpful to characterize what’s going on. If there is ER positivity on that scan that correlates with symptoms, that helps support progression of disease.

One area that is important to note, however, is that a negative FES-PET/CT result does not imply no cancer. It just means that perhaps the receptor expression has changed from ER positive to ER negative through selection pressure, or it could be a completely different process. FES-PET/CT results are more helpful when they are positive. Additionally, there are predictive data showing that if you have a truly negative FES-PET/CT scan in a patient with ER-positive disease, their likelihood for response to endocrine therapy is probably not going to be as high.

How might the use of FES-PET/CT be expanded in the breast cancer field going forward?

There are several scenarios where we have more work to do. One such situation I’ve already referred to is patients with lobular disease that can be difficult to image with standard modalities like CTs and sometimes even FDG-PET/CT. Right now, FES-PET/CT is not approved as a stand-alone modality to follow patients for treatment response; even though we may use it from time to time as a troubleshooting tool, we still…follow treatment response with the standard modalities we’ve been using. Getting more data to support using FES-PET/CT on a more routine basis, especially for those harder-to-image patients, is needed and critical.

There’s also potential for combining FES-PET/CT with other diagnostic tests, like liquid biopsy [for] circulating tumor DNA, to try to get a more cohesive and complete picture of the state of the breast cancer. One can envision a situation where the FES-PET/CT is positive, meaning the [ER] is [expressed], but perhaps that receptor is constitutively activated, like with an ESR1 mutation, so that FES-PET/CT alone doesn’t tell us whether the cancer would respond to an aromatase inhibitor. Combining FES-PET/CT with other data, like liquid biopsies, can help add texture to the full picture of the cancer.

Also, there may be an opportunity to expand FES-PET/CT into the early-stage setting when you’re considering neoadjuvant therapy for a select group of patients with endocrine therapy. There is still much work to be done there. FES-PET/CT is currently not being used that way, but there may be potential to move it up into the early-stage setting.

How is FES-PET/CT used to assess involvement of breast cancer in the brain?

FES-PET/CT does image the brain, which we don’t get with FDG-PET/CT. An additional benefit to FES-PET/CT is that you can sometimes pick up brain metastases. If there’s a question about whether what you’re seeing on a brain MRI or CT looks like a metastasis and is ER positive, you can image that with FES-PET/CT.

What is an example from your clinical practice about the use of FES-PET/CT to guide nuanced breast cancer treatment decision-making?

I was seeing a patient in consultation for an early-stage HER2-positive, ER-positive—what we call triple-positive—breast cancer…and some regional lymph nodes. An [FDG-PET/CT] was done, which showed a mediastinal mass that was retrosternal and not accessible for biopsy. It was unclear whether this was cancer, sarcoid, or something completely unrelated. I recommended an FES-PET/CT; it was done, and it was positive. The patient was then found to have oligometastatic disease to the mediastinum, and that helped guide her remaining systemic therapy.

What are some other clinical applications for FES-PET/CT in breast cancer?

FES-PET/CT can also be used to image the bone marrow. I’ve had patients whose blood looks fine on FDG-PET/CT, but their blood counts are dropping over time, and it’s unclear what’s going on. An FES-PET/CT can light up the bone marrow and show progression where the standard FDG-PET/CT does not pick it up. Lobular disease is difficult to image. Lobular disease can go to strange and obscure areas, but it can be picked up on FES-PET/CT.

What are some of the limitations of FES-PET/CT?

There are some limitations to the test. FES-PET/CT is not helpful for following or assessing [disease in] the liver, because [the radionuclide is] metabolized and excreted in the liver into the small bowel, so the whole liver essentially lights up. Additionally, there are certain therapies that patients can’t [actively] receive in order to undergo an FES-PET/CT scan, such as tamoxifen and fulvestrant [Faslodex]. Any drug that binds the ER and downregulates or destroys it [cannot be taken in conjunction with FES-PET/CT] because you need the receptor there to bind the FES.

References

1. Makhlin I. Dr Makhlin on data to support the use of FES-PET/CT in breast cancer management. OncLive. February 25, 2026. Accessed March 4, 2026. https://www.onclive.com/view/dr-makhlin-on-data-to-support-the-use-of-fes-pet-ct-in-breast-cancer-management
2. Kruse M, O’Brien SR. Breast imaging advances emphasize the importance of patient-focused nuclear medicine collaboration: with Megan Kruse, MD; and Sophia O’Brien, MD. OncLive. February 27, 2026. Accessed March 4, 2026. https://www.onclive.com/view/breast-imaging-advances-emphasize-the-importance-of-patient-focused-nuclear-medicine-collaboration-with-megan-kruse-md-and-sophia-o-brien-md