FES/FDG Imaging Augments the Metastatic Breast Cancer Diagnostic and Treatment Landscape

Sophia Rose O’Brien, MD

Although 18F-Fluoroestradiol (18F-FES; Cerianna) and fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) imaging modalities can often provide accurate disease updates for patients with metastatic breast cancer, their use in diagnosis, staging, and follow-up must be mediated by their respective indications and limitations, according to Sophia Rose O’Brien, MD.

“[These are] powerful tools, but we need to be thoughtful about when and in whom we use them,” O’Brien said.

In an interview with OncLive®, O’Brien discussed the optimal uses for FDG PET/CT and FES PET/CT in patients with metastatic breast cancer; limitations of these imaging modalities to consider, particularly in patients with estrogen receptor (ER)–positive disease; and the potential advantages of using FDG assessment in patients with oligometastatic disease.

O’Brien is an assistant professor of clinical radiology in the Divisions of Nuclear Medicine and Breast Imaging at the Hospital of the University of Pennsylvania, Penn Medicine in Philadelphia.

OncLive: What breast imaging options exist for patients with metastatic breast cancer?

O’Brien: In current clinical use for metastatic breast cancer, we have 2 main PET imaging agents. FDG PET/CT is our workhorse for a lot of cancer imaging. This is indicated in patients with inflammatory breast cancer, is an optional staging mechanism for patients with stage III breast cancer , and is also used for staging and restaging patients with known stage 4 disease, per the National Comprehensive Cancer Network [NCCN] Guidelines. Some clinical work posits that patients with stage II breast cancer might also benefit, but that is not currently in the guidelines. [That is] on the horizon.

[Additionally], we have a newer PET imaging agent, FES. It is an F18-labeled estrogen analogue that binds to the estrogen receptor [that was approved by the FDA] in 2020. It was also approved in France in 2016. In the United States [US], the indication is for patients with ER-positive metastatic or recurrent breast cancer as an adjunct to biopsy. To clarify equivocal findings on other imaging studies, per recent SNMMI [Society of Nuclear Medicine and Molecular imaging] Appropriate Use Criteria.

Additionally, we have whole-body nuclear medicine bone scans, which have been used for decades in staging breast cancers and in follow-up in patients with metastatic breast cancer.

What limitations of previous imaging technologies have spurred advances in the field?

Bone scans have limitations. Treated disease and non-disease areas can show uptake of the radiotracer for a long time. Bone scans can be sensitive but are not specific. Especially [when] looking for change over time, the fact that bone scan uptake can be seen in sites of treated disease is tricky when trying to manage changes in therapy.

FDG PET/CT is actually more sensitive for most bony metastases, except for some low-grade ER-positive lesions. And FDG PET does a good job at assessing therapy response, with decreased uptake seen at partially treated disease and resolution of previously seen uptake at sites of complete metabolic response to therapy for both osseous and non-osseous metastases. This differs from a bone scan which only assesses osteoblastic metastatic disease and, again, can have changes lagging behind treatment, with continued uptake seen at sites of treated disease. FDG also has some specificity issues, however, with FDG uptake seen at sites of inflammation. We can see false positives on FDG PET/CT that can be hard to parse. [For example, if] you perform an FDG PET/CT soon after a breast biopsy, a lymph node draining that breast might be inflamed from the recent procedure and have uptake on FDG PET/CT, which can be confused for nodal metastasis. Additionally, degenerative changes or reactive marrow can have uptake as well, so it can be difficult to determine [whether the uptake is in] a site of disease or a non-diseased, reactive area.

FES PET/CT is increasing in specificity for ER-expressing tumors. FES uptake will not be seen in areas of inflammation, infection, reactive changes, or degenerative changes. FES uptake in the bones will not be from degenerative osseous disease. FES uptake in the bone is specific for ER-positive disease.

[One] limitation of FES PET/CT is it cannot assess disease in the liver. The liver is the critical organ that metabolizes the radiotracer. There is a high background liver uptake, and you cannot assess disease in the liver with FES PET/CT. You can use [any uptake] or even focal lack of uptake you see to lead to other imaging tests to confirm what’s going on. Some sites of ER-positive disease can look FES negative because they are next to the avid normal liver parenchyma. [Another] limitation of FES, similar to FDG, is that it will be excreted through the kidneys. Uptake in the kidneys, ureters, and bladder can obscure nearby disease.

What advances in diagnostic staging with molecular imaging have occurred in years past?

The most recent advance in the diagnosis and staging of metastatic breast cancer, specifically for patients with ER-positive disease, is the FDA approval of FES PET/CT in 2020. FES is an estrogen analog that targets the ER in the nucleus of estrogen-expressing cells. We see it in highly estrogen-expressing organs, notably the uterus, as well as organs [which are] involved in the metabolism and excretion of the radiotracer. We also see it in ER-expressing cancers, both at the primary cancer site and at sites of metastatic disease. This has allowed for a more specific understanding of the overall disease burden in these patients.

In the US, [FES PET/CT] is indicated as an adjunct to biopsy. It’s highly recommended that sites of abnormal FES uptake seen on PET/CT which would change management should be confirmed with a biopsy, just as any abnormal finding on an anatomic imaging study would be confirmed with a biopsy prior to treatment changes. We like to have a confirmatory biopsy before making big changes in patient care.

[In] patients with metastatic or recurrent ER-positive breast cancer, FES PET/CT allows us to do an overall assessment of their disease at 1 point in time and possibly even serially over time. If [a patient] has metastatic breast cancer, we can’t biopsy every site of metastasis to determine if it has the same hormone profile as the index lesion. [In patients with] biopsy-proven ER-positive cancer, up to 30% [will have] metastatic sites [that are] ER-negative cancer at some point in [their] lifetime, according to the literature. We also know that patients with ER-heterogenous disease have poorer outcomes overall and specifically will have poorer response to endocrine therapy. But we cannot biopsy every site of disease to determine whether [the disease is] heterogenous at the time of diagnosis. We also do not do regular, serial biopsies while the patient is receiving treatment. Unlike biopsy, FES is non-invasive, can assess the full burden of disease for functional ER expression, and can be repeated over time. 

Treatment-related changes can lead to heterogeneity being uncovered as well. The power of an imaging agent, which can assess functional ER expression, is that we can do a whole-body assessment of the burden of disease and assess for ER heterogeneity, either spatially at 1 point, or over time. That has changed the way we can assess and theoretically treat patients with ER-positive metastatic or recurrent breast cancer [since, again, we know that patients with FES-negative cancer are poor responders to endocrine therapy].

In the future, we might be able to use FES PET/CT for initial staging for breast cancers that are typically occult. Specifically, we’re evaluating [this in] invasive lobular carcinomas, which are hard to see on all [current] imaging modalities. [With] anatomic imaging, [such as] mammography, ultrasound, and magnetic resonance imaging, it can be difficult to grasp the burden of invasive lobular carcinoma, and this type of breast cancer can be minimally or non-avid on FDG PET/CT. However, typically, [invasive lobular carcinomas] express a high level of estrogen receptors, so they tend to be FES positive on FES PET/CT. [FES PET/CT is] not currently indicated for staging these patients but work right now is investigating this to see if we can use it in the future.

How is imaging used to determine treatment response in patients with ER-positive breast cancer?

When considering molecular imaging in metastatic breast cancer, [we use] FDG and FES PET imaging. [We use] FDG PET for initial staging. The NCCN guidelines [indicate that] initial staging with FDG PET/CT for patients with stage III or higher breast cancer [is optional and recommend this approach] in patients with inflammatory breast cancer.

We can also use FDG PET/CT to monitor changes over time. During treatment, we can do response assessment with FDG PET/CT. We can [also use FDG PET/CT] to assure ongoing response to therapy in patients with a good initial response. FDG PET/CT is a strong tool in our arsenal for this patient population.

[The use of] FES PET/CT [is different]. The indications [for FES PET/CT] are in patients with ER-positive recurrent or metastatic disease. Patients with ER-positive disease who have equivocal findings on other imaging modalities [may benefit from FES PET imaging. It is] not currently used for staging, but for identifying a biopsy target, clarifying indeterminate FDG [PET/CT] findings, or getting an overall assessment of disease burden in patients with known metastatic ER-positive disease. Absence of FES uptake at site of known or suspected active disease implies the loss of functional ER expression, which can be confirmed with biopsy and have significant implications on the patient’s treatment. 

One limitation of FES for imaging post-therapy is that ER-blocking agents, such as tamoxifen and fulvestrant, block FES uptake even if an active tumor is present. This receptor blockage does not happen if a patient is on aromatase inhibitors or CDK 4/6 inhibitors, so those patients can be imaged with FES. However, typically, we do not follow these patients over time with FES to assess their disease response, [since we do not currently have data for this indication]. This may be an indication in the future for patients on non–ER-blocking agents.

Instead, we can use FDG to follow for treatment response, even in patients who have FES-positive disease, as long as they demonstrated sufficient FDG uptake pre-therapy. In fact, imaging with both FES and FDG can be helpful, especially when standard staging studies are equivocal or confusing.

Can molecular imaging be used to assess the presence of adverse effects such as interstitial lung disease (ILD) in patients receiving fam-trastuzumab deruxtecan-nxki (Enhertu)?

While we would not use PET to specifically look for ILD associated with trastuzumab deruxtecan, we are often able to anecdotally recognize ILD by findings on CT. We typically do not use molecular imaging for ILD assessment or follow-up, and if we see concerning findings on a molecular imaging study, we usually recommend a dedicated chest CT for further characterization.

What ongoing research in this area are you excited about?

I’m excited about investigating FDG assessment in patients with oligometastatic disease. A recent article showed that FDG staging can find small, FDG-positive oligometastases that may not be seen in regular staging with anatomic imaging or a nuclear medicine bone scan. The feeling in the oncology community right now is that we don’t want to know about those tiny [metastatic] sites that might upstage a patient to stage IV [disease] and change [their] treatment management [from] curative intent. Also, maybe when we didn’t see [these metastatic sites], we were treating them anyway. Maybe we were curing those sites, and it’s better not to know.

However, the article brought to the forefront that finding those sites of oligometastatic disease may improve patient outcomes. What if we treat those oligometastatic sites? If there’s a single site of disease in a bone, instead of closing our eyes and ears to it, what if we [treat] it with radiation? Will that lead to a greater patient outcome in the end, and still [allow us to] treat these patients with curative intent? Maybe not all [patients with] stage IV disease would [qualify for] palliative intent. That’s exciting, to try to say [that although] FDG PET can be sensitive, maybe more sensitive than our prior imaging studies, that doesn’t necessarily mean we need to change our treatments in a major way. We can just fine-tune them and improve them to lead to better patient outcomes.

On the FES side, there’s a ton of research happening, [including investigating] staging for invasive lobular cancer because [those cancers] tend to be highly ER expressing and difficult to image. That is fabulous. Additionally, even low-grade invasive ductal carcinomas might be highly ER expressing and minimally FDG avid. Patients whose ordering provider would want an FDG PET [may get] dual imaging with FDG and FES to get a better understanding of the overall picture for better treatment and outcomes.

There is also research ongoing for other investigational agents with different targets in patients with breast cancer, such as agents that target the HER2 receptor or PARP enzyme. Lots of exciting work is happening in this field.

What is your main message for medical oncologists and radiologists about the use of molecular imaging in metastatic breast cancer?

Molecular imaging is an exciting modality. It’s powerful, but it does have nuanced indications and specific uses. The best way to help patients is to identify the correct patient populations to image with these different imaging modalities. Using FDG PET/CT in patients with locally advanced or metastatic disease has the most likelihood to affect treatment decisions.

[Similarly], for patients with ER-positive metastatic or recurrent breast cancer, FES PET/CT is a great imaging study, especially if they’re not currently on estrogen-blocking agents. [We can use this to] get a baseline and overall assessment of the entirety of their disease process and look for the burden of disease and heterogeneity. If you find an area that is suspicious for disease and not FES positive, biopsy it, and [if you] identify that it’s a [site] of ER-negative metastasis, that changes the way you treat [the patient] and could change [the patient’s] overall outcome. Oncologists should know that we now have more than one approved PET imaging agent that is useful for patients with breast cancer, with more likely to come in the future.