¹⁸F-FES Whole-Body Imaging Protocol for Evaluating Tumor Estrogen Receptor Status in Patients with Recurrent or Metastatic Breast Cancer

MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS

¹⁸F-FES has a 60%–100% relative binding affinity for the ER, making it an excellent tracer to image ERs throughout the body (2). The pharmacodynamics of ¹⁸F-FES uptake are directly proportional to tumor ER expression measured by in vitro assays: the higher the ER+ expression, the greater the uptake, and vice versa (3). According to the ¹⁸F-FES PI, the relationship between plasma concentrations and image interpretation has not been studied (3).

¹⁸F-FES is rapidly metabolized in the liver, and at 20 min after injection, approximately 20% of circulating radioactivity in the plasma is in the form of nonmetabolized ¹⁸F-FES. At 120 min after injection, less than 5% of the injected dose remains unmetabolized (3).

According to section 12.3 of the PI, 95% of ¹⁸F-FES is bound to plasma proteins after intravenous injection, and the tracer distributes primarily within the hepatobiliary system but also within the small and large intestines, heart wall, blood, kidney, uterus, and bladder. The critical organ is the liver, which receives 0.126 mGy/MBq (3). ¹⁸F-FES is also distributed systemically, with high physiologic uptake in the uterus and ovaries (2). The effective radiation dose resulting from an administration of 222 MBq (6 mCi) to an adult weighing 70 kg is estimated to be 4.9 mSv (3). Excretion is biliary and urinary (3).

PATIENT SELECTION

Physicians must keep several things in mind when selecting the right treatment options. The hormone receptor status in the primary tumor does not necessarily predict the hormone receptor status of metastatic lesions. A primary tumor may be heterotypical, having both ER+ and ER-negative receptors within the lesion instead of a single ER status type. Hormone receptor genes may be downregulated or lost in metastatic lesions (4), complicating accurate treatment decision-making. So, one treatment option might work for the ER+ primary tumor but not for a metastatic lesion whose receptor has become downregulated or lost and is now ER-negative. Lindstrom et al. noted that in about a third of patients, ER status can change after disease recurrence or progression and that a change to ER-negative was associated with a 48% increase in mortality (4). The ability to predict therapeutic response in distant lesions is critical to planning the approach to treating patients with metastatic disease, and ¹⁸F-FES ER imaging is like getting a noninvasive WB biopsy in which all ER+ lesions throughout the body can be visualized on the scan. Most importantly, ¹⁸F-FES ER imaging correlates well with immunohistochemistry results and may be able to predict response to endocrine therapy (5,6). Patients initially diagnosed with lobular breast cancer who are being worked up for recurrent or metastatic breast cancer are perfect candidates for ¹⁸F-FES WB imaging because lobular breast cancer tumors have a low affinity for ¹⁸F-FDG but a high affinity for ¹⁸F-FES. Figures 1 and 2 illustrate 2 patients with lobular breast cancer. ¹⁸F-FDG scans showed uptake in some tumors, but when patients 1 and 2 were scanned with ¹⁸F-FES at 1 d and 1 mo, respectively, after ¹⁸F-FDG PET, the ¹⁸F-FES scans showed multiple lesions not seen on the ¹⁸F-FDG PET scans.

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FIGURE 1.

Patient 1. History: ER+, HER2-negative, T2N0M0 left breast lobular carcinoma treated with neoadjuvant chemotherapy, surgery, adjuvant chemotherapy, radiation therapy, and 5 y of hormone therapy (tamoxifen). Eight years after treatment completion, T10 and T12 fractures emerged, and cancer antigen 15-3 was 3,500 U/mL (reference level, <25 U/mL). Outcome: all lesions expressed ERs on ¹⁸F-FES PET/CT. Accumulation was higher for ¹⁸F-FES than for ¹⁸F-FDG, probably because of lobular histology. Some lesions were barely seen with ¹⁸F-FDG. Treatment: aromatase inhibitor (exemestane), with lesion stabilization and cancer antigen 15-3 reduction from 3,500 to 1,50 U/mL 2 y after treatment began. (Reprinted from (10).)

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FIGURE 2.

Patient 2. History: ER+, progesterone receptor–negative, HER2-negative lobular carcinoma with initial bone metastases. Outcome: lesion heterogeneity (¹⁸F-FES PET/CT scan showing both ¹⁸F-FES–positive lesions [red arrows] and ¹⁸F-FES–negative lesions [blue arrows]). No uptake was seen on ¹⁸F-FES PET/CT scan for lesions that showed uptake on second ¹⁸F-FDG PET/CT scan (blue arrows). ¹⁸F-FES–positive lesions corresponded to progressive lesions seen with ¹⁸F-FDG (yellow arrows), potentially explaining progression with hormone therapy. Treatment: aromatase inhibitor (blocks ERs), which resulted in reduction or disappearance of ¹⁸F-FES PET signal; radiation therapy on T9 and left iliac bone; and exemestane, resulting in bone progression on L5 and left iliac bone. (Reprinted from (10).)

APPROPRIATE-USE CRITERIA FOR ER-TARGETED PET

In October 2022, the appropriate-use criteria for ER-targeted PET imaging with ¹⁸F-FES were created to help medical oncologists, breast surgeons, and interpreting physicians know when to order or not order ER-targeted PET imaging. The working group of experts determined that ordering ¹⁸F-FES PET imaging is appropriate in 3 instances: to assess for ER functionality when endocrine therapy is considered either at initial diagnosis of metastatic breast cancer or after progression of disease on endocrine therapy, to assess the ER status of lesions that are difficult or dangerous to biopsy, and to assess the ER status of lesions when other tests are inconclusive (7).

Inappropriate-use criteria must also be reviewed to make sure physicians are not ordering scans for patients who will not benefit. Ordering a ¹⁸F-FES scan inappropriately results in unnecessary radiation exposure to the patient, increased out-of-pocket costs to the patient, and unnecessary costs to the patient’s insurance company. The working group came up with 14 clinical scenarios in which ¹⁸F-FES PET imaging could be used, grouping the scenarios as “appropriate,” “may be appropriate,” or “rarely appropriate” on a scale from 1 to 9. Scores of 7–9 indicate that the procedure is appropriate for the scenario and is generally considered acceptable. Scores of 4–6 indicate that the procedure may be appropriate for the scenario; this implies that more evidence is needed to classify the scenario definitively. Scores of 1–3 indicate that the procedure is rarely appropriate for the scenario and is generally not considered acceptable (7). Table 1 outlines the scenarios and their scores.

CLINICAL INDICATION AND LIMITATIONS OF USE

¹⁸F-FES PET is indicated for detecting ER+ lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer (3). The ¹⁸F-FES limitations of use state that “Tissue biopsy should be used to confirm recurrence of breast cancer and to verify ER status by pathology. CERIANNA is not useful for imaging other receptors, such as human epidermal growth factor receptor 2 (HER2) and the progesterone receptor (PR)” (3).

PATIENT PREPARATION

The patient should be well hydrated before being injected. If a patient is of childbearing age, it is recommended that pregnancy status be checked per instruction guidelines. The ¹⁸F-FES PI states that “Certain classes of systemic endocrine therapies, including ER modulators and ER down-regulators, block ER, reduce the uptake of fluoroestradiol F 18, and may reduce detection of ER-positive lesions after administration of CERIANNA. Drugs from these classes such as tamoxifen and fulvestrant may block ER for up to 8 and 28 weeks, respectively. Do not delay indicated therapy to administer CERIANNA. Administer CERIANNA prior to starting systemic endocrine therapies that block ER” (3).

Additional information to keep in mind when imaging with ¹⁸F-FES is that lower estrogen levels will result in no or low uptake of ¹⁸F-FES (8). Aromatase inhibitors and the hormone therapy medication mentioned above block ERs and may reduce or eliminate the ¹⁸F-FES PET signal (8).

There are no contraindications before performing a ¹⁸F-FES scan (3); however, knowing when other recent nuclear medicine studies have been performed (radiopharmaceutical-dependent) can be helpful to ensure the highest-quality ¹⁸F-FES PET scan with no interference from any other radiopharmaceutical.

DOSE AND ADMINISTRATION

The recommended dose of ¹⁸F-FES is 222 MBq (6 mCi), with an acceptable dose range of 111–222 MBq (3–6 mCi). ¹⁸F-FES is intravenously injected over a 1- to 2-min time frame followed by a 0.9% sodium chloride flush to ensure proper dose delivery (2). It is preferred that ¹⁸F-FES be injected in an arm contralateral to the primary tumor site (2). The ¹⁸F-FES user guide “Seeing ClearER+” states, “Administering Cerianna through a central port is not contraindicated but is dissuaded” (2). ¹⁸F-FES may be diluted with 0.9% sodium chloride injection (3). Because ¹⁸F-FES imaging can begin anywhere from 20 to 80 min after injection (3), PET imaging departments can pick a postinjection scan time that best fits the department’s workflow. If most scans in the department are done at 45 min or 60 min after injection, then acquiring a ¹⁸F-FES scan at 45 or 60 min after injection is fine and is still follows the PI guidelines for imaging; however, scanning 80 min after injection is preferred (3).

Because ¹⁸F-FES is not glucose-dependent, light, noise, and sound will not affect uptake after tracer injection. Physical activity before a ¹⁸F-FES injection does not need to be avoided as it does for ¹⁸F-FDG. After ¹⁸F-FES is injected, as with all PET procedures, hydration and frequent voiding by the patient are suggested to help decrease radiation exposure. Physical activity is permitted after ¹⁸F-FES injection (2). Sedation can be given if needed before imaging, but patients should not be allowed to drive themselves home afterward.

ACQUISITION AND PROCESSING PARAMETERS

The acquisition and processing parameters for ¹⁸F-FES WB PET are fairly simple. The standard WB ¹⁸F-FDG acquisition protocol can be used for acquiring a WB ¹⁸F-FES scan. The first steps include cloning the existing ¹⁸F-FDG protocol and adding ¹⁸F-FES to the isotope inventory. Once ¹⁸F-FES is loaded into the isotope inventory, it is selected from the available isotopes and the imaging protocol is resaved as ¹⁸F-FES WB PET. With older PET scanners, it is important to increase the time per bed position by 30% (i.e., 3 min to 4 min or 5 min to 6.5 min) to acquire an adequate number of counts per bed position and ensure a good-quality scan. For PET/CT protocols, the manufacturer’s recommendations for CT acquisition parameters should be followed (2,3). Table 2 outlines other important acquisition settings, including PET scanner type, energy peak and energy window, preferred patient positioning, injection-to-scan time, and acquisition area. Preferred acquisition times, number of bed positions, and time per bed position are also listed.

Other important acquisition steps for a ¹⁸F-FES WB PET scan are to have the patient void before scanning, to position the patient supine on the imaging table with arms above head if possible, and to scan from vertex to mid thigh or knees (2). Once the scan is complete, it is also important to review the raw data for image quality and motion or any other defects that may require additional follow-up. If significant motion is detected, making a scan unreadable, the scan should be repeated.

It is recommended that processing of ¹⁸F-FES WB PET scans follow the Society of Nuclear Medicine and Molecular Imaging procedure standards for ¹⁸F-FDG PET/CT (2).

¹⁸F-FES TRACER DISTRIBUTION PATTERNS

Normal uptake of ¹⁸F-FES can be seen in the liver, gastrointestinal tract, kidneys, and urinary bladder (Fig. 3) (2). Increased uptake may also be seen in the injected vessel in most patients; the cause is unknown but is probably due to sticking of the tracer to the vessel wall or endothelial cells. If the uptake appears abnormal or questionable, the interpreting physician should be informed and should determine whether additional images are needed (e.g., a skull image illustrating 2 metastatic brain lesions is shown in Fig. 4).

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FIGURE 3.

Normal increased uptake of ¹⁸F-FES in liver (1), gastrointestinal tract (2), kidneys (3), urinary bladder (4), and injected vessel (5). Uptake in injected vessel, seen in most patients, is probably due to sticking of tracer to vessel wall or endothelial cells (2). (Courtesy of DRA Imaging.)

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FIGURE 4.

Abnormal uptake of ¹⁸F-FES. Although ¹⁸F-FDG WB imaging is not helpful in visualizing brain metastasis, ¹⁸F-FES WB imaging is. (A) WB ¹⁸F-FES image from vertex to mid thighs, with increased uptake in chest and brain. (B) Extra image of skull that clearly illustrates the 2 brain metastatic lesions (2). (Courtesy of DRA Imaging.)

IMAGE INTERPRETATION

Although training is not required for ¹⁸F-FES interpreters, it is strongly suggested. Information on training can be obtained through a Cerianna sales representative or the GE Healthcare website (https://landing1.gehealthcare.com/PDX-US-Cerianna-InterpreterTraining.html).

According to the ¹⁸F-FES user’s guide, in interpretation of an ¹⁸F-FES WB scan, “Detection of ER+ tumors should be based on comparison with tissue background outside of organs with high physiologic uptake and regions with high activity due to hepatobiliary and urinary excretion. As a general rule, all lesions with fluoroestradiol F 18 uptake greater than background (e.g., physiological liver uptake) are considered ER+”. Assessing ER expression in regions with normally high physiologic activity (e.g., liver) is not advised (2).

WARNINGS, PRECAUTIONS, AND ADVERSE REACTIONS

Several sections of the ¹⁸F-FES PI should be reviewed carefully, including the warnings and precautions (section 5) and the adverse reactions (section 6). The former includes a risk of misdiagnosis regarding inadequate tumor characterization and other ER+ pathology, stating, “Breast cancer may be heterogeneous within patients and across time. CERIANNA images ER and is not useful for imaging other receptors such as HER2 and PR. The uptake of fluoroestradiol F 18 is not specific for breast cancer and may occur in a variety of ER-positive tumors that arise outside of the breast, including from the uterus and ovaries. Do not use CERIANNA in lieu of biopsy when biopsy is indicated in patients with recurrent or metastatic breast cancer” (3). Another risk of misdiagnosis regards false-negative ¹⁸F-FES findings. Negative ¹⁸F-FES findings do not rule out ER+ breast cancer. Pathology or clinical characteristics that suggest a patient may benefit from systemic hormone therapy should take precedence over discordantly negative ¹⁸F-FES findings (3).

Regarding adverse reactions, the most common in over 1,200 injections during clinical trials were injection-site pain and dysgeusia (distortion of taste), occurring in less than 1% of patients (3).

USE IN SPECIAL PATIENT POPULATIONS

Use of ¹⁸F-FES in specific patient populations is also important to review. According to the PI (3), pregnant woman should be advised of the potential risks of fetal exposure to radiation doses, and lactating women should be advised to avoid breastfeeding for 4 h after administration. Regarding geriatric use, clinical studies did not reveal any difference in pharmacokinetics or biodistribution in patients aged 65 y or over.

BENEFITS OF ¹⁸F-FES ER IMAGING

There are many benefits to imaging with ¹⁸F-FES; WB imaging can be used when lesions are inaccessible or challenging to biopsy or when lesions are insufficiently suggestive to justify an invasive procedure. ¹⁸F-FES imaging is also beneficial when the tumor pathology is aggressive or a patient refuses biopsy. ¹⁸F-FES imaging can also evaluate potential disease heterogeneity. A study by Yang et al. showed that 37.5% of patients with metastatic breast cancer had a heterogeneous pattern of both ER+ and ER-negative lesions (6). Evaluating all lesions for their ER status is a critical step in determining the appropriate treatment option, helping improve the overall response to therapy, the patient’s outcome, and the patient’s ultimate survival. Breast imaging with ¹⁸F-FES can complement a patient’s biopsy and can noninvasively evaluate multiple areas of the body, including organs such as the brain, which standard ¹⁸F-FDG WB imaging cannot do.

Although ¹⁸F-FES imaging has many benefits, it does have some limitations. It has a limited ability to detect liver metastases because it has increased uptake in the liver due to increased hepatic metabolism (5). Considerable enterohepatic circulation can also complicate abdominal imaging when using ¹⁸F-FES (5). ¹⁸F-FES is not useful for imaging other receptors, such as human epidermal growth factor receptor 2 and the progesterone receptor.

From a sensitivity and specificity perspective, ¹⁸F-FES has a high accuracy for the detection of ER+ lesions, with proven concordance when compared with biopsy immunohistochemistry for determining ER status in metastatic breast cancer. The sensitivity of ¹⁸F-FES is 78% (95% CR, 65.0%–88.0%), and its specificity is 98% (95% CR, 65.0%–100%) (2). When evaluated for efficacy for assessing the ER status of non–primary breast cancer lesions, ¹⁸F-FES WB PET/CT interpretation and biopsy resulted in a 76.6% positive agreement (95% CR, 62.0%–87.7%; P = 0.0018) and a 100% negative agreement (95% CR, 90.8%–100%; P = 0.00053) (2).

SUPPORT WITH ¹⁸F-FES ACCESS

Sometimes when a radiopharmaceutical is newly approved by the Food and Drug Administration, it can be challenging to make sure an imaging facility gets reimbursed properly by Medicare and private insurance companies. When first imaging with ¹⁸F-FES, an imaging center and its billing department must confirm that they have all the billing and coding information, prior-authorization information, and any other information needed for insurance companies to correctly process the claim.

To help, GE Healthcare has created a network of reimbursement services and support ranging from benefits investigation support (determining a patient’s insurance coverage) to medical necessity support (Table 3). Requesting support requires submission of a Cerianna Support Provider Consent Form signed by the physician or provider (available by calling 833-946-6392 or visiting www.cerianna.com/reimbursement) (9).

DISCLOSURE

No potential conflict of interest relevant to this article was reported.