Invited Commentary: A Recently Approved PET Imaging Agent to Guide Breast Cancer Therapy

See also the article by O’Brien et al in this issue.

Breast cancer is the most common malignancy diagnosed in women and the second-leading cause of cancer-related deaths in the United States (1). Hormone receptor–positive breast cancer is the most common subtype, defined as the expression of estrogen receptor (ER) and/or progesterone receptor. The standard treatment for patients with hormone receptor–positive breast cancer is endocrine therapy that inhibits ER function and blocks estrogen stimulation of tumor growth. To determine whether endocrine therapy is indicated, ER expression is assessed using tissue biopsy with immunohistochemical analysis as the standard of care. This approach has some limitations such as sampling error, false-negative or nondiagnostic results, and inaccessible biopsy sites. Furthermore, ER immunohistochemical results obtained from a single lesion may not fully reflect all sites of metastatic disease, which may have distinct responses to endocrine therapy (ie, spatial heterogeneity).

Fluorine 18 (¹⁸F) fluoroestradiol (FES) is a radiolabeled estrogen that binds to ER protein (2). FES can be used with PET as a noninvasive method for localizing sites of functional ER throughout the body. Lesions with nonfunctional ER that cannot bind estrogen are not detected with FES PET (3). In 2020, FES was approved by the U.S. Food and Drug Administration (FDA) under the trade name Cerianna for patients with recurrent or metastatic breast cancer as an adjunct to biopsy to detect ER-positive lesions, with subsequently increasing adoption in clinical practice. Patients appropriate for FES PET include both premenopausal and postmenopausal women (because FES uptake is not affected by circulating physiologic estrogen) and men with recurrent or metastatic ER-positive breast cancer. A strong correlation has been established between FES uptake measured with PET and ER protein measured with tissue immunohistochemical analysis (4). Furthermore, authors of a large prospective multicenter study found excellent positive predictive value (93%) and negative predictive value (85%) of FES uptake and ER protein in biopsied metastases (5). Thus, there is strong evidence supporting the validity of FES PET/CT to assess ER status in patients with metastatic or recurrent breast cancer.

In an image-rich review in this issue of RadioGraphics, O’Brien et al (6) detail the clinically approved uses of FES and its potential future applications. This high-quality educational article includes numerous cases demonstrating FES PET and its imaging features and how it adds clinically relevant information to conventional imaging (eg, CT and bone scintigraphy) and fluorodeoxyglucose (FDG) PET. The article is timely and complementary to the appropriate use criteria recently released by the Society of Nuclear Medicine and Molecular Imaging (7). Current uses of FES PET include (a) assessment of the whole-body disease burden of ER-positive breast cancer, (b) evaluation of spatial differences and temporal changes in the ER status of metastases, (c) resolution of equivocal conventional imaging findings, and (d) identification of a target lesion for confirmatory biopsy. FES PET has been used as a problem-solving tool to resolve clinical dilemmas that remain after inconclusive results from conventional workup and to improve the care of patients with ER-positive breast cancer by resulting in a change in treatment (8). Thus, FES PET has a high potential clinical impact to optimize patient care.

Simple preimaging preparation and imaging protocols for FES PET facilitate clinical implementation into current nuclear medicine workflows. For example, there are no fasting or exercise restrictions. Unlike with FDG, blood glucose testing is not necessary and recent administration of a vaccine does not interfere, because FES uptake is not seen in patients with reactive lymphadenopathy. FES is administered as a 1–2–minute intravenous infusion followed with a saline solution flush. The recommended administered activity of FES is 6 mCi (222 MBq). Most institutions use a 1-hour uptake time, which integrates well in current scheduling templates for administration of other PET radiopharmaceuticals such as FDG.

O’Brien et al (6) educate the reader on proper imaging interpretation, starting with the normal physiologic biodistribution of FES. The biodistribution of FES markedly differs from that of FDG. FES is a steroid-based radiopharmaceutical that is metabolized in the liver. Thus, there is relatively high activity in the liver, gallbladder, and small bowel, which reduces sensitivity for detecting ER-positive metastases in these locations. However, minimal activity is seen in the colon because of small bowel resorption and renal excretion of FES metabolites. The draining vein from the location of FES injection is routinely observed despite saline solution flushing. Unlike that with FDG, there is minimal background uptake of FES in the brain, which increases the conspicuity of ER-positive brain and dural metastases and helps with the diagnostic challenges of FDG PET and contrast-enhanced brain MRI to distinguish between disease recurrence and radiation necrosis (9). Endometrial uptake of FES can be visualized in pre- and postmenopausal patients because of normal ER expression in the uterus. Normal ER expression is also seen in the ovaries, but ovarian uptake of FES on PET/CT images has not been reported.

FES uptake identified in nonphysiologic sites that is visually higher than that of the background should be considered suspicious for ER-positive metastases when interpreting FES PET/CT studies. This approach is supported by evidence from meta-analyses demonstrating high specificity (98%) of FES for ER-positive metastases in patients with breast cancer, with immunohistochemical analysis as the reference standard (10). In addition to this qualitative assessment, quantitative evaluation with a cutoff maximum standardized uptake value of 1.5 has been used in many studies. An important interpretation tip O’Brien et al note is to adjust the window of the PET images (upper window standard uptake value, 2.5–5), because the magnitude of FES uptake in ER-positive breast cancer is generally lower than that observed with other radiopharmaceuticals. Using optimal viewing conditions and interpretive approaches, FES PET has high sensitivity (78% [10] to 95% [5]) for detection of ER-positive metastases, particularly in the bone, lymph nodes, lungs, and brain.

An important feature of the article by O’Brien et al is a discussion of the limitations of FES PET/CT. The most substantial limitation is the high background activity in the liver from normal hepatic metabolism of FES, which reduces the detection of ER-positive liver metastases. False-positive findings include radiation pneumonitis and fibrosis and mild uptake in lung atelectasis. Furthermore, a few benign nonbreast masses can be ER-positive with FES uptake, which has been reported in uterine fibroids and meningiomas. Some gynecologic malignancies can also show ER expression and FES avidity. False-negative results can occur if the lesion is small, with low ER expression, or if the lesion is within or near organs with high physiologic background activity. False-negative results are also possible if patients are imaged while taking selective ER modulators (tamoxifen) or selective ER degraders (fulvestrant), because these are endocrine therapy agents that bind to ER and block FES uptake. Patients treated with aromatase inhibitors or cyclin-dependent kinase 4 or 6 inhibitors can be imaged with FES PET while they are undergoing therapy, because these therapies do not bind to ER. Practical limitations of FES PET/CT such as barriers to more widespread implementation, remaining geographic limitations in FES availability from commercial suppliers, and variable insurance coverage through private payors are not discussed in the article.

The article also highlights uses of FES PET that extend beyond its current FDA-labeled indication. There is considerable evidence supporting FES PET as a predictive biomarker for clinical benefit of endocrine therapy in patients with metastatic ER-positive breast cancer. The clinical impact of FES PET/CT is to help medical oncologists decide between targeted endocrine therapy (if FES positive) and nonspecific chemotherapy (if FES negative). This decision is especially relevant in patients with disease progression after first-line endocrine therapy, because different types of endocrine therapy agents are tried as second- and third-line therapies without a repeat biopsy. FES PET at these critical time points would allow determination of whether metastatic lesions with functional ER remain present after treatment-specific pressure and clonal evolution (temporal heterogeneity). Results of large prospective multicenter trials will be published soon to confirm the clinical value of FES PET as a companion diagnostic for endocrine therapies targeting ER. There is also enthusiasm based on small studies suggesting that FES may be of clinical utility as a staging tool for patients with newly diagnosed or recurrent invasive lobular carcinoma, which is frequently strongly ER positive and manifests more false-negative results with conventional imaging that does invasive ductal carcinoma. Lastly, there is increasing incorporation of FES PET in development of ER-targeted drugs. Dose escalation studies in early-phase clinical trials of ER antagonists have used FES PET to determine the optimal drug dose that maximizes ER binding (preventing FES binding) with the fewest adverse effects.

Given the growing number of newly approved radiopharmaceuticals and radiotherapeutics in oncology, there is increased need for education of nuclear medicine physicians, radiologists, and referring physicians about their appropriate uses. The article by O’Brien et al (6) is an excellent resource as clinical implementation of FES PET/CT expands. An online reader training course for FES PET that includes additional case examples and clinical scenarios is available on the Society of Nuclear Medicine and Molecular Imaging Learning Center website (https://www.snmmi.org). Nuclear medicine physicians and radiologists who are well educated on the appropriate uses of FES PET can add valuable discussion to multidisciplinary conferences to aid in the treatment of patients with ER-positive breast cancer.