The use of 18F-fluoroestradiol (FES) PET/CT in managing estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) is an innovative approach to assess the functional status of estrogen receptors throughout the body. This helps determine the likelihood of response to endocrine therapy (ET), which is a primary treatment for ER+ breast cancer. In the ET-FES trial, researchers are investigating the predictive value of FES PET/CT in patients with ER+/HER2− MBC.

Here’s a general outline of the ET-FES trial:

1. Patient Selection: Patients with ER+/HER2− MBC would be selected to participate in the trial. These patients are typically those who would be considered for endocrine therapy due to the nature of their cancer’s receptor status.

2. FES PET/CT Imaging: Participants would undergo FES PET/CT imaging before initiating endocrine therapy. FES, a radiolabeled analog of estrogen, binds to estrogen receptors, and its uptake can be visualized and quantified using PET/CT. This allows for the visualization of ER expression in both primary and metastatic sites.

3. Assessment: The level of FES uptake is quantified, and the distribution pattern is assessed. High uptake of FES in tumors indicates functional estrogen receptors and suggests that the tumor may be responsive to endocrine therapy.

4. Endocrine Therapy: Patients would then receive standard endocrine therapy as part of their treatment for MBC.

5. Follow-Up and Analysis: The trial would monitor the patient’s responses to therapy, typically through clinical assessments, imaging studies, and possibly biomarker evaluations. The initial FES uptake measurements would be correlated with the clinical outcomes to determine the predictive value of the FES PET/CT imaging.

6. Outcome Measures: The primary outcome measure would likely be progression-free survival (PFS), with secondary measures possibly including overall survival (OS), response rate (RR), and quality of life (QoL).

FES PET/CT imaging, using 16α-18F-fluoro-17β-estradiol (FES) radiotracer to assess estrogen receptor (ER) expression in metastatic breast cancer (MBC), offers several benefits such as non-invasive detection of ER expression and potential for treatment monitoring. However, there are several potential limitations and challenges:

1. Availability and Cost: FES PET/CT imaging may not be widely available in all healthcare settings, limiting accessibility for patients. Additionally, it can be costly, which may restrict its use to certain institutions or specific clinical trials.

2. Radiotracer Specificity: While FES binds to ERs, the specificity of FES PET/CT imaging for distinguishing ER-positive from ER-negative lesions can vary. This variability may impact the accuracy of treatment decisions based on imaging results.

3. Timing and Interpretation: The timing of FES PET/CT imaging in relation to hormonal therapies can influence results. Interpretation of FES uptake requires consideration of various factors, including physiological uptake in normal tissues and background activity, which can affect the accuracy of lesion detection and ER status assessment.

4. Lesion Detection Sensitivity: FES PET/CT imaging may not detect small lesions or metastases with low ER expression levels effectively. This limitation could potentially lead to false-negative results or underestimation of disease burden.

5. Clinical Utility and Impact on Treatment Decisions: The clinical utility of FES PET/CT imaging in guiding treatment decisions, such as selecting hormonal therapies or assessing response to treatment, needs further validation through clinical trials and comparative studies with standard imaging modalities.

6. Integration with Standard of Care: Integrating FES PET/CT imaging into existing clinical practices and treatment algorithms requires coordination among multidisciplinary teams and may involve additional logistical challenges. Moreover, regulatory approval and reimbursement policies may vary across regions, impacting the routine use and adoption of FES PET/CT imaging in clinical practice.

Addressing these limitations involves ongoing research to refine imaging protocols, validate its clinical utility in large patient cohorts, and establish guidelines for optimal use in managing ER+/HER2− MBC. Collaborative efforts between oncologists, radiologists, and researchers are crucial to overcome these challenges and maximize the potential benefits of FES PET/CT imaging in personalized cancer care. If the ET-FES trial demonstrates that FES PET/CT can accurately predict which patients will respond to endocrine therapy, it could become a valuable tool in the personalized treatment of ER+/HER2− MBC. This would allow oncologists to tailor therapy more effectively, possibly sparing patients from ineffective treatments and guiding them toward therapies with a higher likelihood of success.