[18F]FES PET/CT for the Detection of Distant Metastasis in Low-grade ER-positive Stage III Breast Cancer

Breast cancer is highly prevalent, and approximately 75% of cases are estrogen receptor (ER)-positive. Stage III breast cancer carries a significant risk of distant metastasis; therefore, NCCN and ESMO guidelines recommend systemic staging with CT, bone scan, or 18F-FDG PET/CT. However, 18F-FDG PET/CT demonstrates limited sensitivity in low-grade ER-positive tumors and invasive lobular carcinoma (ILC), and can yield false positives due to inflammatory reaction or reactive hyperplasia. Thus, more accurate imaging modalities are needed in this subgroup.

18F-fluoroestradiol (18F-FES) PET/CT visualizes ER expression and has shown high concordance with histopathology. A phase III study demonstrated 77% sensitivity and 100% specificity for metastatic disease. Emerging evidence suggests that 18F-FES PET/CT may detect distant or regional lymph node metastases more accurately than standard imaging, particularly in ILC and low-grade tumors, and can influence management decisions such as surgery and radiotherapy planning.

Accurate identification of regional nodal involvement (axillary, supraclavicular, internal mammary nodes) is essential for determining the extent of axillary surgery after neoadjuvant chemotherapy and for tailoring regional nodal irradiation. Prior studies show that metabolic imaging can alter radiotherapy fields in up to 40% of patients.

The primary objective is to determine the patient-based detection rate of qualitative 18F-FES PET/CT for distant metastases. Secondary objectives include evaluating its patient-based sensitivity and specificity for distant metastases; determining the detection rate, sensitivity, and specificity for cN3 lymph node metastases (infraclavicular, supraclavicular, and internal mammary nodes); assessing the rate of management change attributable to 18F-FES PET/CT; and comparing 18F-FES PET/CT with 18F-FDG PET/CT for detection rate, diagnostic accuracy, and management impact. Exploratory analyses will examine the correlation between qualitative and quantitative 18F-FES PET/CT findings and pathological response to neoadjuvant chemotherapy.

Inclusion criteria

• Male or female patients aged ≥19 years, regardless of race/ethnicity
• Patients newly diagnosed with invasive breast cancer within 90 days prior to screening, with documented histopathological confirmation.
• Patients diagnosed with histologically confirmed estrogen receptor-positive, histologic grade 1 or 2 primary breast cancer
• Patients with clinical stage IIIA-IIIC disease according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system
• Patients who have undergone, or are scheduled to undergo chest computed tomography (CT), abdominal CT, and bone scintigraphy within 90 days prior to screening before the 18F-FES PET/CT scan
• Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≤2

Exclusion criteria

• The subject or the subject's legally authorized representative has not signed the informed consent form
• Subjects who are currently receiving systemic therapy for breast cancer (e.g., neoadjuvant chemotherapy, hormonal therapy)
• Subjects with a history of another invasive malignancy within the past 2 years (except for non-melanoma skin cancer)
• Subjects diagnosed with distant metastases on chest CT, abdominal CT, or bone scintigraphy performed within 90 days prior to screening or before the 18F-FES PET/CT scan
• Subjects for whom neither biopsy nor ≥6 months of follow-up imaging has been performed for lesions suspicious for distant metastases
• Pregnant or breastfeeding women. The following cases are considered not at risk of pregnancy: (1) physiologically postmenopausal (no menses for ≥2 years), (2) surgically sterile (history of bilateral oophorectomy or hysterectomy), (3) women of childbearing potential with a documented negative serum or urine pregnancy test within 24 hours prior to 18F-FES administration, and who agree to use effective contraception during the trial.
• Subjects with serious and/or uncontrolled and/or unstable medical conditions (e.g., congestive heart failure, acute myocardial infarction, severe pulmonary disease, chronic kidney disease, or chronic liver disease)
• Subjects who are relatives or students of the investigator, or otherwise in a dependent relationship with the investigator
• Subjects who, in the judgment of the investigator, are unable to provide complete data for the clinical trial due to personal circumstances or other reasons