Uptake Patterns of [¹⁸F]Fluoroestradiol PET/MRI in Benign Breast Lesions and Molecular Breast Cancer Subtypes

Background/Objectives: Estrogen receptor (ER) expression is a key biomarker in breast cancer (BC) and guides endocrine therapy selection. Estrogen receptor-targeted imaging with 16ɑ-[¹⁸F]-fluoro-17β-estradiol (¹⁸F-FES) PET is recommended in several clinical guidelines for noninvasive assessment of ER status. In clinical practice, ¹⁸F-FES PET may also identify ER-negative malignancies or benign breast lesions with variable uptake patterns. This study aimed to systematically characterize ¹⁸F-FES PET/MRI uptake patterns in benign breast lesions and across breast cancer subtypes defined by receptor status, histology, and molecular phenotype. Methods: This retrospective single-center study included 41 women with 50 breast lesions who underwent simultaneous ¹⁸F-FES PET/MRI prior to any treatment. Histopathology or long-term follow-up served as the standard of reference. Maximum and mean standardized uptake values (SUVmax and SUVmean) were derived using MRI-based lesion delineation. Results: Both benign and malignant breast lesions measuring < 10 mm demonstrated low ¹⁸F-FES uptake (SUVmax < 1.00). ¹⁸F-FES uptake among benign breast lesions was variable, with SUVmax ranging from 0.44 to 1.57. In contrast, ER-positive lesions ≥ 10 mm exhibited substantially higher ¹⁸F-FES uptake (median SUVmax 2.76; range 1.23-9.74) compared with ER-negative tumors of similar size (SUVmax 0.30-0.94). ¹⁸F-FES uptake was consistent across histologic BC subtypes and did not differ significantly among ER-positive molecular subtypes. No significant associations were observed with HER2 status or tumor grade. Conclusions: Awareness of the heterogeneous ¹⁸F-FES uptake patterns in benign breast lesions, as well as the limited sensitivity for detecting ER-positive tumors < 10 mm, is essential for accurate image interpretation. ¹⁸F-FES PET/MRI enables reliable assessment of ER expression in BC lesions ≥ 10 mm, with uptake patterns remaining consistent across molecular and histologic subtypes.