The Role of Estrogen Receptor–Targeted PET with 16α- ¹⁸ F-Fluoro-17β-Estradiol in Predicting Response to Endocrine Therapies in Metastatic Breast Cancer: A Metaanalysis

[¹⁸F]16α-fluoro-17β-fluoroestradiol ([¹⁸F]FES) PET/CT imaging enables whole-body assessment of functional estrogen receptor (ER) expression in metastatic breast cancer (mBC). Identifying imaging biomarkers that predict endocrine therapy (ET) response remains a critical need in optimizing treatment selection. Our objective was to assess the predictive utility of [¹⁸F]FES PET/CT imaging in determining response to ET, with a focus on interlesional heterogeneity and individual patient outcomes. <b>Methods:</b> A systematic literature review and metaanalysis were conducted using 6 major databases through April 2024. Ten studies met inclusion criteria based on quantitative SUV reporting, use of FES PET/CT in mBC, and correlation with clinical outcomes. All patients had ER-positive mBC and received ET. Primary endpoints included progression-free survival (PFS) and response to ET. Patients were stratified by baseline [¹⁸F]FES PET/CT SUV_mean or SUV_max thresholds (including 1.8) and by interlesional [¹⁸F]FES heterogeneity (presence of both [¹⁸F]FES-positive and [¹⁸F]FES-negative lesions). <b>Results:</b> Responders had a significantly higher baseline SUV_mean than nonresponders (standardized mean difference, 0.91; 95% CI, 0.49-1.34; <i>P</i> < 0.001). Patients with a baseline SUV_max below 1.5 were significantly less likely to respond (odds ratio, 0.11; 95% CI, 0.02-0.72; <i>P</i> = 0.02). Across 5 studies, patients with heterogeneous [¹⁸F]FES uptake had a shorter median PFS (2.4-12.4 mo) than did those with all [¹⁸F]FES-positive lesions (14.6-23.6 mo), a statistically significant difference (ratio of median PFS, 0.25; 95% CI, 0.17-0.36; <i>P</i> < 0.001). In an individual-level analysis (<i>n</i> = 101), lesion-level [¹⁸F]FES-heterogeneous uptake was associated with a PFS of 5.5 versus 21.6 mo and a hazard ratio of 5.4 (95% CI, 3.2-9.4; <i>P</i> < 0.001). An [¹⁸F]FES SUV_max threshold of at least 1.8 was more prognostic of PFS than were higher SUV_max thresholds. <b>Conclusion:</b> [¹⁸F]FES PET/CT imaging provides prognostic insight beyond static ER testing by identifying functional heterogeneity in mBC. Lesion-level FES heterogeneity based on an SUV_max threshold of 1.8 may help stratify patients unlikely to benefit from ET, guiding more personalized treatment strategies.