Abstract P2-07-10: The role of [18F]16α-Fluoro-17Î2-Fluoroestradiol (FES) Positron Emission Tomography (PET) in Predicting Response to Endocrine Therapy (ET)

Abstract Background: Seventy percent of breast cancers (BC) are estrogen receptor-positive (ER+). ET improves clinical outcomes in ER+ BC; however, ET effectiveness relies on functional ER. While immunohistochemistry (IHC) is routinely used to quantify ER presence in sampled tissue, its clinical utility has inherent limitations. ER+ by IHC does not confirm function of ER, as illustrated by up to 50% of patients experiencing disease progression while on ET. FES is a radiolabeled form of estrogen and quantification of functional ER binding via FES PET may render important guidance on potential response to ETs, thus optimizing patient management, avoiding futile therapy or associated toxicities, and reducing financial burden. FES PET quantification, as measured by standardized uptake value (SUV), informs on functional ER and ER heterogeneity. This meta-analysis evaluated FES SUVmax and heterogeneity with clinical outcomes following ET. Methods: A systematic review identified five studies with comparable FES SUV and progression-free survival (PFS) measures; patient-level data was obtainable from three studies. All patients had advanced ER+ BC and received ET (n = 53, Palbociclib + ET; n = 48, Fulvestrant monotherapy); all patients were scanned on a Siemens PET/CT. Using Syngo software, two board-certified nuclear medicine physicians measured FES SUVmax per lesion. The number and percentage of FES-positive (FES+) lesions were calculated per patient. A lesion with FES SUVmax > 1.8 was defined as ER+ and heterogeneity as 1-99% of lesions FES+; other thresholds for FES SUVmax and % heterogeneity were considered. PFS was defined as time from initiating ET until disease progression/death from any cause and was censored at last follow-up. PFS was estimated via the Kaplan-Meier method. Cox proportional hazards regression was used to evaluate associations between FES+ and PFS, summarized via hazard ratios (HRs). HRs were estimated using different thresholds to define FES+ lesions (SUVmax from 1.8-6) and different thresholds for heterogeneity (e.g., 1-X% vs. (X+1)-100% FES+ lesions, X from 50-99%). Results: The individual-level data was merged, resulting in 101 distinct patients with 878 quantified lesions (median lesions/patient [inter-quartile range]: 7 [4 - 12]). By FES PET, 40% had only visceral lesions; 31% bone and soft tissue; 16% bone only; and 14% soft tissue only. Lesions were homogeneous (100% FES+) in 75% of patients and heterogeneous in 25%. Overall, 64% of patients progressed or died over follow-up (median PFS: 13.1 months). mPFS was less in the heterogeneous vs. homogeneous group (5.5 vs. 21.6 months), with a corresponding HR for progression or death of 5.4 (95% confidence interval [CI]: 3.2-9.4, p < 0.001). When the SUVmax threshold for FES+ was raised from 1.8, the HR for heterogeneous vs. homogeneous decreased, ranging from 1.1 (95% CI: 0.6-2.0) to 3.3 (95% CI: 2.0-5.5). Similarly, when the heterogeneity threshold was lowered from 99%, the HR also tended to decrease compared to when 1-99% vs. 100% was used, ranging from 1.8 (95% CI: 0.4-7.3) to 5.2 (95% CI: 3.0-8.9). No combination of SUVmax or heterogeneity thresholds resulted in a higher HR than the original combination. Conclusion: To our knowledge, this analysis is the largest individual-level data cohort to date assessing the predictive value of FES in patients receiving ET. FES was strongly predictive of PFS using a threshold of SUVmax > 1.8 for FES+ and 1-99% for heterogeneity threshold. Raising the threshold for SUVmax or heterogeneity did not improve risk stratification. Any amount of heterogeneity was associated with shorter PFS with ET compared to patients with homogeneous FES+ expression. The results support the utility of FES in predicting clinical benefit to ET but warrant further analysis to support more routine use in clinical practice. Citation Format: Nicholas DiGregorio, Hannah Linden, Jennifer Specht, Dan Hippe, Jasper van Geel, Song Shaoli, Liu Cheng, Christine Brand. The role of [18F]16α-Fluoro-17Î2-Fluoroestradiol (FES) Positron Emission Tomography (PET) in Predicting Response to Endocrine Therapy (ET) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-07-10.