[ ¹⁸ F] Fluoroestradiol PET/CT to guide second-line treatment decision-making in patients with estrogen receptor–positive, HER2-negative advanced breast cancer after progression on first-line aromatase inhibitor and CDK4/6 inhibitor: Primary results of ESTROTIMP.

1077 Background: Despite availability of novel endocrine treatment (ET) options for patients with ER+ HER2- ABC, many patients experience early disease progression under 2 nd line ET-based regimen after AI+CDK4/6i, underscoring a significant rate of endocrine resistance. Timely identification of endocrine-refractory disease at progression under 1 st line is critical to optimize treatment selection and consider non-ET strategies, such as antibody-drug conjugates or chemotherapy. FES PET/CT enables a non-invasive, whole-body assessment of ER expression; absent or heterogeneous FES uptake may indicate ER loss or downregulation, key mechanisms of resistance. Our objective was to evaluate the impact of FES PET/CT on 2 nd line treatment decisions. Methods: In this non-randomized prospective multicenter trial (NCT05486182), patients with ER+ HER2- ABC progressing on 1 st line AI+CDK4/6i underwent standard-of-care FDG PET/CT followed by FES PET/CT. Oncologists prospectively documented therapeutic management plans, before and after FES PET/CT. Patients rated pain and apprehension for FES PET/CT vs. biopsy on a Visual Analogue Scale. Primary endpoint was the proportion of patients with a therapeutic management change after FES PET/CT, and primary objective was to demonstrate that at least 10% of patients had their therapeutic management changed after FES PET/CT (Wald test). Results: Of 153 patients enrolled, 129 were evaluable for the primary endpoint. When compared with FDG PET/CT, FES uptake was classified as “all lesions ER+” in 65 (50%), “mixed ER+/- lesions” in 38 (30%), and “all lesions ER-” in 25 (19%) patients. Therapeutic management was changed based on incorporation of FES PET/CT results in 46/129 patients (35.7%; 96% CI [27.0-44.3], p<0.0001), including treatment type (n=38), diagnostic modalities (n=8), and planned follow-up (n=12). Treatment changes mostly consisted of using chemotherapy instead of ET (n=16), ET instead of chemotherapy (n=3), adding targeted therapy to single agent ET (n=2), changing the targeted therapy paired with ET (n=8), adding radiation therapy to disease sites (n=4), and performing surgery (n=2). Oncologist confidence in FES PET/CT was on average 7.8/10 (Q1-Q3: 7-9). Patients reported significantly lower pain and apprehension for FES PET/CT vs. biopsy (Pain: Mean 0.8 vs 4.5; Apprehension: Mean 1.8 vs 5.2; both p<0.0001). Conclusions: ESTROTIMP shows that, at progression under AI+CDK4/6i, ER expression is completely or partially lost in about half of patients with ER+ HER2- ABC. The trial reached its primary endpoint, demonstrating a clinically meaningful impact on therapeutic management, and supporting the use of FES PET/CT as a standard workup at time of progression under 1 st line AI+CDK4/6i. Clinical trial information: NCT05486182 .