Evaluating tumor genomics and FES-PET in estrogen receptor–positive (ER+) breast cancer (BC).

e15072 Background: 18 F-fluoroestradiol positron emission tomography (FES-PET) is a highly specific imaging modality for detecting estrogen receptor-positive (ER+) breast cancer (BC), particularly when biopsy is not feasible or conventional staging is equivocal. Endocrine therapy (ET) resistance often develops during ER+ BC treatment and arises from genomic alterations that promote estrogen-independent signaling and, for some alterations, reduced ER expression. As clinical use of FES-PET expands, understanding the potential impact of these alterations on FES-PET avidity is important. Therefore, we assessed the relationship between tumor genomic profiles and FES-PET positivity in ER+ BC. Methods: We conducted a single-center retrospective study of patients with histologically confirmed ER+ BC at diagnosis who underwent FES-PET/CT or PET/MR between 12/2023-8/2025 and had blood- or tissue-based genomic testing within 6 months of imaging. Human epidermal growth factor receptor 2-positive (HER2+) and negative (HER2-) tumors were included. FES-PET positivity was defined as SUVmax >1.5 in the most avid lesion, assessed by a board-certified nuclear radiologist. Results: Forty-three patients were included (4 local recurrences, 39 metastatic). FES-PET was positive in 22 patients, was non-avid in 9, had mixed ER+ and ER- disease in 2, was indeterminate in 2, and showed no evidence of disease in 8. Of the 9 non-avid FES-PET cases, 3 had ER+ disease on biopsy at metastatic recurrence, 4 had ER- disease, and 2 had mixed ER+ and ER- disease. Genomic profiling was performed via liquid biopsy (n = 33), tissue-based testing (n = 9), or both (n = 1). PIK3CA and TP53 mutations were the most frequent alterations seen in 15 and 11 patients, respectively; 9 patients with PIK3CA mutations and 6 with TP53 alterations had a positive FES-PET. ESR1 mutations were identified in 5 patients, 4 with a positive FES-PET. FGFR1 amplification was seen in 3 patients; one had a strongly positive FES-PET, one had mixed ER+ and ER- lesions, and one had a negative FES-PET despite ER+ disease. KRAS mutations were present in 3 patients; two had a positive FES-PET. The other had ER- disease at recurrence and negative FES-PET. RB1 loss was seen in 2 patients; one had a negative FES-PET in the setting of ER- disease at recurrence, the other had mixed ER+ and ER- lesions. ERBB2 mutations were identified in 2 patients; one had a positive FES-PET, the other had lesions too small to characterize. Conclusions: FES-PET is a valuable imaging tool, though false-negative results can occur and may limit its suitability for initial staging in advanced ER+ BC. In this cohort of ER+ BC patients undergoing FES-PET with concurrent genomic profiling, heterogeneity in FES avidity was seen across multiple genomic alterations associated with resistance to antiestrogen therapies. Further evaluation in a larger cohort is ongoing; updated findings will be presented at the meeting.