Abstract Background: Aromatase inhibitors (AIs), such as letrozole and vorozole, block the final step of estrogen biosynthesis and have been associated with improved survival outcomes in postmenopausal women with hormone receptor - positive breast cancer (BC). Prior studies have validated the utility of 11C-Vorozole PET imaging in detecting aromatase expression in vivo in aromatase-expressing breast tumors. In this study, we aimed to further investigate: (1) differences in aromatase expression in affected and non-affected breasts between ER-positive (ER+) and ER-negative (ER-) patients at baseline and following letrozole administration, and (2) correlations between changes in 11C-Vorozole PET signal and clinical outcomes. Methods: Nineteen postmenopausal women with BCs underwent baseline 11C-Vorozole PET imaging, followed by a single 2.5 mg dose of letrozole. A repeat PET scan was obtained two hours post-ingestion. Mean standardized uptake values (SUVs) were measured at baseline and after letrozole administration in regions of interest including the bilateral breasts and thoracic spine. Clinicopathological characteristics and prior AI treatment history were extracted from the electronic medical record. Continuous variables were compared using the Wilcoxon rank-sum test, and correlations were assessed using Spearman’s rank correlation coefficient. A two-sided p-value 0.05 was considered statistically significant. Results: The average patient age was 63.8 years. Of the 19 patients, 13 had invasive ductal carcinoma and 6 had invasive lobular carcinoma. Ten patients had early-stage disease, and nine had stage IV breast cancer. Fourteen tumors were ER+ and five were ER-. Most patients (n=16) had HER2-negative disease. SUV signals in diseased and healthy breasts were not significantly different in either ER+ or ER- patients at baseline or after letrozole. SUV suppression ranged from -25.8% to 49.6% in the diseased breast following letrozole intake. There was no difference in SUV signal in the whole thoracic spine between patients with and without metastases, but most biopsy-confirmed vertebral metastatic lesions presented high 11C-Vorozole signal. Among ER+ patients with concurrent FDG-PET, signal distribution was largely concordant between FDG and 11C-Vorozole. However, several FDG-negative lesions showed positive 11C-Vorozole uptake and were confirmed malignant by pathology. In early-stage ER+ disease, the average time to progression on AIs was 49.5 months versus 25.9 months in stage IV cases. Baseline SUV and post-letrozole suppression did not correlate with time to progression. Notably, patients with increased 11C-Vorozole uptake post-letrozole had a shorter average time to progression than those with decreased signal (20.9 vs. 30.4 months), though this difference did not reach statistical significance (P=0.63). Conclusions: 11C-Vorozole PET demonstrated higher sensitivity than FDG-PET in detecting certain metastatic lesions. An increase in 11C-Vorozole uptake following letrozole administration may signal resistance to AIs given unsuppressed aromatase expression, and correlate with shorter progression-free survival. These findings suggest that 11C-Vorozole PET has potential as a predictive imaging biomarker to identify patients who may benefit from early alternative treatments such as fulvestrant. Citation Format: L. Lei, G. Sharma, J. Ying, X. Zhang, H. Wang, J. Cohen, A. Biegon, S. Gandhi, C. Huang. ¹¹C-vorozole pet as a predictive imaging biomarker of aromatase inhibitor resistance in postmenopausal er-positive breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-06-23.
Lei et al. (Tue,) studied this question.