Background <p>Fibroblast activation protein (FAP)–targeted tracers have emerged as promising agents for breast cancer imaging, with recent studies demonstrating PET performance comparable to or surpassing, that of [¹⁸F]FDG. Nevertheless, data comparing [⁶⁸Ga]Ga-FAPI-46 and [¹⁸F]FDG uptake in hormone receptor and/or HER2–positive breast cancer (luminal-like vs HER2-positive) remain scarce. Aim of this study was to investigate the diagnostic performance of [⁶⁸Ga]Ga-FAPI-46 versus [¹⁸F]FDG PET/CT in patients with hormone-receptor and/or HER2-positive breast cancer, and to evaluate the uptake of both tracers stratified by molecular subtypes (luminal-like vs HER2-positive). A sub-analysis of a prospective observational trial (NCT04571086) was conducted. Patients with histologically confirmed, hormone receptor- and/or HER2-positive breast cancer who underwent whole-body [⁶⁸Ga]Ga-FAPI-46 and [¹⁸F]FDG PET/CT in the same week for initial staging or follow-up were included. [⁶⁸Ga]Ga-FAPI-46 or [¹⁸F]FDG PET-positive lesions were defined as visually increased lesion uptake compared to adjacent organ background. Semi-automatic segmentation was performed to determine SUVmax, SUVpeak, TLRpeak, total number of lesions, total tumour volume, and total tumour SUV mean. Data were compared between molecular subtypes (luminal-like vs HER2-positive).</p> Results <p>Thirteen patients were included. Overall, the detection performance was comparable between [⁶⁸Ga]Ga-FAPI-46 and [¹⁸F]FDG PET. The semi-quantitative analysis showed comparable mean uptake values in breast cancer lesions on [⁶⁸Ga]Ga-FAPI-46 and [¹⁸F]FDG PET/CT (SUV_max: 13.4 vs. 12.9; TLR_peak: 5.6 vs. 4.5) and revealed no significant differences in the median lesion count (4.5 vs. 5), mean total tumour volume (71.5 vs. 73.2 mL), or mean total tumour SUV_mean (5.4 vs. 5.4). No substantial differences between molecular subtypes (luminal-like vs. HER2-positive) were observed.</p> Conclusion <p>In this small exploratory cohort, comparable uptake patterns in [⁶⁸Ga]Ga-FAPI-46- and [¹⁸F]FDG-positive breast cancer lesions were observed across subtypes, underscoring the potential of [⁶⁸Ga]Ga-FAPI-46 as a versatile imaging tool. Future studies in larger cohorts are warranted to explore the potential of FAP-targeted theranostics in different breast cancer subtypes.</p> Trial registration <p>68-Ga-FAPI-PET for Tumor Detection: A Prospective Observational Trial, NCT04571086, 09-15-2020, <a href="https://clinicaltrials.gov/study/NCT04571086">https://clinicaltrials.gov/study/NCT04571086</a>.</p>