Objective <p>Breast cancer is the most common malignancy among women and remains the leading cause of cancer-related death in this population. Radionuclide-based diagnostic and therapeutic approaches have emerged as effective and low-risk strategies for management of breast cancer. This study aimed to evaluate the diagnostic performance of [⁶⁸Ga]Ga-FAP-2286 PET/CT compared with [¹⁸F]FDG PET/CT, and to provide a preliminary assessment of the clinical potential of [¹⁷⁷Lu]Lu-FAP-2286 radionuclide therapy in patients with advanced breast cancer.</p> Methods <p>A total of twenty patients with clinically suspected recurrent or metastatic breast cancer were prospectively enrolled. All participants underwent both [¹⁸F]FDG PET/CT and [⁶⁸Ga]Ga-FAP-2286 PET/CT imaging within one week. The positivity rate of lesions, maximum standardized uptake value (SUVmax), and tumor-to-background ratio (TBR) were compared between the two imaging modalities across different involved organs. In addition, four patients received a single cycle of [¹⁷⁷Lu]Lu-FAP-2286 radionuclide therapy, and were followed for 4 months to assess therapeutic response and safety.</p> Results <p>The total number of lesions detected by [⁶⁸Ga]Ga-FAP-2286 PET/CT was significantly higher than that detected by [¹⁸F]FDG PET/CT (85.4% vs. 70.5%, <i>P</i> &lt; 0.001). This superiority was particularly evident for hepatic metastases (94.7% vs. 68.9%, <i>P</i> &lt; 0.001) and bone metastases (85.8% vs. 66.4%, <i>P</i> &lt; 0.001). In contrast, both modalities demonstrated comparable sensitivity in identifying primary breast tumors (100% vs. 100%), regional lymph node metastases (85.4% vs. 81.4%, <i>P</i> = 0.388), and distant lymph node metastases (84.2% vs. 75.0%, <i>P</i> = 0.159). With respect to semiquantitative parameters, [⁶⁸Ga]Ga-FAP-2286 PET/CT demonstrated significantly higher uptake in bone metastases than [¹⁸F]FDG PET/CT (SUVmax: 8.7 ± 3.9 vs. 6.7 ± 2.8, <i>P</i> = 0.002; TBR: 5.4 ± 2.2 vs. 3.8 ± 1.3, <i>P</i> &lt; 0.001). However, for primary tumors, regional lymph nodes, distant lymph nodes, pulmonary metastases, and hepatic metastases, no statistically significant differences in SUVmax or TBR values were observed between the two tracers (all <i>P</i> &gt; 0.05). [¹⁷⁷Lu]Lu-FAP-2286 demonstrated sustained high tumor uptake up to 168&#xa0;h post-injection. In the four treated patients, the mean absorbed doses to tumor lesions were 0.21 ± 0.09, 0.27 ± 0.14, 0.14 ± 0.05, and 1.02 ± 0.30&#xa0;Gy/GBq, respectively. Notably, in one patient, the total absorbed dose for all tumor lesions reached 54.23&#xa0;Gy/GBq at 168&#xa0;h. No grade III or IV adverse events were observed, and three of four patients exhibited stable disease (SD) on follow-up.</p> Conclusion <p>[⁶⁸Ga]Ga-FAP-2286 appears to be a promising imaging agent for breast cancer, while [¹⁷⁷Lu]Lu-FAP-2286 may represent a potential therapeutic option for patients with advanced disease.</p>