A recent Phase II study published in Scientific Reports has investigated the utility of urokinase plasminogen activator receptor (uPAR) PET/CT imaging in staging primary breast cancer. The study, a head-to-head comparison with ultrasound (US) and fine-needle biopsy (FNB), found that while uPAR-PET/CT demonstrated a high sensitivity for detecting primary tumors, its performance in identifying axillary lymph node metastases was not significantly better than current standard-of-care methods.
The study hypothesized that the upregulation of uPAR expression in primary tumors and lymph node metastases would enhance the uptake of the imaging agent [68Ga]Ga-NOTA-AE105, facilitating clinically valuable imaging. The results indicated a sensitivity of approximately 33% for detecting axillary lymph node metastases, which was similar to the 41% detection rate achieved by US and FNB. This is in contrast to meta-analysis data where ultrasound exhibited a sensitivity of 55%.
Notably, uPAR-PET/CT identified distant metastases or synchronous primary cancer (NSCLC) in three patients (6%), which had immediate therapeutic consequences. Two additional patients showed uPAR-PET/CT-positive intramammary lymph nodes, though these findings did not alter postsurgical treatment. False-positive lymph nodes were observed in three patients, potentially due to inflammatory responses increasing uPAR expression.
The study highlights that detecting micrometastases or isolated tumor cells in axillary lymph nodes remains a challenge for uPAR-PET/CT and other imaging technologies. While complete axillary nodal status is crucial for adjuvant chemotherapy decisions in certain patient subgroups, noninvasive methods capable of visualizing macrometastatic disease are increasingly relevant.
Technical Limitations and Future Directions
The researchers pointed out that a persistent high level of [68Ga]Ga-NOTA-AE105 in the blood pool, likely due to plasma protein binding, limits rapid clearance from soft tissue and reduces the tumor-to-background ratio. This can make it difficult to identify smaller lesions or those near blood vessels. The study also notes that the positron range of 68Ga (4 mm) may reduce detection ability for small lesions compared to 18F or 64Cu (approximately 1 mm).
The authors suggest that future studies could explore the use of the 64Cu-labeled uPAR-PET tracer [64Cu]Cu-DOTA-AE105 or compare it with [18F]FDG PET for breast cancer staging. While uPAR-PET/CT's diagnostic performance was on par with US + FNB in this study, the high detection rate of primary tumors (94%) suggests potential for further research into uPAR theranostics in primary breast cancer. uPAR PET has demonstrated prognostic value in other malignancies, including neuroendocrine neoplasms, brain cancer, and head and neck cancer.
