PET Imaging of Fibroblast Activation Protein in Various Types of Cancer Using 68Ga-FAP-2286: Comparison with 18F-FDG and 68Ga-FAPI-46 in a Single-Center, Prospective Study

Abstract

PET imaging that targets fibroblast activation protein (FAP) on the surface of cancer-associated fibroblasts has yielded promising tumor diagnostic results. FAP-2286 contains cyclic peptides as FAP-binding motifs to optimize tumor retention compared with the small-molecule FAP inhibitor (FAPI) series (FAPI-04/46). The aim of this study was to evaluate the diagnostic accuracy of ⁶⁸Ga-FAP-2286 to detect primary and metastatic lesions in patients with various types of cancer, compared with ¹⁸F-FDG and ⁶⁸Ga-FAP-2286. Methods: Sixty-four patients with 15 types of cancer underwent ⁶⁸Ga-FAP-2286 PET/CT for initial assessment or detection of recurrence. For comparison, 63 patients underwent paired ⁶⁸Ga-FAP-2286 and ¹⁸F-FDG PET/CT and 19 patients underwent paired ⁶⁸Ga-FAP-2286 and ⁶⁸Ga-FAPI-46 PET/CT. Lesion uptake was quantified as SUV_max and tumor-to-background ratio. The Wilcoxon matched-pairs signed-rank test was used to compare SUV_max between PET modalities, and the McNemar test was used to compare lesion detectability. Results: Uptake of ⁶⁸Ga-FAP-2286 was significantly higher than that of ¹⁸F-FDG in primary tumors (median SUV_max, 11.1 vs. 6.9; P < 0.001), lymph node metastases (median SUV_max, 10.6 vs. 6.2; P < 0.001), and distant metastases, resulting in improved image contrast and lesion detectability. All primary tumors (46/46) were clearly visualized by ⁶⁸Ga-FAP-2286 PET/CT, whereas 9 of the 46 lesions could not be visualized by ¹⁸F-FDG PET/CT. The lesion detection rate of ⁶⁸Ga-FAP-2286 PET/CT was superior to that of ¹⁸F-FDG PET/CT for involved lymph nodes (98% [105/107] vs. 85% [91/107], P = 0.001) and bone and visceral metastases (95% [162/171] vs. 67% [114/171], P < 0.001). ⁶⁸Ga-FAP-2286 yielded tumor uptake and lesion detection rates similar to those of ⁶⁸Ga-FAPI-46 in a subcohort of 19 patients. Conclusion: ⁶⁸Ga-FAP-2286 is a promising FAP-inhibitor derivative for safe cancer diagnosis, staging, and restaging. It may be a better alternative to ¹⁸F-FDG for the cancer types that exhibit low-to-moderate uptake of ¹⁸F-FDG, which include gastric, pancreatic, and hepatic cancers. In addition, ⁶⁸Ga-FAP-2286 and ⁶⁸Ga-FAPI-46 yielded comparable clinical results.

Keywords: FAP-2286; FAPI-46; PET/CT; fibroblast activation protein.

Graphical abstract

FIGURE 1.

Maximum-intensity projections of ¹⁸F-FDG, ⁶⁸Ga-FAP-2286, and ⁶⁸Ga-FAPI-46 PET/CT imaging in 7 patients with different types of cancer (histologically confirmed). Tumor lesions are indicated with arrows. Ca = carcinoma; HNCUP = head and neck carcinoma of unknown primary; NPC = nasopharyngeal carcinoma.

FIGURE 2.

PET-based biodistribution analysis of ⁶⁸Ga-FAP-2286 and ⁶⁸Ga-FAPI-46 in normal organs at 1 h after injection. Results are shown as means and SDs from 19 patients. *P < 0.05. ***P < 0.001. ns = not statistically significant.

FIGURE 3.

A 66-y-old man with nasopharyngeal carcinoma who underwent ⁶⁸Ga-FAP-2286 PET/CT at different time points after injection. Rapid and stable radiotracer uptake was observed in both primary and metastatic lesions. Semiquantitative analysis demonstrated SUV_max increase at 0.5–3 h in primary tumor (by 72.1% [from 8.6 to 14.8]), involved lymph nodes (by 5.2%–69.1%), and 1 bone metastasis (by 64.4%). BM = bone metastasis; LNM = lymph node metastasis.

FIGURE 4.

A 65-y-old woman with metastatic intrahepatic cholangiocarcinoma who underwent imaging for cancer restaging. ⁶⁸Ga-FAP-2286 (A) revealed greater number of metastases and higher uptake than ⁶⁸Ga-FAPI-46 (B) in widespread subcutaneous metastases (arrows).

FIGURE 5.

A 72-y-old man with newly diagnosed nasopharyngeal carcinoma who underwent PET/CT for tumor staging. ⁶⁸Ga-FAP-2286 PET/CT (A) showed higher radiotracer uptake in primary tumor (SUV_max, 17.4 vs. 12.2; arrows) than ⁶⁸Ga-FAPI-46 (B).

FIGURE 6.

A 44-y-old man with glioblastoma who underwent surgical resection 1 y before images were obtained. (A) MRI revealed suggestive recurrent lesions in right frontal lobe adjacent to surgical margin (arrow). (B [axial PET image] and C [fused PET/CT image]) ⁶⁸Ga-FAP-2286 PET/CT yielded higher radiotracer uptake (SUV_max, 4.2 vs. 2.7; arrows) and TBR (70.0 vs. 45.0) than ⁶⁸Ga-FAPI-46 in these lesions. (D [intraoperative view] and E [fluorescence-guided surgery]) Patient subsequently underwent surgical resection, and postoperative pathology confirmed diagnosis of recurrent glioblastoma. T1WI+C = T1-weighted imaging with contrast enhancement; T2WI = T2-weighted imaging.