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68Ga-FAPI-04 vs. 18F-FDG in a longitudinal preclinical PET imaging of metastatic breast cancer

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Abstract

Purpose

This longitudinal study aims to evaluate the performance of 68 Ga-FAPI-04 and 18F-FDG and to profile the dynamic process of tumor metastasis in a preclinical 4T1 breast cancer model. Although both of these two radioligands are wildly used in clinic, no study was reported on their performance in the longitudinal monitoring of tumor metastasis. Also, no correlation between the expression level of fibroblast activation protein (FAP) and the development of tumor metastasis has been elucidated previously. In this study, we evaluated the performance of 68 Ga-FAPI-04 and 18F-FDG PET during the entire process of tumor metastasis, and their potential for the early diagnosis of tumor metastasis. We also clarified the correlation of uptakes as well as the signal-to-background (S/B) ratios between these two probes at different stages of tumor metastasis.

Methods

Forty 4T1 metastatic breast cancer murine models were established using female BALB/c mice, followed by the longitudinal imaging with 68 Ga-FAPI-04 and 18F-FDG once a week for up to 6 weeks. In vitro hematoxylin and eosin (H&E) and immunochemistry (IHE) staining were performed to evaluate FAP expression on the metastatic lesions. Further statistical analysis was performed to evaluate the correlation of 68 Ga-FAPI-04 and 18F-FDG uptake (%ID/cc) at different stages of the metastasis.

Results

68 Ga-FPAI-04 holds an advantage over 18F-FDG with higher sensitivity at the early stage of tumor metastasis. However, with the progress of tumor metastasis, uptake of 68 Ga-FAPI-04 decreases and becomes less sensitive than 18F-FDG. There is also no direct correlation between uptake or S/B ratios of 68 Ga-FAPI-04 and 18F-FDG during this dynamic process.

Conclusion

68 Ga-FAPI-04 is more sensitive than 18F-FDG in detecting the early stage of tumor metastasis, but becomes less sensitive than 18F-FDG at the late stage of tumor metastasis. We envision this result would be meaningful for the explanation of the 68 Ga-FAPI-04 and 18F-FDG imaging both in the future clinic and preclinic studies.

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References

  1. Lindner T, et al. Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med. 2018;59(9):1415–22.

    Article  CAS  Google Scholar 

  2. Loktev A, et al. A tumor-imaging method targeting cancer-associated fibroblasts. J Nucl Med. 2018;59(9):1423–9.

    Article  CAS  Google Scholar 

  3. Giesel FL, et al. (68)Ga-FAPI PET/CT: biodistribution and preliminary dosimetry estimate of 2 DOTA-containing FAP-targeting agents in patients with various cancers. J Nucl Med. 2019;60(3):386–92.

    Article  CAS  Google Scholar 

  4. Roy A, Bera S. CAF cellular glycolysis: linking cancer cells with the microenvironment. Tumour Biol. 2016;37(7):8503–14.

    Article  CAS  Google Scholar 

  5. Houthuijzen JM, Jonkers J. Cancer-associated fibroblasts as key regulators of the breast cancer tumor microenvironment. Cancer Metastasis Rev. 2018;37(4):577–97.

    Article  CAS  Google Scholar 

  6. Ishii G, Ochiai A, Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev. 2016;99(Pt B):186–96.

    Article  CAS  Google Scholar 

  7. Rai A, et al. Exosomes derived from human primary and metastatic colorectal cancer cells contribute to functional heterogeneity of activated fibroblasts by reprogramming their proteome. Proteomics. 2019;19(8):e1800148.

    Article  CAS  Google Scholar 

  8. Paolillo M, Schinelli S. Extracellular matrix alterations in metastatic processes. Int J Mol Sci. 2019;20(19):4947.

    Article  CAS  Google Scholar 

  9. Nerymar Ortiz-Otero ABC, Hope Jacob, Wang Wenjun, Reinhart-King Cynthia A, King Michael R. Cancer associated fibroblasts confer shear resistance to circulating tumor cells during prostate cancer metastatic progression. Oncotarget. 2020;11(12):1037–50.

    Article  Google Scholar 

  10. Fitzgerald AA, Weiner LM. The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Rev. 2020;39(3):783–803.

    Article  CAS  Google Scholar 

  11. Shen K, et al. Suicide gene-engineered stromal cells reveal a dynamic regulation of cancer metastasis. Sci Rep. 2016;6:21239.

    Article  CAS  Google Scholar 

  12. Cortez E, Roswall P, Pietras K. Functional subsets of mesenchymal cell types in the tumor microenvironment. Semin Cancer Biol. 2014;25:3–9.

    Article  CAS  Google Scholar 

  13. Kratochwil C, et al. (68)Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer. J Nucl Med. 2019;60(6):801–5.

    Article  CAS  Google Scholar 

  14. Giesel FL, et al. FAPI-PET/CT improves staging in a lung cancer patient with cerebral metastasis. Eur J Nucl Med Mol Imaging. 2019;46(8):1754–5.

    Article  Google Scholar 

  15. Khreish F, et al. Positive FAPI-PET/CT in a metastatic castration-resistant prostate cancer patient with PSMA-negative/FDG-positive disease. Eur J Nucl Med Mol Imaging. 2020;47(8):2040–1.

    Article  Google Scholar 

  16. Chen H, et al. Comparison of [(68)Ga]Ga-DOTA-FAPI-04 and [(18)F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer. Eur J Nucl Med Mol Imaging. 2020;47(8):1820–32.

    Article  Google Scholar 

  17. Zheng J, Yao S. [(68)Ga]Ga-DOTA-FAPI-04 and [(18)F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with hepatic cancer. Eur J Nucl Med Mol Imaging. 2020;47(9):2078–9.

    Article  Google Scholar 

  18. Liu Q, Shi S, Xu X, et al. The superiority of [68Ga]-FAPI-04 over [18F]-FDG PET/CT in imaging metastatic esophageal squamous cell carcinoma. Eur J Nucl Med Mol Imaging. 2021;48(4):1248–49.

  19. Fu W, et al. Increased FAPI uptake in brain metastasis from lung cancer on 68Ga-FAPI PET/CT. Clin Nucl Med. 2021;46(1):e1–2.

    Article  Google Scholar 

  20. Qin C, Liu F, Huang J, et al. A head-to-head comparison of 68Ga-DOTA-FAPI-04 and 18F-FDG PET/MR in patients with nasopharyngeal carcinoma: a prospective study. Eur J Nucl Med Mol Imaging. 2021. https://doi.org/10.1007/s00259-021-05255-w.

  21. Pang Y, et al. Comparison of (68)Ga-FAPI and (18)F-FDG uptake in gastric, duodenal, and colorectal cancers. Radiology. 2021;298(2):393–402.

    Article  Google Scholar 

  22. Giesel FL, et al. FAPI-74 PET/CT using either (18)F-AlF or cold-kit (68)Ga labeling: biodistribution, radiation dosimetry, and tumor delineation in lung cancer patients. J Nucl Med. 2021;62(2):201–7.

    Article  CAS  Google Scholar 

  23. Pang Y, Zhao L, Chen H. 68Ga-FAPI outperforms 18F-FDG PET/CT in identifying bone metastasis and peritoneal carcinomatosis in a patient with metastatic breast cancer. Clin Nucl Med. 2020;45(11):913–5.

    Article  Google Scholar 

  24. Serfling S, et al. Improved cancer detection in Waldeyer’s tonsillar ring by (68)Ga-FAPI PET/CT imaging. Eur J Nucl Med Mol Imaging. 2021;48(4):1178–87.

  25. Henry LR, et al. Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res. 2007;13(6):1736–41.

    Article  CAS  Google Scholar 

  26. Pulaski BA, Ostrand-Rosenberg S. Mouse 4T1 breast tumor model. Animal Models for Tumor Immunology, 2001. 39(1): p. 20.2.1–20.2.16.

  27. Pulaski BA and Ostrand-Rosenberg S. Mouse 4T1 breast tumor model. Curr Protoc Immunol, 2001. Chapter 20: p. Unit 20 2.

  28. Heppner GH, Miller FR, Shekhar PM. Nontransgenic models of breast cancer. Breast Cancer Res. 2000;2(5):331–4.

    Article  CAS  Google Scholar 

  29. Zhou Y, Han M, Gao J. Prognosis and targeting of pre-metastatic niche. J Control Release. 2020;325:223–34.

    Article  CAS  Google Scholar 

  30. Sleeman JP. The lymph node pre-metastatic niche. J Mol Med (Berl). 2015;93(11):1173–84.

    Article  CAS  Google Scholar 

  31. Hirakawa S, et al. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med. 2005;201(7):1089–99.

    Article  CAS  Google Scholar 

  32. Hirakawa S, et al. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood. 2007;109(3):1010–7.

    Article  CAS  Google Scholar 

  33. Mansfield AS, et al. Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis. Mod Pathol. 2011;24(4):487–94.

    Article  CAS  Google Scholar 

  34. Rasanen K, Vaheri A. Activation of fibroblasts in cancer stroma. Exp Cell Res. 2010;316(17):2713–22.

    Article  CAS  Google Scholar 

  35. Yeung TM, et al. Myofibroblast activation in colorectal cancer lymph node metastases. Br J Cancer. 2013;108(10):2106–15.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank the staff at Renji Hospital for their support with the cyclotron operation, radioisotope production, radiosynthesis, and animal experiments.

Funding

The study was supported by research grants from The National Science Foundation of China (Grant No. 81601536) by Professor Dewei Tang.

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Authors and Affiliations

Authors

Contributions

Conception and design: Dewei Tang.

Development of methodology: Fan Ding, Chen Huang, Chenyi Liang, Cheng Wang.

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): Fan Ding, Chen Huang, Chenyi Liang.

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Dewei Tang, Fan Ding, Chen Huang.

Writing, review, and/or revision of the manuscript: Dewei Tang, Fan Ding, Chen Huang, Jianjun Liu.

Study supervision: Dewei Tang.

Corresponding authors

Correspondence to Jianjun Liu or Dewei Tang.

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This article is part of the Topical Collection on Preclinical Imaging

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Ding, F., Huang, C., Liang, C. et al. 68Ga-FAPI-04 vs. 18F-FDG in a longitudinal preclinical PET imaging of metastatic breast cancer. Eur J Nucl Med Mol Imaging 49, 290–300 (2021). https://doi.org/10.1007/s00259-021-05442-9

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  • DOI: https://doi.org/10.1007/s00259-021-05442-9

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