Phase II study of uPAR-PET/CT for staging of primary breast cancer in comparison with ultrasound and fine needle biopsies.
Humans
Female
Breast Neoplasms
/ pathology
Middle Aged
Positron Emission Tomography Computed Tomography
/ methods
Neoplasm Staging
Aged
Adult
Biopsy, Fine-Needle
/ methods
Receptors, Urokinase Plasminogen Activator
/ metabolism
Prospective Studies
Male
Lymphatic Metastasis
/ diagnostic imaging
Ultrasonography
/ methods
Lymph Nodes
/ pathology
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
30 10 2024
30 10 2024
Historique:
received:
06
02
2024
accepted:
18
10
2024
medline:
31
10
2024
pubmed:
31
10
2024
entrez:
31
10
2024
Statut:
epublish
Résumé
Accurate initial staging of patients with breast cancer is essential for planning optimal treatment strategies. However, currently, no imaging modality is able to detect lymph node metastases preoperatively with sufficient reliability; therefore, the N status depends on the sentinel node procedure for ~ 70% of patients. In a prospective clinical trial of breast cancer patients, we compared head-to-head uPAR-PET/CT with current standard-of-care, ultrasound (US) and fine needle biopsy (FNB) as staging methods. Forty-nine patients (48 women and 1 man) with biopsy-proven early breast cancer underwent uPAR-PET/CT prior to surgery. All image data were analyzed by two separate teams, each consisting of a highly experienced certified specialist in nuclear medicine and a highly experienced certified specialist in radiology for visualization of primary tumor lesions and detection of lymph node and distant metastases. Histopathological assessment and verification of malignancy in the excised tissues (primary tumors and lymph nodes) were considered standard-of-truth. On a per patient basis, uPAR PET/CT demonstrated a sensitivity of 94% [CI: 83-99%] for detecting the primary tumor (both teams). For the detection of axillary lymph nodes the pooled sensitivity of uPAR PET/CT was 33.3% [CI: 16.5-54.0%], specificity 87.0% [CI: 66.4-97.2%] and accuracy 58.0% [CI: 43.2-71.8%]. In comparison, the standard-of-care preoperative clinical staging algorithm with US and FNB had a sensitivity of 41% [CI: 22-61%] and specificity of 100% [CI: 85-100%] for axillary lymph node metastases. We conclude that the results do not support the use of uPAR PET/CT for staging in breast cancer patients. However, the finding that 94% of primary tumors were uPAR-PET positive may be encouraging for pursuing uPAR theranostics in localized disease. Additionally, other potential applications, such as using uPAR-PET as a prognostic imaging biomarker of tumor aggressiveness, remain to be investigated.
Identifiants
pubmed: 39478178
doi: 10.1038/s41598-024-77072-8
pii: 10.1038/s41598-024-77072-8
doi:
Substances chimiques
Receptors, Urokinase Plasminogen Activator
0
Types de publication
Journal Article
Clinical Trial, Phase II
Comparative Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
26183Informations de copyright
© 2024. The Author(s).
Références
Hamran, K., Langhans, L., Vejborg, I., Tvedskov, T. F. & Kroman, N. The accuracy of preoperative staging of the axilla in primary breast cancer: A national register based study on behalf of Danish Breast Cancer Group (DBCG). Acta Oncol. 57, 162–166 (2018).
doi: 10.1080/0284186X.2017.1406138
pubmed: 29202615
Bernsdorf, M. et al. Preoperative PET/CT in early-stage breast cancer. Ann. Oncol. 23, 2277–2282 (2012).
doi: 10.1093/annonc/mds002
pubmed: 22357250
Cardoso, F. et al. Early breast cancer: ESMO Clinical Practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 30, 1194–1220 (2019).
doi: 10.1093/annonc/mdz173
pubmed: 31161190
Groheux, D. FDG-PET/CT for primary staging and detection of recurrence of breast cancer. Semin. Nucl. Med. 52, 508–519 (2022).
doi: 10.1053/j.semnuclmed.2022.05.001
pubmed: 35636977
Duffy, M. J. et al. Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM). Eur. J. Cancer. 75, 284–298 (2017).
doi: 10.1016/j.ejca.2017.01.017
pubmed: 28259011
Hanahan, D. Hallmarks of Cancer: New dimensions. Cancer Discov. 12, 31–46 (2022).
doi: 10.1158/2159-8290.CD-21-1059
pubmed: 35022204
Skovgaard, D. et al. Safety, dosimetry and tumor detection ability of 68 Ga - NOTA - AE105 - a novel radio ligand for uPAR PET imaging : First-in-humans study. J. Nucl. Med. 58, 379–386 (2016).
doi: 10.2967/jnumed.116.178970
pubmed: 27609788
De Bock, C. E. & Wang, Y. Clinical significance of urokinase-type plasminogen activator receptor (uPAR) expression in cancer. Med. Res. Rev. 24, 13–39 (2004).
doi: 10.1002/med.10054
pubmed: 14595671
Grøndahl-Hansen, J. et al. Prognostic significance of the receptor for urokinase plasminogen activator in breast Cancer. Clin. Cancer Res. 10, 1079–1087 (1995).
Danø, K. et al. Plasminogen activation and cancer. Thromb. Haemost. 93, 676–681 (2005).
doi: 10.1160/TH05-01-0054
pubmed: 15841311
de Witte, J. H. et al. Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours. Br. J. Cancer. 85, 85–92 (2001).
doi: 10.1054/bjoc.2001.1867
pubmed: 11437407
pmcid: 2363926
Foekens, J. A. et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res. 60, 636–643 (2000).
pubmed: 10676647
LeBeau, A. M. et al. Imaging the urokinase plasminongen activator receptor in preclinical breast cancer models of acquired drug resistance. Theranostics. 4, 267–279 (2014).
doi: 10.7150/thno.7323
pubmed: 24505235
pmcid: 3915090
Le Beau, A. M. et al. Targeting uPAR with antagonistic recombinant human antibodies in aggressive breast cancer. Cancer Res. 73, 2070–2081 (2013).
doi: 10.1158/0008-5472.CAN-12-3526
Illemann, M. et al. Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases. Int. J. Cancer. 124, 1860–1870 (2009).
doi: 10.1002/ijc.24166
pubmed: 19123477
Dublin, E., Hanby, A., Patel, N. K., Liebman, R. & Barnes, D. Immunohistochemical expression of uPA, uPAR, and PAI-1 in breast carcinoma. Fibroblastic expression has strong associations with tumor pathology. Am. J. Pathol. 157, 1219–1227 (2000).
doi: 10.1016/S0002-9440(10)64637-8
pubmed: 11021826
pmcid: 1850159
Boulc’h, M. L., Gilhodes, J., Steinmeyer, Z., Molière, S. & Mathelin, C. Pretherapeutic imaging for axillary staging in breast cancer: A systematic review and meta-analysis of ultrasound, MRI and FDG PET. J. Clin. Med. 10, 1543 (2021).
doi: 10.3390/jcm10071543
pubmed: 33917590
pmcid: 8038849
Stachs, A. et al. Accuracy of Axillary Ultrasound in Preoperative Nodal Staging of Breast Cancer - Size of Metastases as Limiting Factor. Springerplus 29:2350 (2013)
Donker, M. et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): A randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 15, 1303–1310 (2014).
doi: 10.1016/S1470-2045(14)70460-7
pubmed: 25439688
pmcid: 4291166
LeVasseur, N. et al. Impact of the 21-Gene recurrence score assay on the treatment of Estrogen Receptor-Positive, HER2-Negative, breast Cancer patients with 1–3 positive nodes: A prospective clinical utility study. Clin. Breast Cancer. 22, e74–e79 (2022).
doi: 10.1016/j.clbc.2021.09.004
pubmed: 34690081
Piccart, M. et al. 70-gene signature as an aid for treatment decisions in early breast cancer: Updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol. 22, 476–488 (2021).
doi: 10.1016/S1470-2045(21)00007-3
pubmed: 33721561
Hemsen, A. et al. Comparative evaluation of urokinase-type plasminogen activator receptor expression in primary breast carcinomas and on metastatic tumor cells. Int. J. Cancer. 107, 903–909 (2003).
doi: 10.1002/ijc.11488
pubmed: 14601049
Hildenbrandt, R. et al. Tumor stroma is the predominant uPA-, uPAR-, PAI-1-expressing tissue in human breast cancer: Prognostic impact. Histol. Histopathol. 24, 869–877 (2009).
Persson, M. et al. First-in-human uPAR PET: Imaging of Cancer aggressiveness. Theranostics. 5, 1303–1316 (2015).
doi: 10.7150/thno.12956
pubmed: 26516369
pmcid: 4615734
Johnbeck, C. B. et al. Head-to-Head comparison of 64Cu-DOTATATE and 68Ga-DOTATOC PET/CT: A prospective study of 59 patients with neuroendocrine tumors. J. Nucl. Med. 58, 451–457 (2017).
doi: 10.2967/jnumed.116.180430
pubmed: 27660147
Carlsen, E. A. et al. Prospective phase II trial of prognostication by 68Ga-NOTA-AE105 uPAR PET in patients with neuroendocrine neoplasms: Implications for uPAR-Targeted therapy. J. Nucl. Med. 63, 1371–1377 (2022).
doi: 10.2967/jnumed.121.263177
pubmed: 35058319
pmcid: 9454472
Fosbøl, M. Ø. et al. uPAR PET/CT for Prognostication and Response Assessment in patients with metastatic castration-resistant prostate Cancer undergoing Radium-223 therapy: A prospective phase II study. Diagnostics (Basel). 11, 1087 (2021).
doi: 10.3390/diagnostics11061087
pubmed: 34198666
Risør, L. M. et al. Prognostic value of urokinase-type plasminogen activator receptor PET/CT in Head and Neck Squamous Cell Carcinomas and comparison with 18F-FDG PET/CT: A single-center prospective study. J. Nucl. Med. 63, 1169–1176 (2022).
doi: 10.2967/jnumed.121.262866
pubmed: 34857658
pmcid: 9364350
Fosbøl, M. Ø. et al. Urokinase plasminogen activator receptor (uPAR) PET/MRI of prostate cancer for non-invasive evaluation of aggressiveness: A prospective phase II clinical trial comparing with Gleason Score. J. Nucl. Med. 62, 254–359 (2020).