Skip to main content

Advertisement

SpringerLink
Log in

Imaging and monitoring HER2 expression in breast cancer during trastuzumab therapy with a peptide probe 99mTc-HYNIC-H10F

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The novel molecular imaging probe 99mTc-HYNIC-H10F was developed for patient screening and efficacy monitoring of trastuzumab therapy by SPECT imaging of HER2 expression in breast cancer.

Methods

99mTc-HYNIC-H10F was developed by labeling H10F peptide with 99mTc following an optimized protocol. Biodistribution and SPECT/CT were performed in mouse models bearing HER2-positive SK-BR3 and HER2-negative MDA-MB-231 human breast cancer xenografts, respectively. The treatment response to trastuzumab was monitored and quantified by SPECT/CT in two HER2-positive breast cancer models (SK-BR3 and MDA-MB-361). The preliminary clinical study was performed in two patients with breast cancer.

Results

SPECT/CT with 99mTc-HYNIC-H10F showed that the SK-BR3 tumors were clearly visualized, while the signals from MDA-MB-231 tumors were much lower. The tumor uptake of 99mTc-HYNIC-H10F could be blocked by excess unlabeled H10F peptide but not by excess trastuzumab. The growth of two HER2-positive tumors was prominently suppressed at day 11 post-treatment. However, SPECT/CT reflected much earlier therapy response at day 4 post-treatment. The HER2 expression in tumors of breast cancer patients could be detected by 99mTc-HYNIC-H10F SPECT/CT imaging.

Conclusions

99mTc-HYNIC-H10F specifically accumulates in HER2-positive tumors. Compared with trastuzumab, 99mTc-HYNIC-H10F binds to a different domain of HER2 antigen, providing new opportunities to monitor HER2 expression levels before/during/after trastuzumab treatment for more effective personalized treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.

    CAS  PubMed  Google Scholar 

  2. Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11:263–75. https://doi.org/10.1586/era.10.226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Goldenberg MM. Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clin Ther. 1999;21:309–18. https://doi.org/10.1016/S0149-2918(00)88288-0.

    Article  CAS  PubMed  Google Scholar 

  4. Gonzalez-Angulo AM, Hortobagyi GN, Esteva FJ. Adjuvant therapy with trastuzumab for HER-2/neu-positive breast cancer. Oncologist. 2006;11:857–67. https://doi.org/10.1634/theoncologist.11-8-857.

    Article  CAS  PubMed  Google Scholar 

  5. Leyland-Jones B. Trastuzumab: hopes and realities. Lancet Oncol. 2002;3:137–44.

    CAS  PubMed  Google Scholar 

  6. Carney WP, Leitzel K, Ali S, Neumann R, Lipton A. HER-2/neu diagnostics in breast cancer. Breast Cancer Res. 2007;9:207. https://doi.org/10.1186/bcr1664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chung A, Cui X, Audeh W, Giuliano A. Current status of anti-human epidermal growth factor receptor 2 therapies: predicting and overcoming herceptin resistance. Clin Breast Cancer. 2013;13:223–32. https://doi.org/10.1016/j.clbc.2013.04.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013. https://doi.org/10.1200/JCO.2013.50.9984.

    Article  PubMed  Google Scholar 

  9. Perez EA, Cortes J, Gonzalez-Angulo AM, Bartlett JM. HER2 testing: current status and future directions. Cancer Treat Rev. 2014;40:276–84. https://doi.org/10.1016/j.ctrv.2013.09.001.

    Article  CAS  PubMed  Google Scholar 

  10. Massicano AVF, Marquez-Nostra BV, Lapi SE. Targeting HER2 in nuclear medicine for imaging and therapy. Mol Imaging. 2018;17:1536012117745386. https://doi.org/10.1177/1536012117745386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang Z, Wang W, Bu X, Wei Z, Geng L, Wu Y, et al. Microarray based screening of peptide nano probes for HER2 positive tumor. Anal Chem. 2015;87:8367–72. https://doi.org/10.1021/acs.analchem.5b01588.

    Article  CAS  PubMed  Google Scholar 

  12. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin fab. Nature. 2003;421:756–60. https://doi.org/10.1038/nature01392.

    Article  CAS  PubMed  Google Scholar 

  13. Dong C, Zhao H, Yang S, Shi J, Huang J, Cui L, et al. (99m)Tc-labeled dimeric octreotide peptide: a radiotracer with high tumor uptake for single-photon emission computed tomography imaging of somatostatin receptor subtype 2-positive tumors. Mol Pharm. 2013;10:2925–33. https://doi.org/10.1021/mp400040z.

    Article  CAS  PubMed  Google Scholar 

  14. Liu Z, Huang J, Dong C, Cui L, Jin X, Jia B, et al. 99mTc-labeled RGD-BBN peptide for small-animal SPECT/CT of lung carcinoma. Mol Pharm. 2012;9:1409–17. https://doi.org/10.1021/mp200661t.

    Article  CAS  PubMed  Google Scholar 

  15. Chen Q, Ma Q, Chen M, Chen B, Wen Q, Jia B, et al. An exploratory study on 99mTc-RGD-BBN peptide scintimammography in the assessment of breast malignant lesions compared to 99mTc-3P4-RGD2. PLoS One. 2015;10:e0123401. https://doi.org/10.1371/journal.pone.0123401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rivenbark AG, O'Connor SM, Coleman WB. Molecular and cellular heterogeneity in breast cancer: challenges for personalized medicine. Am J Pathol. 2013;183:1113–24. https://doi.org/10.1016/j.ajpath.2013.08.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wagner F, Hakami YA, Warnock G, Fischer G, Huellner MW, Veit-Haibach P. Comparison of contrast-enhanced CT and [(18)F] FDG PET/CT analysis using kurtosis and Skewness in patients with primary colorectal Cancer. Mol Imaging Biol. 2017;19:795–803. https://doi.org/10.1007/s11307-017-1066-x.

    Article  CAS  PubMed  Google Scholar 

  18. Dialani V, Chadashvili T, Slanetz PJ. Role of imaging in neoadjuvant therapy for breast cancer. Ann Surg Oncol. 2015;22:1416–24. https://doi.org/10.1245/s10434-015-4403-9.

    Article  PubMed  Google Scholar 

  19. Fass L. Imaging and cancer: a review. Mol Oncol. 2008;2:115–52. https://doi.org/10.1016/j.molonc.2008.04.001.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Rauch GM, Adrada BE, Kuerer HM, van la Parra RF, Leung JW, Yang WT. Multimodality imaging for evaluating response to Neoadjuvant chemotherapy in breast Cancer. AJR Am J Roentgenol. 2017;208:290–9. https://doi.org/10.2214/AJR.16.17223.

    Article  PubMed  Google Scholar 

  21. Bensch F, Brouwers AH, Lub-de Hooge MN, de Jong JR, van der Vegt B, Sleijfer S, et al. (89)Zr-trastuzumab PET supports clinical decision making in breast cancer patients, when HER2 status cannot be determined by standard work up. Eur J Nucl Med Mol Imaging. 2018;45:2300–6. https://doi.org/10.1007/s00259-018-4099-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ulaner GA, Lyashchenko SK, Riedl C, Ruan S, Zanzonico PB, Lake D, et al. First-in-human human epidermal growth factor receptor 2-targeted imaging using (89)Zr-Pertuzumab PET/CT: dosimetry and clinical application in patients with breast cancer. J Nucl Med. 2018;59:900–6. https://doi.org/10.2967/jnumed.117.202010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Laforest R, Lapi SE, Oyama R, Bose R, Tabchy A, Marquez-Nostra BV, et al. [(89)Zr]Trastuzumab: evaluation of radiation dosimetry, safety, and optimal imaging parameters in women with HER2-positive breast cancer. Mol Imaging Biol. 2016;18:952–9. https://doi.org/10.1007/s11307-016-0951-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sandstrom M, Lindskog K, Velikyan I, Wennborg A, Feldwisch J, Sandberg D, et al. Biodistribution and radiation dosimetry of the anti-HER2 affibody molecule 68Ga-ABY-025 in breast cancer patients. J Nucl Med. 2016;57:867–71. https://doi.org/10.2967/jnumed.115.169342.

    Article  CAS  PubMed  Google Scholar 

  25. Calce E, Monfregola L, Sandomenico A, Saviano M, De Luca S. Fluorescence study for selecting specific ligands toward HER2 receptor: an example of receptor fragment approach. Eur J Med Chem. 2013;61:116–21. https://doi.org/10.1016/j.ejmech.2012.09.024.

    Article  CAS  PubMed  Google Scholar 

  26. Honarvar H, Calce E, Doti N, Langella E, Orlova A, Buijs J, et al. Evaluation of HER2-specific peptide ligand for its employment as radiolabeled imaging probe. Sci Rep. 2018;8:2998. https://doi.org/10.1038/s41598-018-21283-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Joshi BP, Zhou J, Pant A, Duan X, Zhou Q, Kuick R, et al. Design and synthesis of near-infrared peptide for in vivo molecular imaging of HER2. Bioconjug Chem. 2016;27:481–94. https://doi.org/10.1021/acs.bioconjchem.5b00565.

    Article  CAS  PubMed  Google Scholar 

  28. Li L, Wu Y, Wang Z, Jia B, Hu Z, Dong C, et al. SPECT/CT imaging of the novel HER2-targeted peptide probe 99mTc-HYNIC-H6F in breast cancer mouse models. J Nucl Med. 2017;58:821–6. https://doi.org/10.2967/jnumed.116.183863.

    Article  CAS  PubMed  Google Scholar 

  29. Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol. 2007;18:977–84. https://doi.org/10.1093/annonc/mdl475.

    Article  CAS  PubMed  Google Scholar 

  30. Pinto AC, Ades F, de Azambuja E, Piccart-Gebhart M. Trastuzumab for patients with HER2 positive breast cancer: delivery, duration and combination therapies. Breast. 2013;22(Suppl 2):S152–5. https://doi.org/10.1016/j.breast.2013.07.029.

    Article  PubMed  Google Scholar 

  31. Luque-Cabal M, Garcia-Teijido P, Fernandez-Perez Y, Sanchez-Lorenzo L, Palacio-Vazquez I. Mechanisms behind the resistance to Trastuzumab in HER2-amplified breast cancer and strategies to overcome it. Clin Med Insights Oncol. 2016;10:21–30. https://doi.org/10.4137/Cmo.S34537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Valabrega G, Montemurro F, Sarotto I, Petrelli A, Rubini P, Tacchetti C, et al. TGFalpha expression impairs Trastuzumab-induced HER2 downregulation. Oncogene. 2005;24:3002–10. https://doi.org/10.1038/sj.onc.1208478.

    Article  CAS  PubMed  Google Scholar 

  33. Klapper LN, Waterman H, Sela M, Yarden Y. Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res. 2000;60:3384–8.

    CAS  PubMed  Google Scholar 

  34. McLarty K, Cornelissen B, Scollard DA, Done SJ, Chun K, Reilly RM. Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts. Eur J Nucl Med Mol Imaging. 2009;36:81–93. https://doi.org/10.1007/s00259-008-0923-x.

    Article  CAS  PubMed  Google Scholar 

  35. Song BI, Hong CM, Lee HJ, Kang S, Jeong SY, Kim HW, et al. Prognostic value of primary tumor uptake on F-18 FDG PET/CT in patients with invasive ductal breast cancer. Nucl Med Mol Imaging. 2011;45:117–24. https://doi.org/10.1007/s13139-011-0081-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Groheux D, Giacchetti S, Moretti JL, Porcher R, Espie M, Lehmann-Che J, et al. Correlation of high 18F-FDG uptake to clinical, pathological and biological prognostic factors in breast cancer. Eur J Nucl Med Mol Imaging. 2011;38:426–35. https://doi.org/10.1007/s00259-010-1640-9.

    Article  PubMed  Google Scholar 

  37. Koolen BB, Vrancken Peeters MJ, Wesseling J, Lips EH, Vogel WV, Aukema TS, et al. Association of primary tumour FDG uptake with clinical, histopathological and molecular characteristics in breast cancer patients scheduled for neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging. 2012;39:1830–8. https://doi.org/10.1007/s00259-012-2211-z.

    Article  CAS  PubMed  Google Scholar 

  38. Ueda S, Tsuda H, Asakawa H, Shigekawa T, Fukatsu K, Kondo N, et al. Clinicopathological and prognostic relevance of uptake level using 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in primary breast cancer. Jpn J Clin Oncol. 2008;38:250–8. https://doi.org/10.1093/jjco/hyn019.

    Article  PubMed  Google Scholar 

Download references

Funding

This research was supported by the National Natural Science Foundation of China (NSFC) projects (81630045, 81571727, 81927802, 81771869, 81871384), the National Key R&D Program of China (2017YFA0205600), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020110), the Youth Innovation Promotion Association of Chinese Academy of Sciences (YIPACAS) project (2016090), and the Beijing Natural Science Foundation (BJNSF) project (7142086).

Author information

Author notes

  1. Yue Wu and Liqiang Li are the first authors and contributed equally to this work

Authors and Affiliations

  1. Medical Isotopes Research Center and Department of Radiation Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University, Beijing, 100191, China

    Yue Wu, Liqiang Li & Fan Wang

  2. CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology of China, Beijing, 100190, China

    Zihua Wang & Zhiyuan Hu

  3. Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100010, China

    Jiyun Shi, Chengyan Dong & Fan Wang

  4. Department of Nuclear Medicine, China-Japan Union Hospital, Jilin University, Jilin, 130033, China

    Shi Gao & Qingjie Ma

  5. Department of Nuclear Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China

    Weibing Miao

  6. GE Healthcare, Beijing, 100126, China

    Chengyan Dong

Authors
  1. Yue Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liqiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zihua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiyun Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhiyuan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shi Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weibing Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qingjie Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chengyan Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chengyan Dong or Fan Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Translational research

Electronic supplementary material

ESM 1

(DOCX 1401 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, Y., Li, L., Wang, Z. et al. Imaging and monitoring HER2 expression in breast cancer during trastuzumab therapy with a peptide probe 99mTc-HYNIC-H10F. Eur J Nucl Med Mol Imaging 47, 2613–2623 (2020). https://doi.org/10.1007/s00259-020-04754-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-020-04754-6

Keywords

Search

Navigation