Skip to main content


Log in

Radiolabeled pertuzumab for imaging of human epidermal growth factor receptor 2 expression in ovarian cancer

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



Human epidermal growth factor receptor 2 (HER2) is over-expressed in over 30% of ovarian cancer cases, playing an essential role in tumorigenesis and metastasis. Non-invasive imaging of HER2 is of great interest for physicians as a mean to better detect and monitor the progression of ovarian cancer. In this study, HER2 was assessed as a biomarker for ovarian cancer imaging using 64Cu-labeled pertuzumab for immunoPET imaging.


HER2 expression and binding were examined in three ovarian cancer cell lines (SKOV3, OVCAR3, Caov3) using in vitro techniques, including western blot and saturation binding assays. PET imaging and biodistribution studies in subcutaneous models of ovarian cancer were performed for non-invasive in vivo evaluation of HER2 expression. Additionally, orthotopic models were employed to further validate the imaging capability of 64Cu-NOTA-pertuzumab.


HER2 expression was highest in SKOV3 cells, while OVCAR3 and Caov3 displayed lower HER2 expression. 64Cu-NOTA-pertuzumab showed high specificity for HER2 (Ka = 3.1 ± 0.6 nM) in SKOV3. In subcutaneous tumors, PET imaging revealed tumor uptake of 41.8 ± 3.8, 10.5 ± 3.9, and 12.1 ± 2.3%ID/g at 48 h post-injection for SKOV3, OVCAR3, and Caov3, respectively (n = 3). In orthotopic models, PET imaging with 64Cu-NOTA-pertuzumab allowed for rapid and clear delineation of both primary and small peritoneal metastases in HER2-expressing ovarian cancer.


64Cu-NOTA-pertuzumab is an effective PET tracer for the non-invasive imaging of HER2 expression in vivo, rendering it a potential tracer for treatment monitoring and improved patient stratification.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others


  1. Berchuck A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R, et al. Overexpression of Her-2/Neu is associated with poor survival in advanced epithelial ovarian-cancer. Cancer Res. 1990;50:4087–91.

    CAS  PubMed  Google Scholar 

  2. Bartlett JM, Langdon SP, Simpson BJ, Stewart M, Katsaros D, Sismondi P, et al. The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer. Br J Cancer. 1996;73:301–6. doi:10.1038/bjc.1996.53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tuefferd M, Couturier J, Penault-Llorca F, Vincent-Salomon A, Broet P, Guastalla JP, et al. HER2 status in ovarian carcinomas: a multicenter GINECO study of 320 patients. PLoS One. 2007;2:e1138. doi:10.1371/journal.pone.0001138.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Magnifico A, Albano L, Campaner S, Delia D, Castiglioni F, Gasparini P, et al. Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin Cancer Res. 2009;15:2010–21. doi:10.1158/1078-0432.CCR-08-1327.

    Article  CAS  PubMed  Google Scholar 

  5. Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2011;9:16–32. doi:10.1038/nrclinonc.2011.177.

    Article  PubMed  Google Scholar 

  6. Hodeib M, Serna-Gallegos T, Tewari KS. A review of HER2-targeted therapy in breast and ovarian cancer: lessons from antiquity - CLEOPATRA and PENELOPE. Future Oncol. 2015;11:3113–31. doi:10.2217/fon.15.266.

    Article  CAS  PubMed  Google Scholar 

  7. Solomayer EF, Becker S, Pergola-Becker G, Bachmann R, Kramer B, Vogel U, et al. Comparison of HER2 status between primary tumor and disseminated tumor cells in primary breast cancer patients. Breast Cancer Res Treat. 2006;98:179–84. doi:10.1007/s10549-005-9147-y.

    Article  CAS  PubMed  Google Scholar 

  8. Seol H, Lee HJ, Choi Y, Lee HE, Kim YJ, Kim JH, et al. Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod Pathol. 2012;25:938–48. doi:10.1038/modpathol.2012.36.

    Article  CAS  PubMed  Google Scholar 

  9. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–19. doi:10.1056/NEJMoa1113216.

    Article  CAS  PubMed  Google Scholar 

  10. Faratian D, Zweemer AJ, Nagumo Y, Sims AH, Muir M, Dodds M, et al. Trastuzumab and pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies. Clin Cancer Res. 2011;17:4451–61. doi:10.1158/1078-0432.CCR-10-2461.

    Article  CAS  PubMed  Google Scholar 

  11. Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009;69:9330–6. doi:10.1158/0008-5472.CAN-08-4597.

    Article  CAS  PubMed  Google Scholar 

  12. Lua W-H, Gan SK-E, Lane DP, Verma CS. A search for synergy in the binding kinetics of Trastuzumab and Pertuzumab whole and F(ab) to Her2. npj. Breast Cancer. 2015;1:15012. doi:10.1038/npjbcancer.2015.12.

    CAS  Google Scholar 

  13. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30. doi:10.3322/caac.21332.

    Article  PubMed  Google Scholar 

  14. Luo H, Hernandez R, Hong H, Graves SA, Yang Y, England CG, et al. Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry. Proc Natl Acad Sci U S A. 2015;112:12806–11. doi:10.1073/pnas.1509667112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yang Y, Hernandez R, Rao J, Yin L, Qu Y, Wu J, et al. Targeting CD146 with a 64Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas. Proc Natl Acad Sci U S A. 2015;112:E6525–34. doi:10.1073/pnas.1502648112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stabin MG. MIRDOSE: personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 1996;37:538–46.

    CAS  PubMed  Google Scholar 

  17. Protection R. ICRP publication 103. Ann ICRP. 2007;37:2.

    Google Scholar 

  18. England CG, Ehlerding EB, Hernandez R, Rekoske BT, Graves SA, Sun H, et al. Preclinical pharmacokinetics and biodistribution studies of 89Zr-labeled pembrolizumab. J Nucl Med. 2016. doi:10.2967/jnumed.116.177857.

    Google Scholar 

  19. Bhattacharyya S, Kurdziel K, Wei L, Riffle L, Kaur G, Hill GC, et al. Zirconium-89 labeled panitumumab: a potential immuno-PET probe for HER1-expressing carcinomas. Nucl Med Biol. 2013;40:451–7. doi:10.1016/j.nucmedbio.2013.01.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tang Y, Wang J, Scollard DA, Mondal H, Holloway C, Kahn HJ, et al. Imaging of HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice using (111)In-trastuzumab (Herceptin) Fab fragments. Nucl Med Biol. 2005;32:51–8. doi:10.1016/j.nucmedbio.2004.08.003.

    Article  CAS  PubMed  Google Scholar 

  21. Kramer-Marek G, Kiesewetter DO, Capala J. Changes in HER2 expression in breast cancer xenografts after therapy can be quantified using PET and (18)F-labeled affibody molecules. J Nucl Med. 2009;50:1131–9. doi:10.2967/jnumed.108.057695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Perik PJ, Lub-De Hooge MN, Gietema JA, van der Graaf WT, de Korte MA, Jonkman S, et al. Indium-111-labeled trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2006;24:2276–82. doi:10.1200/JCO.2005.03.8448.

    Article  CAS  PubMed  Google Scholar 

  23. Dijkers EC, Kosterink JG, Rademaker AP, Perk LR, van Dongen GA, Bart J, et al. Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging. J Nucl Med. 2009;50:974–81. doi:10.2967/jnumed.108.060392.

    Article  CAS  PubMed  Google Scholar 

  24. McLarty K, Cornelissen B, Cai Z, Scollard DA, Costantini DL, Done SJ, et al. Micro-SPECT/CT with 111In-DTPA-pertuzumab sensitively detects trastuzumab-mediated HER2 downregulation and tumor response in athymic mice bearing MDA-MB-361 human breast cancer xenografts. J Nucl Med. 2009;50:1340–8. doi:10.2967/jnumed.109.062224.

    Article  CAS  PubMed  Google Scholar 

  25. Marquez BV, Ikotun OF, Zheleznyak A, Wright B, Hari-Raj A, Pierce RA, et al. Evaluation of (89)Zr-pertuzumab in Breast cancer xenografts. Mol Pharm. 2014;11:3988–95. doi:10.1021/mp500323d.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Capelan M, Pugliano L, De Azambuja E, Bozovic I, Saini KS, Sotiriou C, et al. Pertuzumab: new hope for patients with HER2-positive breast cancer. Ann Oncol. 2013;24:273–82. doi:10.1093/annonc/mds328.

    Article  CAS  PubMed  Google Scholar 

  27. Reynolds K, Sarangi S, Bardia A, Dizon DS. Precision medicine and personalized breast cancer: combination pertuzumab therapy. Pharmacogenomics Pers Med. 2014;7:95–105. doi:10.2147/PGPM.S37100.

    Google Scholar 

  28. Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, et al. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015;26:320–5. doi:10.1093/annonc/mdu524.

    Article  CAS  PubMed  Google Scholar 

  29. Lam K, Chan C, Reilly RM. Development and preclinical studies of 64Cu-NOTA-pertuzumab F(ab’)2 for imaging changes in tumor HER2 expression associated with response to trastuzumab by PET/CT. MAbs. 2017;9:154–64. doi:10.1080/19420862.2016.1255389.

    Article  CAS  PubMed  Google Scholar 

  30. Kyriazi S, Kaye SB, deSouza NM. Imaging ovarian cancer and peritoneal metastases—current and emerging techniques. Nat Rev Clin Oncol. 2010;7:381–93. doi:10.1038/nrclinonc.2010.47.

    Article  PubMed  Google Scholar 

  31. Dhanda S, Thakur M, Kerkar R, Jagmohan P. Diffusion-weighted imaging of gynecologic tumors: diagnostic pearls and potential pitfalls. Radiographics. 2014;34:1393–416. doi:10.1148/rg.345130131.

    Article  PubMed  Google Scholar 

  32. Sironi S, Messa C, Mangili G, Zangheri B, Aletti G, Garavaglia E, et al. Integrated FDG PET/CT in patients with persistent ovarian cancer: correlation with histologic findings. Radiology. 2004;233:433–40. doi:10.1148/radiol.2332031800.

    Article  PubMed  Google Scholar 

Download references


This work was supported in part by the University of Wisconsin - Madison, the National Institutes of Health (NIBIB/NCI 1R01CA169365, 1R01EB021336, P30CA014520, T32CA009206, T32GM008505, S10-OD018505), the American Cancer Society (125246-RSG-13-099-01-CCE), and the National Science Foundation of China (81401465, 51573096).

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Peng Huang or Weibo Cai.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

Dawei Jiang, Hyung-Jun Im, and Haiyan Sun contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.


(DOCX 2232 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, D., Im, HJ., Sun, H. et al. Radiolabeled pertuzumab for imaging of human epidermal growth factor receptor 2 expression in ovarian cancer. Eur J Nucl Med Mol Imaging 44, 1296–1305 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: