Skip to main content
SpringerLink
Log in

The prognostic and predictive value of sstr2-immunohistochemistry and sstr2-targeted imaging in neuroendocrine tumors

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

Abstract

Purpose

Our aim was to assess the prognostic and predictive value of somatostatin receptor 2 (sstr2) in neuroendocrine tumors (NETs).

Methods

We established a tissue microarray and imaging database from NET patients that received sstr2-targeted radiopeptide therapy with yttrium-90-DOTATOC, lutetium-177-DOTATOC or alternative treatment. We used univariate and multivariate analyses to identify prognostic and predictive markers for overall survival, including sstr2-imaging and sstr2-immunohistochemistry.

Results

We included a total of 279 patients. In these patients, sstr2-immunohistochemistry was an independent prognostic marker for overall survival (HR: 0.82, 95 % CI: 0.67 – 0.99, n = 279, p = 0.037). In DOTATOC patients, sstr2-expression on immunohistochemistry correlated with tumor uptake on sstr2-imaging (n = 170, p < 0.001); however, sstr2-imaging showed a higher prognostic accuracy (positive predictive value: +27 %, 95 % CI: 3 – 56 %, p = 0.025). Sstr2-expression did not predict a benefit of DOTATOC over alternative treatment (p = 0.93).

Conclusions

Our results suggest sstr2 as an independent prognostic marker in NETs. Sstr2-immunohistochemistry correlates with sstr2-imaging; however, sstr2-imaging is more accurate for determining the individual prognosis.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol: Off J Am Soc Clin Oncol. 2008;26:2124–30. doi:10.1200/JCO.2007.15.2553.

    Article  CAS  Google Scholar 

  2. Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:2416–23. doi:10.1200/JCO.2010.33.7873.

    Article  CAS  Google Scholar 

  3. Villard L, Romer A, Marincek N, Brunner P, Koller MT, Schindler C, et al. Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers. J Clin Oncol: Off J Am Soc Clin Oncol. 2012;30:1100–6. doi:10.1200/JCO.2011.37.2151.

    Article  CAS  Google Scholar 

  4. Romer A, Seiler D, Marincek N, Brunner P, Koller MT, Ng QK, et al. Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2014;41:214–22. doi:10.1007/s00259-013-2559-8.

    Article  CAS  PubMed  Google Scholar 

  5. Marinoni I, Kurrer AS, Vassella E, Dettmer M, Rudolph T, Banz V, et al. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology. 2014;146:453–60. doi:10.1053/j.gastro.2013.10.020. e5.

    Article  CAS  PubMed  Google Scholar 

  6. Iten F, Muller B, Schindler C, Rochlitz C, Oertli D, Macke HR, et al. Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized medullary thyroid cancer: a phase II clinical trial. Clin Cancer Res: Off J Am Assoc Cancer Res. 2007;13:6696–702. doi:10.1158/1078-0432.CCR-07-0935.

    Article  CAS  Google Scholar 

  7. Iten F, Muller B, Schindler C, Rasch H, Rochlitz C, Oertli D, et al. [(90)Yttrium-DOTA]-TOC response is associated with survival benefit in iodine-refractory thyroid cancer: long-term results of a phase 2 clinical trial. Cancer. 2009;115:2052–62. doi:10.1002/cncr.24272.

    Article  CAS  PubMed  Google Scholar 

  8. Korner M, Waser B, Schonbrunn A, Perren A, Reubi JC. Somatostatin receptor subtype 2A immunohistochemistry using a new monoclonal antibody selects tumors suitable for in vivo somatostatin receptor targeting. Am J Surg Pathol. 2012;36:242–52. doi:10.1097/PAS.0b013e31823d07f3.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Rindi G, Arnold R, Bosman F, Capella C, Klimstra D. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman F, Hruban R, Theise N, editors. WHO classification of tumors of the digestive system. 4th ed. Lyon: International Agency for Research on Cancer; 2010. p. 13–4.

    Google Scholar 

  10. Moskowitz CS, Pepe MS. Quantifying and comparing the accuracy of binary biomarkers when predicting a failure time outcome. Stat Med. 2004;23:1555–70. doi:10.1002/sim.1747.

    Article  PubMed  Google Scholar 

  11. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, et al. REporting recommendations for tumor MARKer prognostic studies (REMARK). Nat Clin Pract Oncol. 2005;2:416–22.

    Article  CAS  PubMed  Google Scholar 

  12. Kim HS, Lee HS, Kim WH. Clinical significance of protein expression of cyclooxygenase-2 and somatostatin receptors in gastroenteropancreatic neuroendocrine tumors. Cancer Res Treat: Off J Kor Cancer Assoc. 2011;43:181–8. doi:10.4143/crt.2011.43.3.181.

    Article  Google Scholar 

  13. Asnacios A, Courbon F, Rochaix P, Bauvin E, Cances-Lauwers V, Susini C, et al. Indium-111-pentetreotide scintigraphy and somatostatin receptor subtype 2 expression: new prognostic factors for malignant well-differentiated endocrine tumors. J Clin Oncol: Off J Am Soc Clin Oncol. 2008;26:963–70. doi:10.1200/JCO.2007.12.7431.

    Article  Google Scholar 

  14. Strosberg JR, Wolin EM, Chasen B, Kulke MH, Bushnell DL, Caplin ME, et al. NETTER-1 phase III: Progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177-Lu-Dotatate. J Clin Oncol: Off J Am Soc Clin Oncol. 2016;34.

  15. Kunikowska J, Krolicki L, Hubalewska-Dydejczyk A, Mikolajczak R, Sowa-Staszczak A, Pawlak D. Clinical results of radionuclide therapy of neuroendocrine tumours with 90Y-DOTATATE and tandem 90Y/177Lu-DOTATATE: which is a better therapy option? Eur J Nucl Med Mol Imaging. 2011;38:1788–97. doi:10.1007/s00259-011-1833-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to our nursing, laboratory, and technical staff for their support in patient care, preparation of radiopharmaceuticals, and acquisition of scans. Furthermore, we would like to thank Christoph Stettler for his valuable input on the manuscript. All authors declare no potential conflicts of interest.

HRM, MB, AP and MAW were supported by the Swiss National Science Foundation

Author information

Author notes

    Authors and Affiliations

    1. Institute of Pathology, University Hospital Basel, CH, Basel, Switzerland

      Philippe Brunner, Katharina Glatz & Lukas Bubendorf

    2. Institute of Nuclear Medicine, University Hospital Basel, CH, Basel, Switzerland

      Philippe Brunner, Ann-Catherine Jörg, Nicolas Marincek & Jan Müller-Brand

    3. Institute of Nuclear Medicine, University Hospital Bern, CH, 3010, Bern, Switzerland

      Piotr Radojewski, Maria Umlauft, Nicolas Marincek, Petar-Marko Spanjol, Thomas Krause, Rebecca A. Dumont & Martin A. Walter

    4. Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland

      Helmut R. Maecke

    5. Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, CH, Switzerland

      Matthias Briel

    6. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada

      Matthias Briel

    7. Institute of Pathology, University Bern, Bern, Switzerland

      Anja Schmitt & Aurel Perren

    Authors
    1. Philippe Brunner
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Ann-Catherine Jörg
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Katharina Glatz
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Lukas Bubendorf
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Piotr Radojewski
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Maria Umlauft
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Nicolas Marincek
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Petar-Marko Spanjol
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Thomas Krause
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Rebecca A. Dumont
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Helmut R. Maecke
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Jan Müller-Brand
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Matthias Briel
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Anja Schmitt
      View author publications

      You can also search for this author in PubMed Google Scholar

    15. Aurel Perren
      View author publications

      You can also search for this author in PubMed Google Scholar

    16. Martin A. Walter
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Martin A. Walter.

    Ethics declarations

    The authors declare no potential conflicts of interest. All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

    Additional information

    Philippe Brunner and Ann-Catherine Jörg contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Brunner, P., Jörg, AC., Glatz, K. et al. The prognostic and predictive value of sstr2-immunohistochemistry and sstr2-targeted imaging in neuroendocrine tumors. Eur J Nucl Med Mol Imaging 44, 468–475 (2017). https://doi.org/10.1007/s00259-016-3486-2

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00259-016-3486-2

    Keywords

    Search

    Navigation