EGFR-expression in primary urinary bladder cancer and corresponding metastases and the relation to HER2-expression. On the possibility to target these receptors with radionuclides

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Background. There is limited effect of tyrosine kinase inhibitors or “naked” antibodies binding EGFR or HER2 for therapy of metastasized urinary bladder cancer and these methods are therefore not routinely used. Targeting radionuclides to the extracellular domain of the receptors is potentially a better possibility.

Methods. EGFR- and HER2-expression was analyzed for primary tumors and corresponding metastases from 72 patients using immunohistochemistry and the internationally recommended HercepTest. Intracellular mutations were not analyzed since only the receptors were considered as targets and intracellular abnormalities should have minor effect on radiation dose.

Results. EGFR was positive in 71% of the primary tumors and 69% of corresponding metastases. Local and distant metastases were EGFR-positive in 75% and 66% of the cases, respectively. The expression frequency of HER2 in related lesions was slightly higher (data from previous study). The EGFR-positive tumors expressed EGFR in metastases in 86% of the cases. The co-expression of EGFR and HER2 was 57% for tumors and 53% for metastases. Only 3% and 10% of the lesions were negative for both receptors in tumors and metastases, respectively. Thus, targeting these receptors with radionuclides might be applied for most patients.

Conclusions. At least one of the EGFR- or HER2-receptors was present in most cases and co-expressed in more than half the cases. It is therefore interesting to deliver radionuclides for whole-body receptor-analysis, dosimetry and therapy. This can hopefully compensate for resistance to other therapies and more patients can hopefully be treated with curative instead of palliative intention.

1. Yamaguchi H, Chang SS, Hsu JL, Hung MC. Signaling cross-talk in the resistance to HER family receptor targeted therapy. Oncogene 2014; 33: 1073-81.

2. Sen M, Joyce S, Panahandeh M, Li C, Thomas SM, Maxwell J, Wang L, et al. Targeting Stat3 abrogates EGFR inhibitor resistance in cancer. Clin Cancer Res 2012; 18: 4986-96.

3. Nahta R, Esteva FJ. Trastuzumab: triumphs and tribulations. Oncogene 2007; 26: 3637-43.

4. Morgillo F, Bareschino MA, Bianco R, Tortora G, Ciardiello F. Primary and acquired resistance to anti-EGFR targeted drugs in cancer therapy. Differentiation 2007; 75: 788-99.

5. Calabrò F, Sternberg CN. Metastatic bladder cancer: anything new? Curr Opin Support Palliat Care 2012; 6: 304-9.

6. Siefker-Radtke A. Bladder cancer: can we move beyond chemotherapy? Curr Oncol Rep 2010; 12: 278-83.

7. Adam L, Zhong M, Choi W, Qi W, Nicoloso M, Arora A, et al. miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clin Cancer Res 2009; 15: 5060-72

8. Kassouf W, Dinney CP, Brown G, McConkey DJ, Diehl AJ, Bar-Eli M, et al. Uncoupling between epidermal growth factor receptor and downstream signals defines resistance to the antiproliferative effect of Gefitinib in bladder cancer cells. Cancer Res 2005; 65: 10524-35.

9. Goldenberg DM, and Sharkey RM. Using antibodies to target cancer therapeutics Expert Opin Biol Ther 2012; 12: 1173-90.

10. Thomadsen B, Erwin W, Mourtada F. The physics and radiobiology of targeted radionuclide therapy. In: Speer TW, ed. Targeted radionuclide therapy. Lippincott Williams & Wilkins, Philadelphia; 2011, Chapter 6, p. 71-87. ISBN 978-0-7817-9693-4.

11. Löfblom J, Feldwisch J, Tolmachev V, Carlsson J, Ståhl S, Frejd FY. Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications. FEBS Lett 2010; 584: 2670-80.

12. Carlsson J, Stigbrand T, Adams GP. Introduction to radionuclide therapy. In: Stigbrand T, Adams G, Carlsson J, editors. Targeted radionuclide tumor therapy, biological aspects. Springer Verlag. Springer Science+Business Media France; 2008, Chapter 1, p. 1-11. ISBN 978-1-4020-8695-3.

13. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127-37.

14. Avraham R, Yarden Y. Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat Rev Mol Cell Biol 2011; 12: 104-17.

15. Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol 2007; 19: 124-34.

16. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006; 7: 505-16.

17. Mosesson Y, Yarden Y. Oncogenic growth factor receptors: implications for signal transduction therapy. Semin Cancer Biol 2004; 14: 262-70.

18. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000; 19: 6550-65.

19. Parkin DM. The global burden of urinary bladder cancer. Scand J Urol Nephrol Suppl 2008; 218: 12-20.

20. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893-917.

21. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JWW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013; 49: 1374-403.

22. Gardmark T, Wester K, DeLa Torre M, Carlsson J, Malmström PU. Analysis of HER2 expression in primary urinary bladder carcinoma and corresponding metastases. Brit J Urol (BJU) 2005; 95: 982-86.

23. Wester K, Sjostrom A, de la Torre M, Carlsson J, Malmstrom PU. HER-2--a possible target for therapy of metastatic urinary bladder carcinoma. Acta Oncol 2002; 41: 282-88.

24. Wei Q, Chen L, Sheng L, Nordgren H, Wester K, Carlsson J: EGFR, HER2 and HER3 expression in esophageal primary tumours and corresponding metastases. Int J Oncol 2007; 31: 493-9.

25. Bilous M, Dowsett M, Hanna W, Isola J, Lebeau A, Moreno A, et al. Current perspectives on HER2 testing: a review of national testing guidelines. Mod Pathol 2003; 16: 173-182.

26. Fleischmann A, Rotzer D, Seiler R, Studer UE, Thalmann GN. Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours. Eur Urol 2011; 60: 350-7.

27. Caner V, Turk NS, Duzcan F, Tufan NL, Kelten EC, Zencir S, et al. No strong association between HER-2/neu protein overexpression and gene amplification in high-grade invasive urothelial carcinomas. Pathol Oncol Res 2008; 14: 261-6.

28. Hauser-Kronberger C, Peham K, Grall J, Rausch W, Hutarew G, Dietze O. Novel approach of human epidermal growth factor receptor 2 detection in noninvasive and invasive transitional cell carcinoma of the bladder. J Urol 2006; 175(3 Pt 1): 875-80.

29. Latif Z, Watters AD, Dunn I, Grigor K, Underwood MA, Bartlett JM. HER2/ neu gene amplification and protein overexpression in G3 pT2 transitional cell carcinoma of the bladder: a role for anti-HER2 therapy? Eur J Cancer 2004; 40: 56-63.

30. Sanchez KM, Sweeney CJ, Mass R, Koch MO, Eckert GJ, Geary WA, et al. Evaluation of HER-2/neu expression in prostatic adenocarcinoma: a requested for a standardized, organ specific methodology. Cancer 2002; 95: 1650-5.

31. Baum RP, Prasad V, Muller D, Schuchardt C, Orlova A, Wennborg A, et al. Molecular imaging of HER2-expressing malignant tumors in breast cancer patients using synthetic 111In- or 68Ga-labeled Affibody molecules. J Nucl Med 2010; 51: 89-97.

32. Tolmachev V. Imaging of HER-2 overexpression in tumors for guiding therapy. Curr Pharm Des 2008; 14: 2999-3019.

33. Heskamp S, van Laarhoven HW, Oyen WJ, van der Graaf WT, Boerman OC. Tumor-receptor imaging in breast cancer: a tool for patient selection and response monitoring. Curr Mol Med 2013; 13: 1506-22.

34. Fox JJ, Schöder H, Larson SM. Molecular imaging of prostate cancer. Curr Opin Urol 2012; 22: 320-7.

35. 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.

36. Chen PC, Yu HJ, Chang YH, Pan CC. Her2 amplification distinguishes a subset of non-muscle-invasive bladder cancers with a high risk of progression. J Clin Pathol 2013; 66: 113-9.

37. Bolenz C, Shariat SF, Karakiewicz PI, Ashfaq R, Ho R, Sagalowsky AI, et al. Human epidermal growth factor receptor 2 expression status provides independent prognostic information in patients with urothelial carcinoma of the urinary bladder. BJU Int. 2010; 106: 1216-22.

38. Bolenz C, Lotan Y. Translational research in bladder cancer: from molecular pathogenesis to useful tissue biomarkers. Cancer Biol Ther 2010; 10: 407-15.

39. Kolla SB, Seth A, Singh MK, Gupta NP, Hemal AK, Dogra PN, et al Prognostic significance of Her2/neu overexpression in patients with muscle invasive urinary bladder cancer treated with radical cystectomy. Int Urol Nephrol 2008; 40: 321-7.

40. Black PC, Dinney CP. Growth factors and receptors as prognostic markers in urothelial carcinoma. Curr Urol Rep 2008; 9: 55-61.

41. Krüger S, Weitsch G, Büttner H, Matthiensen A, Böhmer T, Marquardt T, et al. HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic implications. Int J Cancer 2002; 102: 514-8.

42. Jimenez RE, Hussain M, Bianco FJ Jr, Valshampayan U, Tabazcka P, Sakr WA, et al. Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors. Clin Cancer Res 2001; 7: 2440-7.

43. Carlsson J. Potential for clinical radionuclide based imaging and therapy of common cancers expressing EGFR-family receptors. Tumor Biol 2012; 33: 653-9.

44. Chaux A, Cohen JS, Schultz L, Albadine R, Jadallah S, Murphy KM, et al. High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin-fixed, paraffin-embedded archival tissues. Hum Pathol 2012; 43: 1590-5.

45. Carlsson J. EGFR-family expression and implications for targeted radionuclide therapy. In: Stigbrand T, Adams G, Carlsson J, editors. Targeted radionuclide tumor therapy, biological aspects. Springer Verlag. Springer Science+Business Media France; 2008, Chapter 3, p. 25-58. ISBN 978-1-4020-8695-3.

46. Velikyan I, Sundin A, Eriksson B, Lundqvist H, Sörensen J, Bergström M, et al. In vivo binding of [68Ga]-DOTATOC to somatostatin receptors in neuroendocrine tumours--impact of peptide mass. Nucl Med Biol 2010; 37: 265-75.

47 . Tolmachev V, Tran TA, Rosik D, Sjoberg A, Abrahmsen L, Orlova A. Tumor targeting using affibody molecules: interplay of affinity, target expression level, and binding site composition. J Nucl Med 2012; 53: 953-60.

48 . Tolmachev V, Wallberg H, Sandstrom M, Hansson M, Wennborg A, Orlova A. Optimal specific radioactivity of anti-HER2 Affibody molecules enables discrimination between xenografts with high and low HER2 expression levels. Eur J Nucl Med Mol Imaging 2011; 38: 531-39.

49. Damjanov I, Mildner B, Knowles BB. Immunohistochemical localization of the epidermal growth factor receptor in normal human tissues. Lab Invest 1986; 55: 588-92.

50. Gusterson B, Cowley G, Smith JA, Ozanne B. Cellular localisation of human epidermal growth factor receptor. Cell Biol Int Rep 1984; 8: 649-58.

51. Skagias L, Politi E, Karameris A, Sambaziotis D, Archondakis A, Vasou O, et al. Prognostic impact of HER2/neu protein in urothelial bladder cancer. Survival analysis of 80 cases and an overview of almost 20 years’ research. J BUON 2009; 14: 457-62.

52. Naik DS, Sharma S, Ray A, Hedau S. Epidermal growth factor receptor expression in urinary bladder cancer. Indian J Urol 2011; 27: 208-14.

53. Natali PG, Nicotra MR, Bigotti A, Venturo I, Slamon DJ, Fendly BM, et al. Expression of the p185 encoded by HER2 oncogene in normal and transformed human tissues. Int J Cancer 1990; 45: 457-61.

54. Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu protooncogene in normal human adult and fetal tissues. Oncogene 1990; 5: 953-62.

55. Govindan SV, Goldenberg DM. Designing immunoconjugates for cancer therapy. Expert Opin Biol Ther 2012; 12: 873-90.

56. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367: 1783-91.

57. Witzig TE, Fishkin P, Gordon LI, Gregory SA, Jacobs S, Macklis R, et al. Treatment recommendations for radioimmunotherapy in follicular lymphoma: a consensus conference report. Leuk Lymphoma 2011; 52: 1188-99.

58. Press OW. Radiolabeled antibody therapy of B-cell lymphomas. Semin Oncol 1999; 26(5 Suppl 14): 58-65.

59. Kam BL, Teunissen JJ, Krenning EP, de Herder WW, Khan S, van Vliet EI, et al. Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2012; 39(Suppl 1): S103-12.

60. Sandström M, Garske U, Granberg D, Sundin A, Lundqvist H. Individualized dosimetry in patients undergoing therapy with (177)Lu-DOTA-D-Phe (1)-Tyr (3)-octreotate. Eur J Nucl Med Mol Imaging 2010; 37: 212-25.

61. Williams SP. Tissue distribution studies of protein therapeutics using molecular probes: molecular imaging. AAPS J 2012; 14: 389-99.

62. Matthews PM, Rabiner EA, Passchier J, Gunn RN. Positron emission tomography molecular imaging for drug development. Br J Clin Pharmacol 2012; 73: 175-86.

63. Ståhl S, Friedman M, Carlsson J, Tolmachev V, Frejd F. Affibody molecules for targeted radionuclide therapy. In: Speer TW, editor. Targeted radionuclide therapy. Lippincott Williams & Wilkins; 2011. Chapter 4, p. 49-58.

64. Gomes CM, Abrunhosa AJ, Ramos P, Pauwels EK. Molecular imaging with SPECT as a tool for drug development. Adv Drug Deliv Rev 2011; 63: 547-54.

65. Fondell A, Edwards K, Ickenstein LM, Sjöberg S, Carlsson J, Gedda L. Nuclisome: A novel concept for radionuclide therapy using targeting liposomes. Eur J Nucl Med Mol Imaging 2010; 37: 114-23.

66. Stigbrand T, Carlsson J, Adams GP. Developmental trends in targeted radionuclide therapy - biological aspects. In: Stigbrand T, Adams G, Carlsson J, editors. Targeted radionuclide tumor therapy, biological aspects. Springer verlag. Springer Science+Business Media France; 2008, Chapter 21, p. 387-97. ISBN 978-1-4020-8695-3.

67. Persson M, Gedda L, Lundqvist H, Tolmachev V, Nordgren H, Malmstrom PU et al. [177Lu]pertuzumab: experimental therapy of HER-2-expressing xenografts. Cancer Res 2007; 67: 326-31.

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