Skip to main content

Advertisement

SpringerLink
Log in

β-catenin and Her2/neu expression in rectal cancer: association with histomorphological response to neoadjuvant therapy and prognosis

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background

Neoadjuvant treatment strategies have been developed to improve survival of patients with advanced rectal cancer. Since mainly patients with major histopathological response benefit from this therapy, predictive and prognostic markers are needed. We examined the association of β-catenin and Her2/neu protein expression with histopathologic response to neoadjuvant radiochemotherapy and prognosis in patients with locally advanced rectal cancer.

Methods

Fifty-four patients (33 male; 21 female; median age 60.4 years) with locally advanced rectal cancer were included in this study. All patients received a neoadjuvant radiochemotherapy (50.4 Gy, 5-FU) followed by surgical resection. Histomorphologic regression was evaluated by Dworak and Cologne staging system. Major response was defined by Dworak classification when resected specimens contained less than 50% vital tumor cells (n = 14) and by Cologne grading system when resected specimens contained less than 10% vital tumor cells (n = 15). Intratumoral β-catenin (nuclear/membranous) and Her2/neu (cytoplasmatic/membranous) expression was determined by immunohistochemistry in pre- and post-therapeutic specimens and correlated with clinicopathologic parameters.

Results

A significant association was detected between pre-therapeutic membranous β-catenin levels and response: patients with a lower β-catenin protein expression showed significantly more often a major response compared with patients having high intratumoral protein levels (p = 0.011). In addition, patients with a higher Her2/neu protein expression showed a significant survival benefit compared with patients having low intratumoral protein levels (5-year survival rate: 81% vs. low 41%; p = 0.023).

Conclusions

The pre-therapeutic β-catenin and Her2/neu protein expression seem to be valuable predictive and prognostic markers in the multimodality treatment of advanced rectal cancer.

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

Similar content being viewed by others

References

  1. Bosset JF, Calais G, Daban A, Berger C, Radosevic-Jelic L, Maingon P, Bardet E, Pierart M, Briffaux A (2004) Preoperative chemoradiotherapy versus preoperative radiotherapy in rectal cancer patients: assessment of acute toxicity and treatment compliance. Report of the 22921 randomised trial conducted by the EORTC Radiotherapy Group. Eur J Cancer 40:219–224

    Article  PubMed  CAS  Google Scholar 

  2. Kim JS, Hur H, Kim NK, Kim YW, Cho SY, Kim JY, Min BS, Ahn JB, Keum KC, Kim H, Sohn SK, Cho CH (2009) Oncologic outcomes after radical surgery following preoperative chemoradiotherapy for locally advanced lower rectal cancer: abdominoperineal resection versus sphincter-preserving procedure. Ann Surg Oncol 16:1266–1273

    Article  PubMed  Google Scholar 

  3. Minsky BD (2009) Is preoperative chemoradiotherapy still the treatment of choice for rectal cancer? J Clin Oncol 27:5115–5116

    Article  PubMed  Google Scholar 

  4. Pasetto LM (2005) Preoperative versus postoperative treatment for locally advanced rectal carcinoma. Future Oncol 1:209–220

    Article  PubMed  Google Scholar 

  5. Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, Kahlenberg MS, Baez-Diaz L, Ursiny CS, Petrelli NJ, Wolmark N (2009) Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 27:5124–5130

    Article  PubMed  Google Scholar 

  6. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740

    Article  PubMed  CAS  Google Scholar 

  7. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, Quirke P, Couture J, de Metz C, Myint AS, Bessell E, Griffiths G, Thompson LC, Parmar M (2009) Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 373:811–820

    Article  PubMed  Google Scholar 

  8. Guillem JG, Chessin DB, Cohen AM, Shia J, Mazumdar M, Enker W, Paty PB, Weiser MR, Klimstra D, Saltz L, Minsky BD, Wong WD (2005) Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg 241:829–836, discussion 836–828

    Article  PubMed  Google Scholar 

  9. Rosenberg R, Nekarda H, Zimmermann F, Becker K, Lordick F, Hofler H, Molls M, Siewert JR (2008) Histopathological response after preoperative radiochemotherapy in rectal carcinoma is associated with improved overall survival. J Surg Oncol 97:8–13

    Article  PubMed  CAS  Google Scholar 

  10. Horisberger K, Hofheinz RD, Palma P, Volkert AK, Rothenhoefer S, Wenz F, Hochhaus A, Post S, Willeke F (2008) Tumor response to neoadjuvant chemoradiation in rectal cancer: predictor for surgical morbidity? Int J Colorectal Dis 23:257–264

    Article  PubMed  CAS  Google Scholar 

  11. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767

    Article  PubMed  CAS  Google Scholar 

  12. de Lau W, Barker N, Clevers H (2007) WNT signaling in the normal intestine and colorectal cancer. Front Biosci 12:471–491

    Article  PubMed  Google Scholar 

  13. Kitisin K, Mishra L (2006) Molecular biology of colorectal cancer: new targets. Semin Oncol 33:S14–S23

    Article  PubMed  CAS  Google Scholar 

  14. Yang VW (1999) The molecular genetics of colorectal cancer. Curr Gastroenterol Rep 1:449–454

    Article  PubMed  CAS  Google Scholar 

  15. Su LK, Vogelstein B, Kinzler KW (1993) Association of the APC tumor suppressor protein with catenins. Science 262:1734–1737

    Article  PubMed  CAS  Google Scholar 

  16. Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P (1993) Association of the APC gene product with beta-catenin. Science 262:1731–1734

    Article  PubMed  CAS  Google Scholar 

  17. Ochs AM, Wong L, Kakani V, Neerukonda S, Gorske J, Rao A, Riggs M, Ward H, Keville L (2004) Expression of vascular endothelial growth factor and HER2/neu in stage II colon cancer and correlation with survival. Clin Colorectal Cancer 4:262–267

    Article  PubMed  CAS  Google Scholar 

  18. Kapitanovic S, Radosevic S, Kapitanovic M, Andelinovic S, Ferencic Z, Tavassoli M, Primorac D, Sonicki Z, Spaventi S, Pavelic K, Spaventi R (1997) The expression of p185(HER-2/neu) correlates with the stage of disease and survival in colorectal cancer. Gastroenterology 112:1103–1113

    Article  PubMed  CAS  Google Scholar 

  19. Tsioulias GJ, Muto T, Morioka Y, Yamamoto T, Mori S (1990) erbB-2 gene expression in colorectal cancer. Jpn J Exp Med 60:343–349

    PubMed  CAS  Google Scholar 

  20. D'Emilia J, Bulovas K, D'Ercole K, Wolf B, Steele G Jr (1989) Summerhayes IC: expression of the c-erbB-2 gene product (p185) at different stages of neoplastic progression in the colon. Oncogene 4:1233–1239

    PubMed  Google Scholar 

  21. Schneider PM, Baldus SE, Metzger R, Kocher M, Bongartz R, Bollschweiler E, Schaefer H, Thiele J, Dienes HP, Mueller RP, Hoelscher AH (2005) Histomorphologic tumor regression and lymph node metastases determine prognosis following neoadjuvant radiochemotherapy for esophageal cancer: implications for response classification. Ann Surg 242:684–692

    Article  PubMed  Google Scholar 

  22. International Union Against Cancer (UICC) (2002) TNM classification of malignant tumors, 6th edn. Wiley, New York

    Google Scholar 

  23. Dworak O, Keilholz L, Hoffmann A (1997) Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19–23

    Article  PubMed  CAS  Google Scholar 

  24. Rödel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Fietkau R, Liersch T, Hohenberger W, Raab R, Sauer R, Wittekind C (2005) Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23:8688–8696

    Article  PubMed  Google Scholar 

  25. Jakob C, Liersch T, Meyer W, Baretton GB, Schwabe W, Hausler P, Kulle B, Becker H, Aust DE (2006) Prognostic value of histologic tumor regression, thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase in rectal cancer UICC Stage II/III after neoadjuvant chemoradiotherapy. Am J Surg Pathol 30:1169–1174

    PubMed  Google Scholar 

  26. Lindebjerg J, Spindler KL, Ploen J, Jakobsen A (2009) The prognostic value of lymph node metastases and tumour regression grade in rectal cancer patients treated with long-course preoperative chemoradiotherapy. Colorectal Dis 11:264–269

    Article  PubMed  CAS  Google Scholar 

  27. Brabletz T, Kirchner T (2003) Morphogenetic aspects of colorectal cancer. Pathologe 24:44–48

    PubMed  CAS  Google Scholar 

  28. Savas B, Ensari A, Percinel S, Kuzu I, Kuzu MA, Bektas M, Cetinkaya H, Kursun N (2007) The significance of beta-catenin, E-cadherin, and P-cadherin expressions in neoplastic progression of colorectal mucosa: an immunohistochemical study. Acta Gastroenterol Belg 70:339–344

    PubMed  Google Scholar 

  29. Gunther K, Brabletz T, Kraus C, Dworak O, Reymond MA, Jung A, Hohenberger W, Kirchner T, Kockerling F, Ballhausen WG (1998) Predictive value of nuclear beta-catenin expression for the occurrence of distant metastases in rectal cancer. Dis Colon Rectum 41:1256–1261

    Article  PubMed  CAS  Google Scholar 

  30. Fernebro E, Bendahl PO, Dictor M, Persson A, Ferno M, Nilbert M (2004) Immunohistochemical patterns in rectal cancer: application of tissue microarray with prognostic correlations. Int J Cancer 111:921–928

    Article  PubMed  CAS  Google Scholar 

  31. Baldus SE, Monig SP, Huxel S, Landsberg S, Hanisch FG, Engelmann K, Schneider PM, Thiele J, Holscher AH, Dienes HP (2004) MUC1 and nuclear beta-catenin are coexpressed at the invasion front of colorectal carcinomas and are both correlated with tumor prognosis. Clin Cancer Res 10:2790–2796

    Article  PubMed  CAS  Google Scholar 

  32. Ross JS, Fletcher JA (1998) The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Oncologist 3:237–252

    PubMed  Google Scholar 

  33. Kruser TJ, Wheeler DL (2010) Mechanisms of resistance to HER family targeting antibodies. Exp Cell Res 316(7):1083–1100

    Article  PubMed  CAS  Google Scholar 

  34. Kluftinger AM, Robinson BW, Quenville NF, Finley RJ, Davis NL (1992) Correlation of epidermal growth factor receptor and c-erbB2 oncogene product to known prognostic indicators of colorectal cancer. Surg Oncol 1:97–105

    Article  PubMed  CAS  Google Scholar 

  35. Natali PG, Nicotra MR, Bigotti A, Venturo I, Slamon DJ, Fendly BM, Ullrich A (1990) Expression of the p185 encoded by HER2 oncogene in normal and transformed human tissues. Int J Cancer 45:457–461

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Cologne University Research Fund: Köln Fortune.

Author information

Authors and Affiliations

  1. Institute of Pathology, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany

    Uta Drebber, Martin Madeja, Margarete Odenthal, Inga Wedemeyer & Hans P. Dienes

  2. Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany

    Stefan P. Mönig, Jan Brabender, Elfriede Bollschweiler, Arnulf H. Hölscher & Daniel Vallböhmer

  3. Department of Visceral and Transplantation Surgery, University Hospital Zurich, Rämistr. 100, 8091, Zürich, Switzerland

    Paul M. Schneider

Authors
  1. Uta Drebber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Madeja
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Margarete Odenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Inga Wedemeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefan P. Mönig
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan Brabender
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elfriede Bollschweiler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arnulf H. Hölscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paul M. Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hans P. Dienes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daniel Vallböhmer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Uta Drebber.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drebber, U., Madeja, M., Odenthal, M. et al. β-catenin and Her2/neu expression in rectal cancer: association with histomorphological response to neoadjuvant therapy and prognosis. Int J Colorectal Dis 26, 1127–1134 (2011). https://doi.org/10.1007/s00384-011-1213-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-011-1213-9

Keywords

Search

Navigation