Breast Cancer Research and Treatment

, Volume 100, Issue 2, pp 139–148

E-cadherin Immunohistochemical Expression as a Prognostic Factor in Infiltrating Ductal Carcinoma of the Breast: a Systematic Review and Meta-Analysis

Pre-clinical study

Abstract

Purpose

Multiple studies examining the relationship between loss of E-cadherin expression, a pivotal event for evolving metastatic behavior among epithelially derived cancers, and 5-year survival in infiltrating ductal breast carcinoma have yielded inconclusive and contradictory results.

Experimental design

We conducted a systematic review of the PubMed database through August 2005 with no language restrictions to identify cohort studies that evaluated E-cadherin immunohistochemical expression as a prognostic marker for ductal breast carcinoma. 5-year all-cause mortality or 5-year breast cancer-specific mortality were the primary study outcomes. Meta-analysis was conducted using the REVMAN software and summary hazard ratios assuming both fixed effect and random effect models were calculated.

Results

Ten retrospective cohort studies were identified. Reduced or absent E-cadherin expression significantly increased the risk of all-cause mortality [combined HR = 1.55; 95% CI = 1.08–2.23] whereas a non-significant association was observed for breast cancer-specific mortality [combined HR = 0.70; 95% CI = 0.39–1.27]. We documented substantial inter-study heterogeneity with respect to all aspects of clinical data collection, immunohistochemical staining and interpretation as well as statistical modeling. These factors could not be formally analyzed but they challenge the robustness of our calculated summary estimates.

Conclusions

Loss of E-cadherin expression may be an independent negative prognostic indicator for infiltrating ductal breast carcinoma and randomized, controlled studies evaluating this finding are justified. We encourage standardization of immunohistochemical techniques, data interpretation algorithms across laboratories and use of all-cause mortality to increase data compatibility and facilitate future efforts summarizing the utility of alternate prognostic markers in cancer.

Key words

Breast cancer Cancer prognosis E-cadherin Immunohistochemistry Meta-analysis 

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References

  1. 1.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130PubMedCrossRefGoogle Scholar
  2. 2.
    Wood WC, Muss HB, Solin LJ, Olopade OI (2005). Chapter 33: Cancer of the breast—Section 2: Malignant tumors of the breast. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer: Principles and practice of oncology, 7th edn. Lippincott Williams & Wilkins, Philadelphia, pp 1415–1477Google Scholar
  3. 3.
    Look MP, van Putten WLJ, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Ferno M, Eppenberger-Castori S, Sweep CG, Peyrat JP, Martin PM, Magdelenat H, Brunner N, Duggan C, Lisboa BW, Bendahl PO, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder ME, Manders P, Fiets WE, Blankenstein MA, Broet P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LV, Klijn JG, O’Higgins N, Eppenberger U, Janicke F, Schmitt M, Foekens JA (2002) Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 94:116–128PubMedGoogle Scholar
  4. 4.
    van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R (2002) A gene expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009PubMedCrossRefGoogle Scholar
  5. 5.
    Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JF, Macmillan D, Blamey RW, Ellis IO (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116:340–350PubMedCrossRefGoogle Scholar
  6. 6.
    Goodwin M, Yap AS (2004) Classical cadherin adhesion molecules: coordinating cell adhesion, signaling and the cytoskeleton. J Mol Histol 35:839–844PubMedCrossRefGoogle Scholar
  7. 7.
    Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D, Birchmeier W (1991) E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113:173–185PubMedCrossRefGoogle Scholar
  8. 8.
    Perl A-K, Wilgenbus P, Dahl U, Semb H, Christofori G (1998) A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392:190–193PubMedCrossRefGoogle Scholar
  9. 9.
    Pagliarini RA, Xu T (2003) A genetic screen in Drosophila for metastatic behavior. Science 302:1227–1231PubMedCrossRefGoogle Scholar
  10. 10.
    Siitonen SM, Kononen JT, Helin HJ, Rantala IS, Holli KA, Isola JJ (1996) Reduced E-cadherin expression is associated with invasiveness and unfavorable prognosis in breast cancer. Am J Clin Pathol 105:394–402PubMedGoogle Scholar
  11. 11.
    Gonzalez MA, Pinder SE, Wencyk PM, Bell JA, Elston CW, Nicholson RI, Robertson JFR, Blamey RW, Ellis IO (1999) An immunohistochemical examination of the expression of E-cadherin, alpha- and beta/gamma-catenins and alpha2- and beta1-integrins in invasive breast cancer. J Pathol 187:523–529PubMedCrossRefGoogle Scholar
  12. 12.
    Sarrio D, Perez-Mies B, Hardisson D, Moreno-Bueno G, Suarez A, Cano A, Martin-Perez J, Gamallo C, Palacios J (2004) Cytoplasmic localization of p120ctn and E-cadherin loss characterize lobular breast carcinoma from preinvasive to metastatic lesions. Oncogene 23:3272–3282PubMedCrossRefGoogle Scholar
  13. 13.
    Oka H, Shiozaki H, Kobayashi K, Inoue M, Tahara H, Kobayashi T, Takatsua Y, Matsuyoshi N, Hirano S, Takeichi M, Mori T (1993) Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res 53:1696–1701PubMedGoogle Scholar
  14. 14.
    Jones JL, Royall JE, Walker RA (1996) E-cadherin relates to EGFR expression and lymph node metastasis in primary breast carcinoma. Br J Cancer 74:1273–1241Google Scholar
  15. 15.
    Howard EM, Lau SK, Lyles RH, Birdsong GC, Tadros TS, Umbreit JN, Kochhar R (2004) Correlation and expression of p53, Her-2, vascular endothelial growth factor (VEGF), and E-cadherin in a high risk breast cancer population. Int J Clin Oncol 9:154–160PubMedCrossRefGoogle Scholar
  16. 16.
    Gupta SK, Douglas-Jones AG, Jasani B, Morgan JM, Pignatelli M, Mansel RE (1997) E-cadherin (E-cad) expression in ductal carcinoma in situ (DCIS) of the breast. Virchows Arch 430:23–28PubMedCrossRefGoogle Scholar
  17. 17.
    Rakha EA, Abd El Rehim D, Pinder SE, Lewis SA, Ellis IO (2005) E-cadherin expression in invasive non-lobular carcinoma of the breast and its prognostic significance. Histopathology 46:685–693PubMedCrossRefGoogle Scholar
  18. 18.
    Swiatoniowski G, Matkowski R, Suder E, Bruzewicz S, Setta M, Kornafel J, Polozowski A, Surowiak P (2005) E-cadherin and fibronectin expressions have no prognostic role in stage II ductal breast cancer. Anticancer Res 25:2879–2884PubMedGoogle Scholar
  19. 19.
    Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, Meert AP, Vallot F, Lafitte JJ, Sculier JP (2001) Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with meta-analysis. Eur Respir J 18:705–719PubMedCrossRefGoogle Scholar
  20. 20.
    Parker C, Rampaul RS, Pinder SE, Bell JA, Wencyk PM, Blamey RW, Nicholson RI, Robertson JF (2001) E-cadherin as a prognostic indicator in primary breast cancer. Br J Cancer 85:1958–1963PubMedCrossRefGoogle Scholar
  21. 21.
    Gamallo C, Moren-Bueno G, Sarrio D, Calero F, Hardisson D, Palacios J (2001) The prognostic significance of P-cadherin in infiltrating ductal breast carcinoma. Mod Pathol 14:650–654PubMedCrossRefGoogle Scholar
  22. 22.
    Hirayama R, Nihei Z, Osanai T, Ichikawa W, Yoshinaga K, Sawai S, Mishima Y (1995) Expression of E-cadherin as related to prognostic factors and survivals in breast cancer. Nippon Rinsho 53:1613–1618PubMedGoogle Scholar
  23. 23.
    Bankfalvi A, Terpe H-J, Breukelmann D, Bier B, Rempe D, Pschadka G, Krech R, Lelle R-J, Boecker W (1999) Immunophenotypic and prognostic analysis of E-cadherin and beta-catenin expression during breast carcinogenesis and tumor progression: a comparative study with CD44. Histopathology 34:25–34PubMedCrossRefGoogle Scholar
  24. 24.
    Nakopoulou L, Gakiopoulou H, Kermapoulos A, Giannopoulou I, Athanassiadou P, Mavrommatis J, Davaris PS (2000) c-met tyrosine kinase receptor expression is associated with abnormal beta-catenin expression and favorable prognostic factors in invasive breast cancer. Histopathology 36:313–325PubMedCrossRefGoogle Scholar
  25. 25.
    Nakopoulou L, Gakiopoulou-Givalou H, Karayiannakis AJ, Giannopoulou I, Kermapoulos A, Davaris P, Pignatelli M (2002) Abnormal alpha-catenin expression in invasive breast cancer correlates with poor patient survival. Histopathology 40:536–546PubMedCrossRefGoogle Scholar
  26. 26.
    Elzagheid A, Kuopio T, Ilmen M, Collan Y (2002) Prognostication of invasive ductal breast cancer by quantification of E-cadherin immunostaining: the methodology and clinical relevance. Histopathology 41:127–133PubMedCrossRefGoogle Scholar
  27. 27.
    Zou W, Hu CH, Zhou JP (2002) Relationship between the expression of E-cadherin-catenins and alpha-, beta-, gamma-catenin and the metastasis and prognosis of breast cancer. Hunan Yi Ke Da Xue Xue Bao 27:499–502PubMedGoogle Scholar
  28. 28.
    Wang LH, Liu DY, Chen YJ, Hou L, Wang B, Mao L-M, Lu S (2002) Relationship between lymph node metastasis and the expressions of E-cadherin, N-cadherin and matrix metalloproteinase in breast cancer. Ai Zheng 21:965–969PubMedGoogle Scholar
  29. 29.
    Kowalski PJ, Rubin MA, Kleer CG (2003) E-cadherin expression in primary carcinomas of the breast and its distant metastases. Breast Cancer Res 5:R217-R222PubMedCrossRefGoogle Scholar
  30. 30.
    Ugur Y, Sari O, Ugur O, Korkusuz P, Varoglu E, Arslan N, Gurcan N, Yildirim M, Sokmensuer C, Asan E, Aras T (2003) Lack of correlation between Tc-99m-sesta-MIBI uptake and cadherin expression in infiltrating ductal carcinoma as prognostic indicators. Ann Nucl Med 17:281–287PubMedCrossRefGoogle Scholar
  31. 31.
    Mirlacher M, Kasper M, Storz M, Knecht Y, Durmuller U, Simon R, Mihatsch MJ, Sauter G (2004) Influence of slide aging on results of translational research studies using immunohistochemistry. Mod Pathol 17:1414–1420PubMedCrossRefGoogle Scholar
  32. 32.
    Howard EM, Lau SK, Lyles RH, Birdsong GC, Umbreit JN, Kochhar R (2005) Expression of E-cadherin in high-risk breast cancer. J Cancer Res Clin Oncol 131:14–18PubMedCrossRefGoogle Scholar
  33. 33.
    Lipponen P, Saarelainen E, Ji H, Aaltomaa S, Syrjanen K (1994) Expression of E-cadherin (E-CD) as related to other prognostic factors and survival in breast cancer. J Pathol 174:101–109PubMedCrossRefGoogle Scholar
  34. 34.
    Song ZC, Wang GL, Qi YX, Cui DC, Li Y (2001) Relationship between expression of multiple tumor suppressor (MTS1) and E-cadherin and metastasis of breast carcinoma. Ai Zheng 22:526–528Google Scholar
  35. 35.
    Madhavan M, Srinivas P, Abraham E, Mathew A, Vijayalekshmi NR, Balaram P (2001) Cadherins as predictive markers of nodal metastasis in breast cancer. Mod Pathol 14:423–427PubMedCrossRefGoogle Scholar
  36. 36.
    Heimann R, Lan F, McBride R, Hellman S (2000) Separating favorable from unfavorable prognostic markers in breast cancer: the role of E-cadherin. Cancer Res 60:298–304PubMedGoogle Scholar
  37. 37.
    Elkhuizen PHM, Hermans J, Leer JWH, van de Vijver MJ (2001) Isolated late local recurrences with high mitotic count and early local recurrences following breast-conserving therapy are associated with increased risk on distant metastases. Int J Radiat Oncol Biol Phys 50:387–396PubMedCrossRefGoogle Scholar
  38. 38.
    Goldstein NS (2002) Does the level of E-cadherin expression correlate with primary breast carcinoma infiltration pattern and type of systemic metastases? Am J Clin Pathol 118:425–434PubMedCrossRefGoogle Scholar
  39. 39.
    Ferlicot S, Vincent-Salomon A, Medioni J, Genin P, Rosty C, Sigal-Zafrani B, Freneaux P, Jouve M, Thiery JP, Sastre-Garau X (2004) Wide metastatic spreading in infiltrating lobular carcinoma of the breast. Eur J Cancer 40:336–341PubMedCrossRefGoogle Scholar
  40. 40.
    Maguire TM, Shering SG, McDermott EW, O’Higgins N, Fennelly JJ, Crown J, Duffy MJ (1997) Assay of E-cadherin by ELISA in human breast cancer. Eur J Cancer 33:404–408PubMedCrossRefGoogle Scholar
  41. 41.
    Tan DS, Potts HW, Leong AC, Gillett CE, Skilton D, Harris WH, Liebmann RD, Hanby AM (1999) The biological and prognostic significance of cell polarity and E-cadherin in grade I infiltrating ductal carcinoma of the breast. J Pathol 189:20–27PubMedCrossRefGoogle Scholar
  42. 42.
    Gillett CE, Miles DW, Ryder K, Skilton D, Liebman RD, Springall RJ, Barnes DM, Hanby AM (2001) Retention of the expression of E-cadherin and catenins is associated with shorter survival in grade III ductal carcinoma of the breast. J Pathol 193:433–441PubMedCrossRefGoogle Scholar
  43. 43.
    Charpin C, Garcia S, Bonnier P, Martini F, Andrac L, Choux R, Lavaut MN, Allasia C (1998) Reduced E-cadherin immunohistochemical expression in node-negative breast carcinoma correlates with 10-year survival. Am J Clin Pathol 109:431–438PubMedGoogle Scholar
  44. 44.
    Peralta Soler A, Knudsen KA, Salazar H, Han AC, Keshgegian AA (1999) P-cadherin expression in breast carcinoma indicates poor survival. Cancer 86:1263–1272PubMedCrossRefGoogle Scholar
  45. 45.
    Asgeirsson KS, Jonasson JG, Tryggvadottir L, Olafsdottir K, Sigurgiersdottir JR, Ingvarsson S, Ogmundsdottir HM (2000) Altered expression of E-cadherin in breast cancer: patterns, mechanisms and clinical significance. Eur J Cancer 36: 1098–1106PubMedCrossRefGoogle Scholar
  46. 46.
    Yoshida R, Kimura N, Harada Y, Ohuchi N (2001) The loss of E-cadherin, α- and β-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer. Int J Oncol 18:513–520PubMedGoogle Scholar
  47. 47.
    Lim SC, Lee MS (2002) Significance of E-cadherin/beta-catenincomplex and cyclin D1 in breast cancer. Oncol Rep 9:915–928PubMedGoogle Scholar
  48. 48.
    Pedersen KB, Nesland JM, Fodstad O, Maelandsmo GM (2002) Expression of S100A4, E-cadherin, alpha- and beta-catenin in breast cancer biopsies. Br J Cancer 87:1281–1286PubMedCrossRefGoogle Scholar
  49. 49.
    Harigopal M, Berger AJ, Camp RL, Rimm DL, Kluger HM (2005) Automated quantitative analysis of E-cadherin expression in lymph node metastases is predictive of survival in invasive ductal breast cancer. Clin Cancer Res 11: 4083–4089PubMedCrossRefGoogle Scholar
  50. 50.
    Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histologic grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410PubMedGoogle Scholar
  51. 51.
    Deeks JJ, Altman DG, Bradburn MJ (2001) Chapter 15: Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Smith GD, Altman DG (eds) Systematic reviews in health care: meta-analysis in context. 2nd edn. BMJ Press, Cornwall UK, pp 285–312Google Scholar
  52. 52.
    Der Simonian R, Laird N (1986) Meta-analysis in clinical trials. Controlled Clin Trials 7:177–188CrossRefGoogle Scholar
  53. 53.
    Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analysis. BMJ 327:557–560PubMedCrossRefGoogle Scholar
  54. 54.
    Wiegand S, Dunne AA, Muller HH, Mandic R, Barth P, Davis RK, Werner JA (2005) Metaanalysis of the significance of matrix metalloproteinases for lymph node disease in patients with head and neck squamous cell carcinoma. Cancer 104:94–100PubMedCrossRefGoogle Scholar
  55. 55.
    Black WC, Haggstrom DA, Welch HG (2002) All-cause mortality in randomized trials of cancer screening. J Natl Cancer Inst 94:167–173PubMedGoogle Scholar
  56. 56.
    Early Breast Cancer Trialists’ Collaborative Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 365:1687–1717CrossRefGoogle Scholar
  57. 57.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97:1180–1184Google Scholar
  58. 58.
    Camp RL, Chung GG, Rimm DL (2002) Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med 8:1323–1327PubMedCrossRefGoogle Scholar
  59. 59.
    Greenland S (1995) Dose–response and trend analysis in epidemiology: alternatives to categorical analysis. Epidemiology 6:356–365PubMedCrossRefGoogle Scholar
  60. 60.
    Altman DG, Lausen B, Sauerbrei W, Shumacher M (1994) Dangers of using “optimal” cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst 86:829–835PubMedGoogle Scholar
  61. 61.
    Mills JL (1993) Data Torturing. New Engl J Med 329: 1196–1199PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Bonnie E. Gould Rothberg
    • 1
  • Michael B. Bracken
    • 1
    • 2
  1. 1.Section of Chronic Disease EpidemiologyYale University School of Public HealthNew HavenUSA
  2. 2.Center for Perinatal, Pediatric and Environmental EpidemiologyYale University School of Public HealthNew HavenUSA

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