Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 May 1;80(3-4):419–426. doi: 10.1038/sj.bjc.6690373

Risk-group discrimination in node-negative breast cancer using invasion and proliferation markers: 6-year median follow-up

N Harbeck 1, P Dettmar 2, C Thomssen 4, U Berger 3, K Ulm 3, R Kates 3, H Höfler 2, F Jänicke 4, H Graeff 1, M Schmitt 1
PMCID: PMC2362313  PMID: 10408848

Abstract

Factors reflecting two major aspects of tumour biology, invasion (urokinase-type plasminogen activator (uPA), plasminogen activator inhibiter (PAI-1), cathepsin D) and proliferation (S-phase fraction (SPF), Ki-67, p53, HER-2/neu), were assessed in 125 node-negative breast cancer patients without adjuvant systemic therapy. Median follow-up time was 76 months. Antigen levels of uPA, PAI-1 and cathepsin D were immunoenzymatically determined in tumour tissue extracts. SPF and ploidy were determined flow-cytometrically, Ki‴-67, p53, and HER-2/neu immunohistochemically in adjacent paraffin sections. Their prognostic impact on disease-free (DFS) and overall survival (OS) was compared to that of traditional factors (tumour size, grading, hormone receptor status). Univariate analysis determined PAI-1 (P < 0.001), uPA (P = 0.008), cathepsin D (P = 0.004) and SPF (P = 0.023) as significant for DFS. All other factors failed to be of significant prognostic value. In a Cox model, only PAI-1 was significant for DFS (P < 0.001, relative risk (RR) 6.2). In CART analysis for DFS, the combination of PAI-1 and uPA gave the best risk group discrimination. For OS, PAI-1, cathepsin D, tumour size and ploidy were statistically significant in univariate, but PAI-1 was the only independently significant factor in Cox analysis (P < 0.001, RR 8.9). In particular, this analysis shows that PAI-1 is still a strong and independent prognostic factor in node-negative breast cancer after extended 6-year median follow-up. © 1999 Cancer Research Campaign

Keywords: breast cancer, plasminogen activator inhibitor type 1 (PAI-1), prognosis, S-phase fraction, tumour biology, urokinase-type plasminogen activator (uPA)

Full Text

The Full Text of this article is available as a PDF (143.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bagwell C. B., Mayo S. W., Whetstone S. D., Hitchcox S. A., Baker D. R., Herbert D. J., Weaver D. L., Jones M. A., Lovett E. J., 3rd DNA histogram debris theory and compensation. Cytometry. 1991;12(2):107–118. doi: 10.1002/cyto.990120203. [DOI] [PubMed] [Google Scholar]
  2. Benraad T. J., Geurts-Moespot J., Grøndahl-Hansen J., Schmitt M., Heuvel J. J., de Witte J. H., Foekens J. A., Leake R. E., Brünner N., Sweep C. G. Immunoassays (ELISA) of urokinase-type plasminogen activator (uPA): report of an EORTC/BIOMED-1 workshop. Eur J Cancer. 1996 Jul;32A(8):1371–1381. doi: 10.1016/0959-8049(96)00118-9. [DOI] [PubMed] [Google Scholar]
  3. Bouchet C., Spyratos F., Martin P. M., Hacène K., Gentile A., Oglobine J. Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas. Br J Cancer. 1994 Feb;69(2):398–405. doi: 10.1038/bjc.1994.74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brown R. W., Allred C. D., Clark G. M., Osborne C. K., Hilsenbeck S. G. Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer. Clin Cancer Res. 1996 Mar;2(3):585–592. [PubMed] [Google Scholar]
  5. Clark G. M., McGuire W. L. Steroid receptors and other prognostic factors in primary breast cancer. Semin Oncol. 1988 Apr;15(2 Suppl 1):20–25. [PubMed] [Google Scholar]
  6. D'hautcourt J. L., Spyratos F., Chassevent A. Quality control study by the French Cytometry Association on flow cytometric DNA content and S-phase fraction (S%). The Association Française de Cytométrie. Cytometry. 1996 Mar 15;26(1):32–39. doi: 10.1002/(SICI)1097-0320(19960315)26:1<32::AID-CYTO5>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  7. Danø K., Andreasen P. A., Grøndahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266. doi: 10.1016/s0065-230x(08)60028-7. [DOI] [PubMed] [Google Scholar]
  8. Dettmar P., Harbeck N., Thomssen C., Pache L., Ziffer P., Fizi K., Jänicke F., Nathrath W., Schmitt M., Graeff H. Prognostic impact of proliferation-associated factors MIB1 (Ki-67) and S-phase in node-negative breast cancer. Br J Cancer. 1997;75(10):1525–1533. doi: 10.1038/bjc.1997.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Duffy M. J., Reilly D., O'Sullivan C., O'Higgins N., Fennelly J. J., Andreasen P. Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res. 1990 Nov 1;50(21):6827–6829. [PubMed] [Google Scholar]
  10. Elston C. W., Ellis I. O. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991 Nov;19(5):403–410. doi: 10.1111/j.1365-2559.1991.tb00229.x. [DOI] [PubMed] [Google Scholar]
  11. Fernö M., Bendahl P. O., Borg A., Brundell J., Hirschberg L., Olsson H., Killander D. Urokinase plasminogen activator, a strong independent prognostic factor in breast cancer, analysed in steroid receptor cytosols with a luminometric immunoassay. Eur J Cancer. 1996 May;32A(5):793–801. doi: 10.1016/0959-8049(95)00652-4. [DOI] [PubMed] [Google Scholar]
  12. Foekens J. A., Schmitt M., van Putten W. L., Peters H. A., Kramer M. D., Jänicke F., Klijn J. G. Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncol. 1994 Aug;12(8):1648–1658. doi: 10.1200/JCO.1994.12.8.1648. [DOI] [PubMed] [Google Scholar]
  13. Gasparini G., Boracchi P., Verderio P., Bevilacqua P. Cell kinetics in human breast cancer: comparison between the prognostic value of the cytofluorimetric S-phase fraction and that of the antibodies to Ki-67 and PCNA antigens detected by immunocytochemistry. Int J Cancer. 1994 Jun 15;57(6):822–829. doi: 10.1002/ijc.2910570610. [DOI] [PubMed] [Google Scholar]
  14. Gasparini G. Tamoxifen and chemotherapy in the treatment of metastatic melanoma: are there other possible mechanisms explaining their potentiation? J Clin Oncol. 1994 Sep;12(9):1994–1996. doi: 10.1200/JCO.1994.12.9.1994. [DOI] [PubMed] [Google Scholar]
  15. Grøndahl-Hansen J., Christensen I. J., Briand P., Pappot H., Mouridsen H. T., Blichert-Toft M., Danø K., Brünner N. Plasminogen activator inhibitor type 1 in cytosolic tumor extracts predicts prognosis in low-risk breast cancer patients. Clin Cancer Res. 1997 Feb;3(2):233–239. [PubMed] [Google Scholar]
  16. Grøndahl-Hansen J., Christensen I. J., Rosenquist C., Brünner N., Mouridsen H. T., Danø K., Blichert-Toft M. High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res. 1993 Jun 1;53(11):2513–2521. [PubMed] [Google Scholar]
  17. Grøndahl-Hansen J., Hilsenbeck S. G., Christensen I. J., Clark G. M., Osborne C. K., Brünner N. Prognostic significance of PAI-1 and uPA in cytosolic extracts obtained from node-positive breast cancer patients. Breast Cancer Res Treat. 1997 Apr;43(2):153–163. doi: 10.1023/a:1005744914124. [DOI] [PubMed] [Google Scholar]
  18. Harbeck N., Dettmar P., Thomssen C., Henselmann B., Kuhn W., Ulm K., Jänicke F., Höfler H., Graeff H., Schmitt M. Prognostic impact of tumor biological factors on survival in node-negative breast cancer. Anticancer Res. 1998 May-Jun;18(3C):2187–2197. [PubMed] [Google Scholar]
  19. Harris J. R., Lippman M. E., Veronesi U., Willett W. Breast cancer (3). N Engl J Med. 1992 Aug 13;327(7):473–480. doi: 10.1056/NEJM199208133270706. [DOI] [PubMed] [Google Scholar]
  20. Hilsenbeck S. G., Clark G. M. Practical p-value adjustment for optimally selected cutpoints. Stat Med. 1996 Jan 15;15(1):103–112. doi: 10.1002/(SICI)1097-0258(19960115)15:1<103::AID-SIM156>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  21. Jänicke F., Pache L., Schmitt M., Ulm K., Thomssen C., Prechtl A., Graeff H. Both the cytosols and detergent extracts of breast cancer tissues are suited to evaluate the prognostic impact of the urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1. Cancer Res. 1994 May 15;54(10):2527–2530. [PubMed] [Google Scholar]
  22. Jänicke F., Schmitt M., Graeff H. Clinical relevance of the urokinase-type and tissue-type plasminogen activators and of their type 1 inhibitor in breast cancer. Semin Thromb Hemost. 1991 Jul;17(3):303–312. doi: 10.1055/s-2007-1002624. [DOI] [PubMed] [Google Scholar]
  23. Jänicke F., Schmitt M., Pache L., Ulm K., Harbeck N., Höfler H., Graeff H. Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat. 1993;24(3):195–208. doi: 10.1007/BF01833260. [DOI] [PubMed] [Google Scholar]
  24. Lauffenburger D. A. Cell motility. Making connections count. Nature. 1996 Oct 3;383(6599):390–391. doi: 10.1038/383390a0. [DOI] [PubMed] [Google Scholar]
  25. McGuire W. L., Clark G. M. Prognostic factors and treatment decisions in axillary-node-negative breast cancer. N Engl J Med. 1992 Jun 25;326(26):1756–1761. doi: 10.1056/NEJM199206253262607. [DOI] [PubMed] [Google Scholar]
  26. Osborne C. K. DNA flow cytometry in early breast cancer: a step in the right direction. J Natl Cancer Inst. 1989 Sep 20;81(18):1344–1345. doi: 10.1093/jnci/81.18.1344. [DOI] [PubMed] [Google Scholar]
  27. Press M. F., Bernstein L., Thomas P. A., Meisner L. F., Zhou J. Y., Ma Y., Hung G., Robinson R. A., Harris C., El-Naggar A. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol. 1997 Aug;15(8):2894–2904. doi: 10.1200/JCO.1997.15.8.2894. [DOI] [PubMed] [Google Scholar]
  28. Ravdin P. M. Evaluation of cathepsin D as a prognostic factor in breast cancer. Breast Cancer Res Treat. 1993;24(3):219–226. doi: 10.1007/BF01833262. [DOI] [PubMed] [Google Scholar]
  29. Rochefort H. Cathepsin D in breast cancer: a tissue marker associated with metastasis. Eur J Cancer. 1992;28A(11):1780–1783. doi: 10.1016/0959-8049(92)90003-k. [DOI] [PubMed] [Google Scholar]
  30. Schmitt M., Harbeck N., Thomssen C., Wilhelm O., Magdolen V., Reuning U., Ulm K., Höfler H., Jänicke F., Graeff H. Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. Thromb Haemost. 1997 Jul;78(1):285–296. [PubMed] [Google Scholar]
  31. Schmitt M., Thomssen C., Ulm K., Seiderer A., Harbeck N., Höfler H., Jänicke F., Graeff H. Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer. Br J Cancer. 1997;76(3):306–311. doi: 10.1038/bjc.1997.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Spyratos F., Martin P. M., Hacène K., Romain S., Andrieu C., Ferrero-Poüs M., Deytieux S., Le Doussal V., Tubiana-Hulin M., Brunet M. Multiparametric prognostic evaluation of biological factors in primary breast cancer. J Natl Cancer Inst. 1992 Aug 19;84(16):1266–1272. doi: 10.1093/jnci/84.16.1266. [DOI] [PubMed] [Google Scholar]
  33. Stefansson S., Lawrence D. A. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature. 1996 Oct 3;383(6599):441–443. doi: 10.1038/383441a0. [DOI] [PubMed] [Google Scholar]
  34. Wei Y., Lukashev M., Simon D. I., Bodary S. C., Rosenberg S., Doyle M. V., Chapman H. A. Regulation of integrin function by the urokinase receptor. Science. 1996 Sep 13;273(5281):1551–1555. doi: 10.1126/science.273.5281.1551. [DOI] [PubMed] [Google Scholar]
  35. Wenger C. R., Beardslee S., Owens M. A., Pounds G., Oldaker T., Vendely P., Pandian M. R., Harrington D., Clark G. M., McGuire W. L. DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients. Breast Cancer Res Treat. 1993 Oct;28(1):9–20. doi: 10.1007/BF00666351. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES