Skip to main content

Advertisement

SpringerLink
Log in

Vascular proliferation is a prognostic factor in breast cancer

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Angiogenesis is important for the growth and spread of malignant tumors, and anti-angiogenesis treatment is currently being evaluated for breast cancer and other tumors. Although microvessel density is the most commonly used tissue-based marker of tumor associated angiogenesis, it has significant limitations and has not proven effective as a predictive factor in selecting patients for treatment. We here wanted to explore the significance of vascular endothelial cell proliferation in breast carcinoma. We examined microvessel proliferation in breast cancer by dual immunohistochemical staining, using the pan-endothelial marker Factor-VIII combined with proliferation of endothelial cells by Ki-67 expression, in three independent series of breast cancer, including a total of 499 patients and 141 events during follow-up. Common statistical tests of associations as well as univariate and multivariate regression analysis of patient survival were used. By counting vessels with actively proliferating endothelium, we show that microvascular proliferation is a significant predictor of disease progression in breast cancer, especially among high-grade and ER-negative tumors. Our findings indicate that this novel marker of active tumor angiogenesis might be of value in patient management and should be further studied in the context of patient selection for anti-angiogenesis treatment.

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

Similar content being viewed by others

References

  1. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186

    Article  PubMed  CAS  Google Scholar 

  2. FDA (2004) FDA approves first angiogenesis inhibitor to treat colorectal cancer. US Food and Drug Administration. http://www.fda.gov/bbs/topics/NEWS/2004/NEW01027.html. Accessed 24 Oct 2008

  3. FDA (2008) New approval for Bevacizumab (Avastin). US Food and Drug Administration. http://www.fda.gov/cder/Offices/OODP/whatsnew/bevacizumab200802.htm. Accessed 24 Oct 2008

  4. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–2676. doi:10.1056/NEJMoa072113

    Article  PubMed  CAS  Google Scholar 

  5. Miles DW, Chan A, Dirix LY, Cortes J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G (2010) Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28(20):3239–3247. doi:10.1200/JCO.2008.21.6457

    Article  PubMed  CAS  Google Scholar 

  6. Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O’Shaughnessy J (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29(10):1252–1260. doi:10.1200/JCO.2010.28.0982

    Article  PubMed  CAS  Google Scholar 

  7. D’Agostino RB Sr (2011) Changing end points in breast-cancer drug approval–the Avastin story. N Engl J Med 365(2):e2. doi:10.1056/NEJMp1106984

  8. Couzin-Frankel J, Ogale Y (2011) FDA. Once on “fast track,” avastin now derailed. Science 333(6039):143–144. doi:10.1126/science.333.6039.143

  9. Ratner M (2011) FDA panel votes to pull Avastin in breast cancer, again. Nat Biotechnol 29(8):676. doi:10.1038/nbt0811-676c

    Google Scholar 

  10. NCI (2008) Clinical Trials Search. National Cancer Institute. http://www.cancer.gov/search/ResultsClinicalTrials.aspx?protocolsearchid=4586362&sort=4&page=1&batchsize=10#. Accessed Oct 24 2008

  11. Brem S, Cotran R, Folkman J (1972) Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst 48(2):347–356

    PubMed  CAS  Google Scholar 

  12. Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma. N Engl J Med 324(1):1–8

    Article  PubMed  CAS  Google Scholar 

  13. Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G (1992) Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma [see comments]. J Natl Cancer Inst 84(24):1875–1887

    Article  PubMed  CAS  Google Scholar 

  14. Rubin MA, Buyyounouski M, Bagiella E, Sharir S, Neugut A, Benson M, de la Taille A, Katz AE, Olsson CA, Ennis RD (1999) Microvessel density in prostate cancer: lack of correlation with tumor grade, pathologic stage, and clinical outcome. Urology 53(3):542–547

    Article  PubMed  CAS  Google Scholar 

  15. Hlatky L, Hahnfeldt P, Folkman J (2002) Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn’t tell us. J Natl Cancer Inst 94(12):883–893

    Article  PubMed  Google Scholar 

  16. Stefansson IM, Salvesen HB, Akslen LA (2006) Vascular proliferation is important for clinical progress of endometrial cancer. Cancer Res 66(6):3303–3309

    Article  PubMed  CAS  Google Scholar 

  17. Tavassoli F, Devillee PE (2003) World Health Organization classification of tumours, pathology and genetics of tumours of the breast and female genital organs, World Health Organization Monograph Series. IARC Press, Lyon

    Google Scholar 

  18. Elston CW, Ellis IO (1991) 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 19(5):403–410

    Article  PubMed  CAS  Google Scholar 

  19. Baak JP, Gudlaugsson E, Skaland I, Guo LH, Klos J, Lende TH, Soiland H, Janssen EA, Zur Hausen A (2009) Proliferation is the strongest prognosticator in node-negative breast cancer: significance, error sources, alternatives and comparison with molecular prognostic markers. Breast Cancer Res Treat 115(2):241–254. doi:10.1007/s10549-008-0126-y

    Article  PubMed  CAS  Google Scholar 

  20. van Diest PJ, van der Wall E, Baak JP (2004) Prognostic value of proliferation in invasive breast cancer: a review. J Clin Pathol 57(7):675–681

    Article  PubMed  Google Scholar 

  21. Baak JP, van Diest PJ, Voorhorst FJ, van der Wall E, Beex LV, Vermorken JB, Janssen EA (2005) Prospective multicenter validation of the independent prognostic value of the mitotic activity index in lymph node-negative breast cancer patients younger than 55 years. J Clin Oncol 23(25):5993–6001

    Article  PubMed  Google Scholar 

  22. Arnes JB, Brunet JS, Stefansson I, Begin LR, Wong N, Chappuis PO, Akslen LA, Foulkes WD (2005) Placental cadherin and the basal epithelial phenotype of BRCA1-related breast cancer. Clin Cancer Res 11(11):4003–4011

    Article  PubMed  CAS  Google Scholar 

  23. Foulkes WD, Brunet JS, Stefansson IM, Straume O, Chappuis PO, Begin LR, Hamel N, Goffin JR, Wong N, Trudel M, Kapusta L, Porter P, Akslen LA (2004) The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res 64(3):830–835

    Article  PubMed  CAS  Google Scholar 

  24. Goffin JR, Straume O, Chappuis PO, Brunet JS, Begin LR, Hamel N, Wong N, Akslen LA, Foulkes WD (2003) Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancer. Br J Cancer 89(6):1031–1034

    Article  PubMed  CAS  Google Scholar 

  25. Geisler S, Lonning PE, Aas T, Johnsen H, Fluge O, Haugen DF, Lillehaug JR, Akslen LA, Borresen-Dale AL (2001) Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer. Cancer Res 61(6):2505–2512

    PubMed  CAS  Google Scholar 

  26. Geisler S, Borresen-Dale AL, Johnsen H, Aas T, Geisler J, Akslen LA, Anker G, Lonning PE (2003) TP53 gene mutations predict the response to neoadjuvant treatment with 5-fluorouracil and mitomycin in locally advanced breast cancer. Clin Cancer Res 9(15):5582–5588

    PubMed  CAS  Google Scholar 

  27. DAKO Dako website (home). http://www.dako.com

  28. Straume O, Chappuis PO, Salvesen HB, Halvorsen OJ, Haukaas SA, Goffin JR, Begin LR, Foulkes WD, Akslen LA (2002) Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers. Cancer Res 62(23):6808–6811

    PubMed  CAS  Google Scholar 

  29. Weidner N (2004) The importance of tumor angiogenesis: the evidence continues to grow. Am J Clin Pathol 122(5):675–677

    Article  PubMed  Google Scholar 

  30. Sharma S, Sharma MC, Sarkar C (2005) Morphology of angiogenesis in human cancer: a conceptual overview, histoprognostic perspective and significance of neoangiogenesis. Histopathology 46(5):481–489

    Article  PubMed  CAS  Google Scholar 

  31. Uzzan B, Nicolas P, Cucherat M, Perret GY (2004) Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res 64(9):2941–2955

    Article  PubMed  CAS  Google Scholar 

  32. Straume O, Salvesen HB, Akslen LA (1999) Angiogenesis is prognostically important in vertical growth phase melanomas. Int J Oncol 15(3):595–599

    PubMed  CAS  Google Scholar 

  33. Hatzis C, Pusztai L, Valero V, Booser DJ, Esserman L, Lluch A, Vidaurre T, Holmes F, Souchon E, Wang H, Martin M, Cotrina J, Gomez H, Hubbard R, Chacon JI, Ferrer-Lozano J, Dyer R, Buxton M, Gong Y, Wu Y, Ibrahim N, Andreopoulou E, Ueno NT, Hunt K, Yang W, Nazario A, DeMichele A, O’Shaughnessy J, Hortobagyi GN, Symmans WF (2011) A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. JAMA 305(18):1873–1881. doi:10.1001/jama.2011.593

    Article  PubMed  CAS  Google Scholar 

  34. Fox SB, Gatter KC, Bicknell R, Going JJ, Stanton P, Cooke TG, Harris AL (1993) Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res 53(18):4161–4163

    PubMed  CAS  Google Scholar 

  35. Vartanian RK, Weidner N (1994) Correlation of intratumoral endothelial cell proliferation with microvessel density (tumor angiogenesis) and tumor cell proliferation in breast carcinoma. Am J Pathol 144(6):1188–1194

    PubMed  CAS  Google Scholar 

  36. Vartanian RK, Weidner N (1995) Endothelial cell proliferation in prostatic carcinoma and prostatic hyperplasia: correlation with Gleason’s score, microvessel density, and epithelial cell proliferation. Lab Invest 73(6):844–850

    PubMed  CAS  Google Scholar 

  37. Vermeulen PB, Verhoeven D, Hubens G, Van Marck E, Goovaerts G, Huyghe M, De Bruijn EA, Van Oosterom AT, Dirix LY (1995) Microvessel density, endothelial cell proliferation and tumour cell proliferation in human colorectal adenocarcinomas. Ann Oncol 6(1):59–64

    PubMed  CAS  Google Scholar 

  38. Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG (2000) Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res 60(5):1388–1393

    PubMed  CAS  Google Scholar 

  39. Hillen F, van de Winkel A, Creytens D, Vermeulen AH, Griffioen AW (2006) Proliferating endothelial cells, but not microvessel density, are a prognostic parameter in human cutaneous melanoma. Melanoma Res 16(5):453–457

    Article  PubMed  Google Scholar 

  40. Hayes DF, Isaacs C, Stearns V (2001) Prognostic factors in breast cancer: current and new predictors of metastasis. J Mammary Gland Biol Neoplasia 6(4):375–392

    Article  PubMed  CAS  Google Scholar 

  41. Gasparini G (2001) Clinical significance of determination of surrogate markers of angiogenesis in breast cancer. Crit Rev Oncol Hematol 37(2):97–114

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study has received financial support from the University of Bergen, The Norwegian Cancer Society, The Norwegian Research Council and Helse Vest RHF. We thank Gerd Lillian Hallseth and Bendik Nordanger for their excellent technical support.

Disclaimers

No known conflicts of interest.

Author information

Authors and Affiliations

  1. Section for Pathology, The Gade Institute, University of Bergen, Haukeland University Hospital, 5021, Bergen, Norway

    Jarle B. Arnes, Ingunn M. Stefansson, Oddbjørn Straume & Lars A. Akslen

  2. Department of Pathology, Stavanger University Hospital, Stavanger, Norway

    Jan P. Baak

  3. The Gade Institute, University of Bergen, Bergen, Norway

    Jan P. Baak

  4. Free University, Amsterdam, The Netherlands

    Jan P. Baak

  5. Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway

    Per E. Lønning

  6. Department of Oncology, Haukeland University Hospital, Bergen, Norway

    Per E. Lønning

  7. Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada

    William D. Foulkes

  8. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montréal, Canada

    William D. Foulkes

  9. Segal Cancer Centre, Jewish General Hospital, Montréal, Canada

    William D. Foulkes

  10. McGill University, Montréal, QC, Canada

    William D. Foulkes

Authors
  1. Jarle B. Arnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ingunn M. Stefansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oddbjørn Straume
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan P. Baak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Per E. Lønning
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William D. Foulkes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lars A. Akslen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lars A. Akslen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arnes, J.B., Stefansson, I.M., Straume, O. et al. Vascular proliferation is a prognostic factor in breast cancer. Breast Cancer Res Treat 133, 501–510 (2012). https://doi.org/10.1007/s10549-011-1785-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1785-7

Keywords

Search

Navigation