Skip to main content
Log in

Angiogenesis Sustains Tumor Dormancy in Patients with Breast Cancer Treated with Adjuvant Chemotherapy

  • Conference Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Experimental studies performed in Folkman laboratories suggest that angiogenesis is involved in the biology of tumor dormancy. We determined the vascular index in a series of 190 women operated of node-positive invasive breast cancer treated with adjuvant chemotherapy (CMF schedule) and we studied the relationship between vascularity of primary tumors with the behaviour in time of metastasis. The study of the hazard function of recurrence (in any site) was performed resorting to a generalized linear modelling approach with a binominal error according to Efron. A total of 80 cases developed recurrences during the period of observation. We found that the hazard function of metastasis in time presented two peaks of incidence at 20 and 60 months, respectively. We also plotted the curves of the hazard function by considering three values of microvessel counts corresponding to the quartiles of their distribution. The risk of first recurrence was associated with vascular index, and the patients of the third quartile of distribution of microvessels had the highest risk. In the final full model for the risk of recurrence at 5 years vascular index provided the highest prognostic contribution followed by the number of involved axillary lymph nodes. The observation that the patients with highly angiogenic tumors are at high risk of recurrence coupled with the identification of the second peak of incidence after 5 years which was also mainly sustained by angiogenic tumors suggest that a fraction of breast cancers promote metastasis after a period of tumor dormancy. The clinical and therapeutic implications of our results are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

References

  1. Demicheli R, Abbattista A, Miceli R, Valagussa P, Bonadonna G: Time distribution of the reccurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumor dormancy. Breast Cancer Res Treat 41: 177-185, 1996

    Google Scholar 

  2. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14: 2738-2746, 1996

    Google Scholar 

  3. Karrison TG, Ferguson DJ, and Meier P: Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst 91: 80-85, 1999

    Google Scholar 

  4. Uhr JW, Scheuermann RH, Street NE, Vitetta ES: Cancer dormancy: opportunities for new therapeutic approaches. Nature Med 3: 505-509, 1997

    Google Scholar 

  5. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J: Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79: 315-328, 1994

    Google Scholar 

  6. Holmgren L, O'Reilly MS, Folkman J: Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med 1: 149-153, 1995

    Google Scholar 

  7. O'Reilly MS, Holmgren L, Chen C, Folkman J: Angiostat in induces and sustains dormancy of human primary tumors in mice. Nature Med 2: 689-692, 1996

    Google Scholar 

  8. Greenberg PD: Adoptive T cell therapy of tumors: Mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol 49: 281-355, 1991

    Google Scholar 

  9. Wheelock EF, Weinhold KJ, Levich J: The tumor dormant state. Adv Cancer Res 34: 107-140, 1981

    Google Scholar 

  10. Marches R, Racila E, Tucker TF, Picker L, Mongini P, Vitetta ES, Scheuermann RH: Tumor dormancy and cell signaling-III: Role of hypercrosslinking of IgM and CD40 on the induction of cell cycle arrest and apoptosis in B lymphoma cells. Ther Immunol 2: 125-136, 1995

    Google Scholar 

  11. Albelda SM: Role of integrins and other cell adhesion molecules in tumor progression and metastasis. Lab Invest 68: 4-17, 1993

    Google Scholar 

  12. Rounov-Jessen L, Peterson OW, Bissell MJ: Cellular changes involved in conversion of normal to malignant breast: Importance of the stromal reaction. Physiol Rev 76: 69-125, 1996

    Google Scholar 

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

    Google Scholar 

  14. Gasparini G, Weidner N, Bevilacqua P, Maluta S, Dalla Palma P, Caffo O, Barbareschi M, Boracchi P, Marubini E, Pozza F: Tumor microvessel density, p53 expression, tumor size and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol 12: 454-466, 1994

    Google Scholar 

  15. Efron B: Logistic regression, survival analysis, and the Kaplan-Meier curve. J Am Stat Assoc 83: 414-425, 1988

    Google Scholar 

  16. Akaike H: Information theory and an extension of the maximum likelihood principle. In: Patrov BN Csaki F (eds) Proceedings of the 2nd International Symposium on Information Theory. Akademia Kiado, Budapest, 1973, pp 267-281.

  17. Gasparini, G: Clinical significance of determination of surrogate markers of angiogenesis in breast cancer. Crit Rev Oncol/Hematol 33: in press 2000

  18. Gasparini G, Barbareschi M, Boracchi P, Verderio P, Caffo O, Meli S, Dalla Palma P, Marubini E, Bevilacqua P: Tumor angiogenesis predicts clinical outcome of nodepositive breast cancer patients treated with adjuvant hormone therapy or chemotherapy. Cancer J Sci Am 1: 131-141, 1995

    Google Scholar 

  19. Gasparini G, Toi M, Miceli R, Vermeulen PB, Dittadi R, Biganzoli E, Morabito A, Fanelli M, Gatti C, Suzuki H, Tominaga T, Dirix LY, Gion M: Clinical relevance of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) in patients with node-positive breast cancer treated either with adjuvant chemotherapy or hormonetherapy. Cancer J Sci Am 5: 101-111, 1999

    Google Scholar 

  20. Toi M, Kondo S, Suzuki H, Yamamoto Y, Inada K, Imazawa T, Taniguchi T, Tominaga T: Quantitative analysis of vascular endothelial growth factor in primary breast cancer. Cancer 77: 1101-1106, 1996

    Google Scholar 

  21. Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27-31, 1995

    Google Scholar 

  22. Hamada J, Cavanaugh PG, Lotan A, Nicolson GL: Separable growth and migration factors from large-cell lymphoma cells secreted by microvascular endothelial cells derived from target organs for metastasis. Br J Cancer 66: 349-354, 1992

    Google Scholar 

  23. Fidler IJ, Rodinsky R: Search for genes that suppress cancer metastasis. J Natl Cancer Inst 83: 1700-1703, 1996

    Google Scholar 

  24. Gasparini G: The rationale and future potential of angiogenesis inhibitors in neoplasia. Drugs 58: 17-38, 1999

    Google Scholar 

  25. Gasparini G, Gion M: Molecular-targeted anticancer treatments to biological targets. Challanges related to studydesign and choice of proper end-points. Cancer J 6: 117-131, 2000

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gasparini, G., Biganzoli, E., Bonoldi, E. et al. Angiogenesis Sustains Tumor Dormancy in Patients with Breast Cancer Treated with Adjuvant Chemotherapy. Breast Cancer Res Treat 65, 71–75 (2001). https://doi.org/10.1023/A:1006476401801

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006476401801

Navigation