Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Oct;81(4):727–732. doi: 10.1038/sj.bjc.6690755

Does vascular endothelial growth factor (VEGF) predict local relapse and survival in radiotherapy-treated node-negative breast cancer?

B Linderholm 1, B Tavelin 1, K Grankvist 2, R Henriksson 1
PMCID: PMC2362894  PMID: 10574263

Abstract

The aim of this study was to determine the association of vascular endothelial growth factor (VEGF) content in 302 consecutive node-negative breast cancer (NNBC) patients treated with only locoregional radiotherapy to relapse free- (RFS) and overall survival (OS). VEGF content in tumour cytosols was measured by an enzymatic immunoassay for the major isoform VEGF165. The median age was 56 years, the median follow-up time 56 months. A wide range (0.01–144.79 pg μg−1 DNA) of VEGF content was found (median 1.92). Significant associations were found between VEGF and oestrogen receptor (ER) content, progesterone receptor (PR) and tumour size (P = 0.005). Univariate analysis displayed significant reduced RFS and OS for patients with higher VEGF content (P = 0.0113 and P = 0.0075 respectively). A total of 43 recurrences have been found (ten local relapses within the breast, five in the axillary or supraclavicular lymph nodes and 28 distant metastasis). There was no significant correlation between the localization of the relapse and the VEGF content. Multivariate analysis suggested VEGF as the only predictor of OS (relative risk (RR) = 3.6, 95% confidence interval (CI) = 0.97–13.37), and in patients with T1 tumours (n = 236) the multivariate analysis clearly displayed VEGF as the only independent predictor of both RFS and OS (RR = 5.1, CI = 1.07–24.59). In the sub-group with ER-positive tumours (n = 229), multivariate analysis showed VEGF as the only significant predictor of RFS and OS (RR = 10.44, CI = 1.26–86.38). The results suggest VEGF165 as a predictor of RFS and OS in NNBC patients treated with locoregional radiotherapy, comprising especially patients with favourable prognosis of T1 tumours, or ER-positive tumours. The high VEGF expression might define a radioresistant phenotype, or indicate an early distant spread which might require adjuvant systemic treatment. © 1999 Cancer Research Campaign

Keywords: VEGF, node-negative breast carcinoma, radiotherapy, relapse, survival

Full Text

The Full Text of this article is available as a PDF (69.5 KB).

Selected References

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

  1. Bosari S., Lee A. K., DeLellis R. A., Wiley B. D., Heatley G. J., Silverman M. L. Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Pathol. 1992 Jul;23(7):755–761. doi: 10.1016/0046-8177(92)90344-3. [DOI] [PubMed] [Google Scholar]
  2. Cuzick J., Stewart H., Rutqvist L., Houghton J., Edwards R., Redmond C., Peto R., Baum M., Fisher B., Host H. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994 Mar;12(3):447–453. doi: 10.1200/JCO.1994.12.3.447. [DOI] [PubMed] [Google Scholar]
  3. Eppenberger U., Kueng W., Schlaeppi J. M., Roesel J. L., Benz C., Mueller H., Matter A., Zuber M., Luescher K., Litschgi M. Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients. J Clin Oncol. 1998 Sep;16(9):3129–3136. doi: 10.1200/JCO.1998.16.9.3129. [DOI] [PubMed] [Google Scholar]
  4. Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
  5. Ferrara N., Houck K., Jakeman L., Leung D. W. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992 Feb;13(1):18–32. doi: 10.1210/edrv-13-1-18. [DOI] [PubMed] [Google Scholar]
  6. Fisher B., Redmond C., Poisson R., Margolese R., Wolmark N., Wickerham L., Fisher E., Deutsch M., Caplan R., Pilch Y. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med. 1989 Mar 30;320(13):822–828. doi: 10.1056/NEJM198903303201302. [DOI] [PubMed] [Google Scholar]
  7. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990 Jan 3;82(1):4–6. doi: 10.1093/jnci/82.1.4. [DOI] [PubMed] [Google Scholar]
  8. Fox S. B., Leek R. D., Smith K., Hollyer J., Greenall M., Harris A. L. Tumor angiogenesis in node-negative breast carcinomas--relationship with epidermal growth factor receptor, estrogen receptor, and survival. Breast Cancer Res Treat. 1994 Jan;29(1):109–116. doi: 10.1007/BF00666186. [DOI] [PubMed] [Google Scholar]
  9. 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 node-positive breast cancer patients treated with adjuvant hormone therapy or chemotherapy. Cancer J Sci Am. 1995 Jul-Aug;1(2):131–141. [PubMed] [Google Scholar]
  10. Gasparini G., Fox S. B., Verderio P., Bonoldi E., Bevilacqua P., Boracchi P., Dante S., Marubini E., Harris A. L. Determination of angiogenesis adds information to estrogen receptor status in predicting the efficacy of adjuvant tamoxifen in node-positive breast cancer patients. Clin Cancer Res. 1996 Jul;2(7):1191–1198. [PubMed] [Google Scholar]
  11. Gasparini G., Pozza F., Harris A. L. Evaluating the potential usefulness of new prognostic and predictive indicators in node-negative breast cancer patients. J Natl Cancer Inst. 1993 Aug 4;85(15):1206–1219. doi: 10.1093/jnci/85.15.1206. [DOI] [PubMed] [Google Scholar]
  12. Gasparini G., Toi M., Gion M., Verderio P., Dittadi R., Hanatani M., Matsubara I., Vinante O., Bonoldi E., Boracchi P. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst. 1997 Jan 15;89(2):139–147. doi: 10.1093/jnci/89.2.139. [DOI] [PubMed] [Google Scholar]
  13. 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. 1994 Mar;12(3):454–466. doi: 10.1200/JCO.1994.12.3.454. [DOI] [PubMed] [Google Scholar]
  14. Hobson B., Denekamp J. Endothelial proliferation in tumours and normal tissues: continuous labelling studies. Br J Cancer. 1984 Apr;49(4):405–413. doi: 10.1038/bjc.1984.66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Horak E. R., Leek R., Klenk N., LeJeune S., Smith K., Stuart N., Greenall M., Stepniewska K., Harris A. L. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet. 1992 Nov 7;340(8828):1120–1124. doi: 10.1016/0140-6736(92)93150-l. [DOI] [PubMed] [Google Scholar]
  16. Houck K. A., Ferrara N., Winer J., Cachianes G., Li B., Leung D. W. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991 Dec;5(12):1806–1814. doi: 10.1210/mend-5-12-1806. [DOI] [PubMed] [Google Scholar]
  17. Liljegren G., Holmberg L., Adami H. O., Westman G., Graffman S., Bergh J. Sector resection with or without postoperative radiotherapy for stage I breast cancer: five-year results of a randomized trial. Uppsala-Orebro Breast Cancer Study Group. J Natl Cancer Inst. 1994 May 4;86(9):717–722. doi: 10.1093/jnci/86.9.717. [DOI] [PubMed] [Google Scholar]
  18. Linderholm B., Tavelin B., Grankvist K., Henriksson R. Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J Clin Oncol. 1998 Sep;16(9):3121–3128. doi: 10.1200/JCO.1998.16.9.3121. [DOI] [PubMed] [Google Scholar]
  19. Lindgren M., Johansson M., Sandström J., Jonsson Y., Bergenheim A. T., Henriksson R. VEGF and tPA co-expressed in malignant glioma. Acta Oncol. 1997;36(6):615–618. doi: 10.3109/02841869709001324. [DOI] [PubMed] [Google Scholar]
  20. McGuire W. L. Adjuvant therapy of node-negative breast cancer: another point of view. J Natl Cancer Inst. 1988 Sep 7;80(13):1075–1076. doi: 10.1093/jnci/80.13.1075. [DOI] [PubMed] [Google Scholar]
  21. Norgren A., Fernö M., Borg A. Observations on wet weight, protein and DNA as reference for steroid receptors in malignant mammary tumours. Anticancer Res. 1986 Jan-Feb;6(1):59–64. [PubMed] [Google Scholar]
  22. Obermair A., Kurz C., Czerwenka K., Thoma M., Kaider A., Wagner T., Gitsch G., Sevelda P. Microvessel density and vessel invasion in lymph-node-negative breast cancer: effect on recurrence-free survival. Int J Cancer. 1995 Jul 17;62(2):126–131. doi: 10.1002/ijc.2910620203. [DOI] [PubMed] [Google Scholar]
  23. Overgaard M., Hansen P. S., Overgaard J., Rose C., Andersson M., Bach F., Kjaer M., Gadeberg C. C., Mouridsen H. T., Jensen M. B. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med. 1997 Oct 2;337(14):949–955. doi: 10.1056/NEJM199710023371401. [DOI] [PubMed] [Google Scholar]
  24. Schlaeppi J. M., Eppenberger U., Martiny-Baron G., Küng W. Chemiluminescence immunoassay for vascular endothelial growth factor (vascular permeability factor) in tumor-tissue homogenates. Clin Chem. 1996 Nov;42(11):1777–1784. [PubMed] [Google Scholar]
  25. Scott P. A., Gleadle J. M., Bicknell R., Harris A. L. Role of the hypoxia sensing system, acidity and reproductive hormones in the variability of vascular endothelial growth factor induction in human breast carcinoma cell lines. Int J Cancer. 1998 Mar 2;75(5):706–712. doi: 10.1002/(sici)1097-0215(19980302)75:5<706::aid-ijc8>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  26. Scott P. A., Smith K., Poulsom R., De Benedetti A., Bicknell R., Harris A. L. Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E. Br J Cancer. 1998 Jun;77(12):2120–2128. doi: 10.1038/bjc.1998.356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
  28. Sigurdsson H., Baldetorp B., Borg A., Dalberg M., Fernö M., Killander D., Olsson H. Indicators of prognosis in node-negative breast cancer. N Engl J Med. 1990 Apr 12;322(15):1045–1053. doi: 10.1056/NEJM199004123221505. [DOI] [PubMed] [Google Scholar]
  29. Toi M., Kashitani J., Tominaga T. Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma. Int J Cancer. 1993 Sep 30;55(3):371–374. doi: 10.1002/ijc.2910550305. [DOI] [PubMed] [Google Scholar]
  30. 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. 1996 Mar 15;77(6):1101–1106. doi: 10.1002/(sici)1097-0142(19960315)77:6<1101::aid-cncr15>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  31. Veronesi U., Marubini E., Del Vecchio M., Manzari A., Andreola S., Greco M., Luini A., Merson M., Saccozzi R., Rilke F. Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events. J Natl Cancer Inst. 1995 Jan 4;87(1):19–27. doi: 10.1093/jnci/87.1.19. [DOI] [PubMed] [Google Scholar]
  32. Veronesi U., Saccozzi R., Del Vecchio M., Banfi A., Clemente C., De Lena M., Gallus G., Greco M., Luini A., Marubini E. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N Engl J Med. 1981 Jul 2;305(1):6–11. doi: 10.1056/NEJM198107023050102. [DOI] [PubMed] [Google Scholar]
  33. Weidner N., Semple J. P., Welch W. R., Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med. 1991 Jan 3;324(1):1–8. doi: 10.1056/NEJM199101033240101. [DOI] [PubMed] [Google Scholar]

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

RESOURCES