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Correspondence re: K. Heer et al., Serum Vascular Endothelial Growth Factor in Breast Cancer: Its Relation with Cancer Type and Estrogen Receptor Status. Clin. Cancer Res., 7: 3491–3494, 2001.

Leeds Breast Cancer Research Group The Breast Unit St. James’s University Hospital Leeds LS9 7TF, United Kingdom

We read with great interest the paper by Heer et al., (1) published recently in Clinical Cancer Research. In their paper, the authors show serum VEGF¹ is elevated in patients with breast cancer compared with normal healthy control subjects. However, questions have been raised over the accuracy of using serum VEGF as a marker, with the observation that VEGF is released from platelets during venepuncture (2 , 3) . Studies have additionally shown that the association of high serum levels of VEGF with poor prognosis in cancer patients may be correlated with an elevated platelet count (4) . We have addressed this by comparing VEGF in serum and plasma in a cohort of breast cancer patients and matched controls. Using a cohort matched for size and geographical location we showed that plasma VEGF and not serum VEGF is increased compared with controls in breast cancer patients (5) .

The observation by Heer et al. (1) that serum VEGF levels were increased in patients with invasive ductal carcinomas but not invasive lobular carcinomas is in keeping with previous observations of a difference in VEGF protein expression between these two biologically distinct tumor types (6) . Indeed, the lack of an association between immunohistochemically detected VEGF protein expression and microvessel density in lobular carcinomas suggests the possibility of dissociation between VEGF production and angiogenesis in these tumours.

The observation by Heer et al. (1) of a marked increase in serum VEGF with ductal carcinoma in situ is of great interest given recent suggestions that angiogenesis is important in the transition from preinvasive to invasive disease and the potential for therapeutic intervention with antiangiogenic agents (7) . Given the possibility that invasive diagnostic procedures may result in platelet activation and elevate serum rather than plasma VEGF, it would be interesting to know whether there was any possibility that preoperative hookwire insertion could have influenced the serum levels.

The authors showed a correlation between VEGF and ER (-?) positivity but dismiss the possibility of a steroid promoter(s) in the VEGF response element. We would like to point out that the VEGF gene contains consensus estrogen response elements both at the 5' and 3' ends (8) . Furthermore, there is accumulating evidence of an inhibitory relationship between ER expression and production of angiogenic factors, with the observation of down regulation of VEGF in breast cancer xenografts engineered to overexpress ER (9) .

VEGF is arguably the single most important angiogenic factor identified to date. Until the factors influencing its expression are better understood, determination of blood levels will be of limited diagnostic or prognostic use in the clinic.

FOOTNOTES

¹ The abbreviations used are: VEGF, vascular endothelial growth factor; ER, estrogen receptor.

² To whom requests for reprints should be addressed, at Leeds Breast Cancer Research Group, The Breast Unit, St. James’s University Hospital, Leeds LS9 7TF, United Kingdom. E-mail: clairemurphy{at}doctors.org.uk

Received 9/10/02; accepted 3/ 5/03.

REFERENCES

1. Heer K., Kumar H., Read J. R., Fox J. N., Monson J. R., Kerin M. J. Serum vascular endothelial growth factor in breast cancer: its relation with cancer type and estrogen receptor status. Clin. Cancer Res., 7: 3491-3494, 2001.[Abstract/Free Full Text]
2. Banks R. E., Forbes M. A., Kinsey S. E., Stanley A., Ingham E., Walters C., Selby P. J. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br. J. Cancer, 77: 956-964, 1998.[Medline]
3. Webb N. J., Bottomley M. J., Watson C. J., Brenchley P. E. Vascular endothelial growth factor (VEGF) is released from platelets during blood clotting: implications for measurement of circulating VEGF levels in clinical disease. Clin. Sci., 94: 395-404, 1998.[Medline]
4. O’Byrne K. J., Dobbs N., Propper D., Smith K., Harris A. L. Vascular endothelial growth factor platelet counts, and prognosis in renal cancer. Lancet, 353: 1494-1495, 1999.
5. Adams J., Carder P. J., Downey S., Forbes M. A., MacLennan K., Allgar V., Kaufman S., Hallam S., Bicknell R., Walker J. J., Cairnduff F., Selby P. J., Perren T. J., Lansdown M., Banks R. E. Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res., 60: 2898-2905, 2000.[Abstract/Free Full Text]
6. Lee A. H., Dublin E. A., Bobrow L. G., Poulsom R. Invasive lobular and invasive ductal carcinoma of the breast show distinct patterns of vascular endothelial growth factor expression and angiogenesis. J. Pathol., 185: 394-401, 1998.[CrossRef][Medline]
7. Rice A., Quinn C. M. Angiogenesis, thrombospondin and the ductal carcinoma in situ of the breast. J. Clin. Pathol., 55: 569-574, 2002.[Abstract/Free Full Text]
8. Hyder S. M., Nawaz Z., Chiappetta C., Stancel G. M. Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. Cancer Res., 60: 3183-3190, 2000.[Abstract/Free Full Text]
9. Ali S. H., O’Donnell A. L., Balu D., Pohl M. B., Seyler M. J., Mohamed S., Mousa S., Dandona P. Estrogen receptor- in the inhibition of cancer growth and angiogenesis. Cancer Res., 60: 7094-7098, 2000.[Abstract/Free Full Text]

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