Re: Plasma Folate, Vitamin B6, Vitamin B12, Homocysteine, and Risk of Breast Cancer
KATHARINA SCHROECKSNADEL BARBARA FRICK DIETMAR FUCHS
REFERENCES (1) Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, et al. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 2003;95:373–80. (2) Sun CF, Haven TR, Wu TL, Tsao KC, Wu JT. Serum total homocysteine increases with the rapid proliferation rate of tumor cells and decline upon cell death: a potential new tumor marker. Clin Chim Acta 2002;321:55–62. (3) Wu LL, Wu JT. Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker. Clin Chim Acta 2002;322: 21–8. (4) Fuchs D, Jaeger M, Widner B, Wirleitner B, Artner-Dworzak E, Leblhuber F. Is hyperhomocysteinemia due to the oxidative depletion of folate rather than to insufficient dietary intake? Clin Chem Lab Med 2001;39:691–4. (5) Murr C, Fuith LC, Widner B, Wirleitner B, Baier-Bitterlich G, Fuchs D. Increased neopterin concentrations in patients with cancer: indicator of oxidative stress? Anticancer Res 1999;19:1721–8. (6) Murr C, Bergant A, Widschwendter M, Heim K, Schrocksnadel H, Fuchs D. Neopterin is an independent prognostic variable in females with breast cancer. Clin Chem 1999;45: 1998–2004. (7) Wirleitner B, Reider D, Ebner S, et al. Monocyte-derived dendritic cells release neopterin. J Leukocyte Biol 2002;72:1148–53.
NOTES Affiliations of authors: K. Schroecksnadel, B. Frick, D. Fuchs, Leopold Franzens University and Ludwig Boltzmann Institute of AIDS Research, Innsbruck, Austria. Correspondence to: Dietmar Fuchs, Ph.D., Leopold Franzens University and Ludwig Boltzmann Institute of AIDS Research, Fritz Pregl Strasse 3, A-6020 Innsbruck, Austria (e-mail: dietmar.
[email protected]).
RESPONSE The authors thank Schroecksnadel et al. for their interesting comments in regard to the suggested role for homocysteine as a potential tumor marker among cancer patients. They suggest that this observation seems to contradict the results from our study (1) that showed no association between plasma homocysteine and breast cancer risk. However, our study did not specifically address the role of homocysteine as a
Journal of the National Cancer Institute, Vol. 95, No. 14, July 16, 2003
tumor marker because the blood samples that we analyzed were drawn (on average) several years before diagnosis of breast cancer among women (1). Our study was designed to investigate whether prediagnostic plasma homocysteine status predicts the future risk of breast cancer. However, we did not observe a statistically significant association between plasma homocysteine and breast cancer risk at either the first 2 years of follow-up (multivariable relative risk [RR] ⳱ 1.18, 95% confidence interval [CI] ⳱ 0.49 to 2.88, for highest versus lowest quintile; unpublished data) or at the last 4 years of follow-up (multivariable RR ⳱ 0.85, 95% CI ⳱ 0.54 to 1.35, for highest versus lowest quintile) (1). Thus, if homocysteine is a tumor marker, our data would suggest that it does not appear early in the disease process. SHUMIN M. ZHANG WALTER C. WILLETT JACOB SELHUB DAVID J. HUNTER EDWARD L. GIOVANNUCCI MICHELLE D. HOLMES GRAHAM A. COLDITZ SUSAN E. HANKINSON
REFERENCES (1) Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, et al. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 2003; 95:373–80.
NOTES Affiliations of Authors: S. M. Zhang, Department of Epidemiology, Harvard School of Public Health, and Division of Preventive Medicine and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; W.C. Willett, D. J. Hunter, E. L. Giovannucci, Departments of Nutrition and Epidemiology, Harvard School of Public Health, and Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School; J. Selhub, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston; M. D. Holmes, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School; G. A. Colditz, S. E. Hankinson, Department of Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston. Correspondence to: Shumin M. Zhang, M.D., Sc.D., Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115 (e-mail: shumin.zhang@channing. harvard.edu).
CORRESPONDENCE 1091
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We read with great interest the article by Zhang et al. (1) in which they examined the association of plasma folate, vitamin B6, vitamin B12, and homocysteine with the risk of breast cancer. Although high plasma folate and vitamin B12 concentrations were associated with a lower risk of breast cancer, plasma homocysteine concentration was not associated with risk. This finding seems to contradict the recently suggested role of homocysteine as a potential tumor marker (2,3). In vitro, tumor cells and other proliferating cells release homocysteine (2,3), which might explain why hyperhomocysteinemia is observed in patients with various kinds of cancers. Plasma homocysteine and neopterin concentrations are closely associated with each other in patients with various types of diseases (4). In cancer patients, increased urine and plasma neopterin concentrations have been reported (5,6), which suggest enhanced cellular immune activation. Within cellular immune activation, T cells release large amounts of the cytokine interferon-␥, which stimulates human monocyte-derived macrophages and dendritic cells to produce neopterin (7). Immune activation cascades and proliferation and stimulation of immunocompetent cells could also be important in the accumulation of plasma homocysteine in various diseases, including malignancies. When different tumors are compared, the frequency of increased neopterin concentration is much lower in patients with breast cancer than it is in patients with other types of cancers (5). Indeed, less than 20% of patients with breast cancer present with neopterin levels above normal. Although no association between neopterin and tumor size or lymph node status has been shown in women with breast cancer, follow-up examinations reveal that higher urine neopterin concentrations at diagnosis are associated with shorter survival (6). The finding that plasma homocysteine concentrations, like neopterin concentrations, are only rarely elevated in breast cancer patients further supports the notion that immune activation and
proliferation of immunocompetant cells rather than tumor cell proliferation is the explanation for hyperhomocysteinemia in cancer patients.
