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Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women^1,2,3

¹ From the Division of Preventive Medicine, Department of Medicine (JL, IML, NRC, JEM, JEB, and SMZ), Channing Laboratory (JEM), and Department of Ambulatory Care and Prevention (JEB), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; the Department of Epidemiology, Harvard School of Public Health, Boston, MA (IML, NRC, JEM, JEB, and SMZ); the Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JS)

Background: B vitamins such as folate, vitamin B-6, and vitamin B-12 are coenzymes that are important for DNA integrity and stability. Deficiency in these B vitamins may promote tumor carcinogenesis.

Objective: We prospectively evaluated plasma concentrations of folate, pyridoxal 5-phosphate (PLP; the principal active form of vitamin B-6), and vitamin B-12 in relation to breast cancer risk.

Design: We included 848 incident cases of invasive breast cancer identified as of 31 March 2004, and 848 individually matched control subjects from 28 345 women in the Women's Health Study aged 45 y who provided blood samples and had no history of cancer and cardiovascular disease at baseline in 1993. Logistic regression controlling for matching factors and other risk factors for breast cancer was used to estimate relative risks (RRs) and 95% CIs. All statistical tests were 2 sided.

Results: Plasma concentrations of folate, PLP, and vitamin B-12 were not associated with overall risk of breast cancer. Women in the highest quintile group relative to those in the lowest quintile had multivariate RRs of 1.42 (95% CI: 1.00, 2.02) for plasma folate (P for trend = 0.21), 0.91 (95% CI: 0.63, 1.30) for plasma PLP (P for trend = 0.48), and 1.29 (95% CI: 0.92, 1.82) for plasma vitamin B-12 (P for trend = 0.18). However, higher plasma folate concentrations were moderately associated with an increased risk of developing premenopausal breast cancer (P for trend = 0.04) and for developing estrogen receptor (ER)–positive or progesterone receptor (PR)–positive breast tumors (P for trend 0.06). Conversely, an inverse association was seen between plasma PLP and postmenopausal breast cancer (P for trend = 0.04).

Conclusions: Data from this study suggest that B vitamins, including folate, vitamin B-6, and vitamin B-12, may confer little or no reduction in overall risk of developing breast cancer. The observed positive associations of folate status with risk of developing premenopausal breast cancer and ER-positive or PR-positive tumors are unexpected. Additional research is needed to elucidate the role of folate in breast cancer development.

Key Words: Folate • vitamin B-6 • vitamin B-12 • breast cancer • cohort study • plasma marker