Abstract 3221: Plasma B-vitamin and one-carbon metabolites and risk of breast cancer before and after folic acid fortification in the US
Authors: Houghton Serena C. , Eliassen A. Heather , Zhang Shumin M. , Selhub Jacob , Rosner Bernard A. , Willett Walter C. , Hankinson Susan E. 
Published: August 2018

Abstract
Background: Prior epidemiologic findings for plasma folate and B-vitamins and breast cancer risk are inconsistent and have not assessed the possible influence of folic acid fortification mandated in 1998. Excess folate, through the one-carbon cycle, might promote neoplastic lesions through DNA synthesis and methylation and inactivation of tumor suppressor genes. However, deficiencies in folate and other B-vitamins may also stimulate carcinogenesis through this same cycle. With concern for carcinogenesis at both low and high folate levels, folic acid fortification has been controversial. Therefore, we examined the associations between plasma folate, B12, B6, homocysteine, cysteine, and cysteinylglycine and breast cancer risk, before and after fortification.
Methods: We conducted a nested case-control study within the prospective Nurses' Health Study. In 1989-1990 (pre-fortification), 32,826 women donated a first blood sample and 18,743 donated an additional blood sample in 2000-2001 (post-fortification). From 1989 to 2006, 1874 incident breast cancer cases with at least one blood sample and 367 with two blood samples were matched 1:1 to controls on age, date/ time of blood draw, fasting status, postmenopausal hormones use, and menopausal status. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) adjusting for age at menarche, parity/age at first birth, age at menopause, family history of breast cancer, history of benign breast disease, height, body mass index at 18, weight change since 18, and alcohol intake. Additionally to assess the effect of fortification, we cross-classified plasma levels at the median for women with two bloods and used unconditional logistic regression adjusting for breast cancer risk factors using low (&lt;median) in both 1990 and 2000 as the referent group.
Results: Overall, higher plasma folate, B12, B6, homocysteine, cysteine, and cysteinylglycine levels were not associated with breast cancer risk. For example, comparing women in the highest versus lowest quintile of 1990 plasma folate, adjusted RR (95% CI) was 0.95 (0.77-1.17) for breast cancer. Associations did not vary by in situ /invasive, hormone receptor status, or molecular subtype of the tumor. Additionally, associations did not vary before/after fortification. For example, compared to those with consistently low plasma folate levels, RRs (95% CI) were 0.90 (0.58-1.40) among those that were low 1990/ high 2000, 0.93 (0.59-1.45) among those high 1990/ low 2000, and 1.10 (0.75-1.63) among those that were consistently high.
Conclusion: Plasma folate, B12, B6, homocysteine, cysteine, and cysteinylglycine were not significantly associated with breast cancer overall, before and after fortification, or with specific molecular subtypes. These results do not support concerns about folic acid fortification and breast cancer risk.
Citation Format: Serena C. Houghton, A. Heather Eliassen, Shumin M. Zhang, Jacob Selhub, Bernard A. Rosner, Walter C. Willett, Susan E. Hankinson. Plasma B-vitamin and one-carbon metabolites and risk of breast cancer before and after folic acid fortification in the US [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3221.