Produced by the Royal College of Physicians of Edinburgh and Royal College of Physicians and Surgeons of Glasgow

Folic acid and breast cancer

  • Dr IH Kunkler, Consultant and part-time Senior Lecturer in Clinical Oncology, Western General Hospital, University of Edinburgh, Edinburgh, Scotland

Summary

In this BTMH user-requested article Dr Ian Kunkler aims to answer concerns about the safety of folic acid following the publication of a study which suggested an increased risk of breast cancer for women taking oral folic acid Supplements. How safe is folic acid, what link is there with breast cancer and should women continue to take folic acid?

Key Points

  • It is well established that folic acid supplementation reduces the risk of neural tube defects.
  • Most of the evidence suggests that folic acid contributes to preventing breast cancer rather than causing it.
  • The apparent association between taking high doses of folic acid and increased risk of dying from breast cancer may be a chance finding. Further studies are needed.
  • Women contemplating pregnancy should take folic acid supplements to reduce the risk of neural tube defects in the developing child.
  • More studies are needed.

Declaration of interests: No conflict of interests declared

Folic acid and health

Folic acid is a B vitamin which plays an important role in cell synthesis and repair. Leafy vegetables, fruits and animal protein are all rich sources of folic acid, but folic acid is easily destroyed by prolonged cooking. Total body stores of folate are quite small and deficiency can occur within weeks leading mainly to megaloblastic anaemia. Folate stores in the body are best reflected in the folate concentrations in red blood cells. Folate can also be measured in the plasma, but plasma concentrations can change rapidly and do not accurately reflect body stores. Natural folates in foods lose their activity relatively rapidly over a period of days or weeks because of their chemical instability. In contrast, synthetic folic acid is virtually completely stable for months or years. This means that synthetic folate provides a much more reliable source of dietary intake than naturally occurring folates.

Folic acid plays an important role in preventing birth defects

There is good evidence that dietary supplementation with folate before conception and during the first trimester reduces the risk of NTDs. It is between the seventeenth and thirtieth day after conception or four to six weeks after the first day of the last menstrual period that the neural tube forms in the embryo and then closes. Neural tube defects occur when the neural tube fails to close properly leaving the brain and spinal cord exposed to amniotic fluid. Anencephaly and spina bifida are the commonest NTDs. Current advice is that women should receive 400 mcg (0·4 mg) of folic acid per day before they become pregnant.

Folic acid preventing or causing breast cancer?

Most of the published evidence shows that plasma folate concentrations are inversely associated with the risk of developing breast cancer. Folate deficiency may lead to DNA damage. An example is the misincorporation of uracil into DNA and the development of single and double-strand chromosomal breaks in DNA.1 These defects may result in a reduced DNA repair capacity. Three large prospective epidemiological studies, the Nurses’ Health Study,2 the Iowa Women’s Health Study,3 and the Canadian National Breast Screening Study4 have demonstrated that low dietary folate carries an increased risk of breast cancer. In the Nurses’ Health Study,2 of 121,700 female registered nurses aged between 30 and 55 years, the multivariate OR for breast cancer risk from low folate was 0·73 (95% CI, 0·50–1·07) for the highest versus lowest quintile.

The mechanisms by which folate deficiency might stimulate carcinogenesis are unclear. However, folate deficiency is known to reduce the methylation of dUMP to dTMP, causing imbalance in the dNTP pool and excessive misincorporation of uracil into DNA during DNA repair and replication. The base excision repair pathway is responsible for repairing uracil in DNA. Single strand breaks are created by the excision of uracil by uracil DNA glycosylase. Where folate is deficient, excision repair and uracil misincorporation occur due to thymidine deficiency.

The Aberdeen Study

More recently, Charles et al.5 reported a study from Aberdeen, Scotland, of folate supplementation in pregnancy which suggested an increase in breast cancer risk in women receiving oral supplements of folic acid. These authors report on a trial in 2,928 women. They were randomly allocated between 1966–67 to folate tablets in six colours, two of which contained 0·2 mg and 5 mg of folate respectively. The trial was double-blinded. At each patient’s booking visit, blood was taken for serum folate. Information was collected on maternal age, parity, gestation, weight and blood pressure. The data was linked to the Aberdeen and neonatal databank for information on smoking and maternal height. Causes of death were ascertained by linkage to the NHS Central Registry in Edinburgh.

Follow-up to September 2002 showed that 210 women had died. Of these deaths 40 were from cardiovascular disease and 31 from breast cancer. For women randomised to the higher 5 mg dose of folate, all-cause mortality was one fifth higher and deaths due to breast cancer were doubled. For the lower 0·2 mg folic acid dose all-cause mortality was 18% higher, and breast cancer mortality was 50% higher. How can the findings of the Aberdeen study be reconciled with the bulk of the literature which suggests that folic acid has a protective effect against breast cancer? It should be noted that the 5 mg dose used in the one arm of the Aberdeen study was >10 times higher than the currently recommended dose of (0·4 mg). However, even in patients receiving less than the current recommended dose to reduce NTDs, the breast cancer mortality was increased. The authors acknowledge that these observations could be chance findings; the number of breast cancer deaths is small, the confidence limits wide. In addition, they admit that they had no specified hypothesis that folate supplements in pregnancy would increase the risk of cancer.

Criticisms of the Aberdeen study

The Aberdeen study has been criticised on a number of counts.7 First, the trial is not a randomised trial since the treatments were given sequentially. Secondly, it was not really double-blind since the colours of the tablets corresponding to specific doses of folic acid could be known to the trialists. Only in the 5 mg folic acid group was cancer mortality statistically significantly increased (p=0·02). Statistical significance at the 0·05 level was not reached for breast cancer mortality for either the 0·2 mg (p=0·35) or 5 mg (p=0·10) doses of folic acid. It could well be that the observation of a relationship between folic acid supplementation and increased breast cancer mortality could be due to well recognised phenomenon of multiple testing for statistical associations.

How do the findings in the Aberdeen study fit with the other published literature?

These findings contrast with the Nurses’ Health Study2 in which the highest plasma folate levels (>14 ng/ml) had a 27% lower risk of breast cancer than did women with a lowel level (<6·4 ng/ml). A higher level of protection against breast cancer was found in women who regularly drank alcohol (one drink per day or more). A particularly strong inverse association between serum folate and risk of breast cancer was found in women drinking at least 15 g/day of alcohol. Women with the highest folate levels had an 89% lower risk of breast cancer than did women with low levels. Alcohol is known to antagonise the action of folate. It might therefore increase an individual’s requirement for folate.

The Canadian Breast Screening study4 suggested that dietary intake of folate might be associated with a reduced risk of breast cancer at comparatively high levels of alcohol, especially in postmenopausal women. The authors acknowledge their findings could be due to chance. However in a prospective study a US group found no evidence of a protective association between higher concentrations of folate and subsequent breast cancer.5

Should patients wishing to become pregnant take folic acid supplements?

In the light of the methodological and analytical limitations of the Aberdeen study, it is premature to conclude that folic acid supplements really increase the risk of breast cancer. There is more evidence that folic acid may prevent rather than promote breast cancer. More studies are needed. In the meantime, women should be encouraged to take folic acid supplements at the recommended dosage of 400 mcg/day since the benefits in reducing NTDs are unequivocal.

References

  1. Blomt BC, Mack MM, Weir CM et al. Folate deficiency causes uracil misincorporation into human DNA and chromosomal breakage:implications for cancer and neuronal damage. Proc Natl Acad Sci USA 1997; 94:3290–5.
  2. Zhang S, Hunter DJ, Hankinson SE et al. A prospective study of folate intake and the risk of breast cancer. JAMA 1999; 281:1632–7.
  3. Sellers TA, Kashi LH,Cerhan JR et al. Dietary folate intake, alcohol and risk of breast cancer in a prospective study of postmenopausal women. Epidemiol 2001; 12:420–8.
  4. Rohan TE, Jain MG, Howe GR et al. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000; 42:266–9.
  5. Wu K, Helzsouer KJ, Comstock GW et al. A prospective study of folate, B12 and pyridoxal 5α­-phosphate (B6) and breast cancer. Cancer Epidemiol Biomarkers Prev 1999; 8:209–17.
  6. Charles D, Ness AR, Campbell D et al. Taking folate in pregnancy and risk of maternal breast cancer. BMJ 2004; 329:1375–6.
  7. Bland MJ. What’­s in a name? BMJ 2005; 330:600.