Position statement - Folate and cancer prevention summary evidence tables

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Bowel cancer

Author & Date Study Type Form of Folate Key Results
WCRF (2007)[1] Meta-analysis Dietary folate Meta-analysis on four cohort studies showed that higher dietary folate was associated with a significantly decreased risk of bowel cancer (relative risk (RR) per 100 μg/d= 0.84, 95% confidence interval (CI)= 0.76-0.93) with low heterogeneity among studies.
Mackerras et al. (2014)[2] Meta-analysis Folic acid supplementation Meta-analysis of eight randomised controlled trials showed that folic acid was not associated with bowel cancer incidence (RR= 1.00, 95% CI= 0.82-1.23).
Kennedy et al. (2011)[3] Meta-analysis Total folate Meta-analysis of 27 cohort and case-control studies found total folate intake was associated with lower risk of colorectal cancer for case-control studies (RR= 0.85, 95% CI= 0.74-0.99), but not for cohort studies (RR= 0.92, 95% CI= 0.81-1.05).
Kim et al. (2011)[3] Meta-analysis Dietary folate and total folate Meta-analysis of 13 prospective studies found total folate was associated with a decrease in colon cancer risk (RR= 0.85, 95% CI= 0.77-0.95). There was no association between dietary folate and colon cancer risk (RR= 0.92, 95% CI= 0.84-1.00).
Sanjoaquin et al. (2005)[4] Meta-analysis Dietary folate and total folate Meta-analysis on five cohort studies showed that higher dietary folate significantly reduced the risk of bowel cancer (RR= 0.75, 95% CI= 0.64-0.89), while meta-analysis on three cohort studies showed that there was no association between total folate (folate from foods and supplements) and bowel cancer (RR= 0.95, 95% CI= 0.81-1.11).

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Bowel adenoma

Author & Date Study Type Form of Folate Key Results
Mackerras et al. (2014)[2] Meta-analysis Folic acid supplementation Meta-analysis of six randomised controlled trials showed that folic acid was not associated with recurrence of bowel adenomas (RR= 0.97, 95% CI= 0.83-1.14), and analysis of four randomised controlled trials found that folic acid was not associated with recurrence of advanced colorectal adenoma (RR= 1.11 95% CI= 0.87-1.42).
Cole et al. (2007)[5] Randomised controlled trial (Aspirin/Folate Polyp Prevention Study) 1 mg folic acid At 3-5 years follow-up, there was no association between folic acid and incidence of at least one bowel adenoma (RR= 1.13, 95% CI= 0.93-1.37). However folic acid was associated with a non-significant increased risk of at least one advanced lesion (RR= 1.67, 95% CI= 1.00-2.80) and a significant risk of three or more adenomas (RR= 2.32, 95% CI= 1.23-4.35).
Figueiredo et al. (2008)[6] Randomised controlled trial (Aspirin/Folate Polyp Prevention Study) 1 mg folic acid There was no evidence that baseline dietary (dietary intake and total intake) and circulating (plasma and red blood cell) folate levels modified the association between folic acid and risk of any adenomas or advanced lesions. However higher baseline total folate intake (RR= 0.69, 95% CI= 0.51-0.94) and plasma folate (RR= 0.72, 95% CI= 0.54-0.97) was associated with a significantly decreased risk of bowel adenomas in the placebo group.
Logan et al. (2008)[7] Randomised controlled trial (UKCAP) 0.5 mg folic acid There was no association between folate supplementation and adenoma recurrence (RR= 1.07, 95% CI= 0.85-1.34).
Martinez et al. (2006)[8] Randomised controlled trial (Wheat Bran Fibre Trial) 140 μg folic acid Plasma folate was associated with a significantly decreased risk of bowel adenoma recurrence in the whole population (OR= 0.64, 95% CI= 0.44-0.93), but this risk became non-significant when stratified by non-multivitamin users (OR= 0.65, 95% CI= 0.40-1.06) and multivitamin users (OR= 1.03, 95% CI= 0.55-1.92).
Martinez et al. (2004)[9] Randomised controlled trial (Wheat Bran Fibre Trial) 140 μg folic acid Higher plasma folate (OR= 0.66, 95% CI= 0.46-0.97) and total folate (OR= 0.61, 95% CI= 0.42-0.89) significantly reduced the risk of bowel adenoma recurrence, but there was no association with dietary folate intake (OR= 0.79, 95% CI= 0.53-1.14).
Murphy et al. (2007)[10] Randomised controlled trial (Polyp Prevention Trial) n/a Intervention was a high-fibre, low-fat, high fruit and vegetable diet. When the highest and lowest quartiles were compared for dietary folate, no statistically significant associations were found for any adenoma recurrence (RR= 1.07, 95% CI= 0.75-1.52), multiple adenoma recurrence (RR= 1.41, 95% CI= 0.87-2.29) and advanced adenoma recurrence (RR= 1.42, 95% CI= 0.69-2.96). No statistically significant associations were found for total folate intake and any adenoma recurrence (RR= 0.91, 95% CI= 0.67-1.23), multiple adenoma recurrence (RR= 1.01, 95% CI= 0.66-1.54) and advanced adenoma recurrence (RR= 0.91, 95% CI= 0.50-1.65).

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Lung cancer

Author & Date Study Type Form of Folate Key Results
Mackerras et al. (2014)[2] Meta-analysis Folic acid supplementation Meta-analysis of five randomised controlled trials showed that folic acid was not associated with lung cancer incidence (RR= 1.00, 85% CI= 0.84-1.21).
Cho et al. (2006)[11] Meta-analysis Dietary folate and total folate Meta-analysis on eight cohort studies found no significant association between dietary folate and total folate intake and lung cancer risk. The pooled multivariate RR comparing highest with lowest quintile of dietary folate intake was 0.88 (95% CI= 0.74-1.04) and for total folate was 1.02 (95% CI= 0.83-1.26).

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Breast cancer (postmenopausal)

Author & Date Study Type Form of Folate Key Results
Ericson et al. (2007)[12] Cohort study (Malmö Diet and Cancer Cohort) Dietary folate and total folate Compared with the lowest quintile, the incidence of invasive breast cancer was significantly reduced in the highest quintile of dietary folate (RR= 0.56, 95% CI= 0.35-0.90) and total folate intake (RR= 0.59, 95% CI= 0.36-0.97).
Lajous et al. (2006)[13] Cohort study (French E3N Cohort) Dietary folate High dietary folate intake was associated with a significantly decreased risk of breast cancer (RR= 0.78, 95% CI= 0.67-0.90). There was no evidence that alcohol consumption modified the effect.
Sellers et al. (2004)[14] Cohort study (Iowa Women’s Health Study) Dietary folate Among all women with no family history of breast cancer, low dietary folate intake did not affect breast cancer risk (RR= 1.11, 95% CI= 0.90-1.38). Among women with a family history of breast cancer, low dietary folate intake was a significant risk factor for breast cancer (RR= 2.26, 95% CI= 1.59-3.21)

When alcohol drinking status was considered among women with no family history of breast cancer, low dietary folate intake did not affect breast cancer risk in non-drinkers (RR= 0.96, 95% CI= 0.73-1.26) but significantly increased the risk in drinkers (RR= 1.40, 95% CI= 1.05-1.86). However among women with a family history of breast cancer, low dietary folate intake was a significant risk factor for breast cancer among non-drinkers (RR= 2.21, 95% CI= 1.43-3.41) and drinkers (RR= 2.39, 95% CI= 1.36-4.20).

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Breast cancer

Author & Date Study Type Form of Folate Key Results
Mackerras et al. (2014)[2] Meta-analysis Folic acid supplementation Meta-analysis of four randomised controlled trials showed that folic acid was not associated with breast cancer incidence (RR= 0.82, 95% CI=0.63-1.07).
Larsson et al. (2007)[15] Meta-analysis Dietary folate, total folate and blood folate Meta-analysis on cohort studies found there was no association with breast cancer risk for dietary folate (RR= 0.97, 95% CI= 0.88-1.07) in eight studies, total folate (RR= 1.01, 95% CI= 0.97-1.05) in six studies and high blood folate (OR= 0.81, 95% CI= 0.59-1.10) in three studies.

However among two cohort studies and two case-control studies that stratified for alcohol consumption, high folate intake was associated with a significantly decreased risk of breast cancer in women with high to moderate alcohol intake (RR= 0.51, 95% CI= 0.41-0.63).

Lewis et al. (2006)[16] Meta-analysis Dietary folate Meta-analysis on nine cohort studies found no association between dietary folate intake (100 µg/d increase) and breast cancer risk (RR= 0.99, 95% CI= 0.98-1.01). Meta-analysis on three cohort studies found no association between use of folate supplements and breast cancer risk (RR= 1.00, 95% CI= 0.86-1.17).
Zhang et al. (2008)[17] Randomised controlled trial (Women’s Antioxidant and Folic Acid Cardiovascular Study) 2.5 mg folic acid Folic acid supplementation had no association with the risk of developing breast cancer (HR= 0.83, 95% CI= 0.60-1.14).

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Ovarian cancer

Author & Date Study Type Form of Folate Key Results
Navarro Silvera et al. (2007)[18] Cohort study (Canadian National Breast Screening Study) Dietary folate Higher dietary folate was associated with a non-significant decreased risk of ovarian cancer (HR= 0.75, 95% CI= 0.42-1.34). For women consuming 4 g or more per day of alcohol, the risk decreased more but was still non-significant (HR= 0.59, 95% CI= 0.26-1.37), while in women consuming less than 4 g per day, there was no association (HR= 0.97, 95% CI= 0.43-2.15).
Larsson et al. (2004)[19] Cohort Study (Swedish Mammography Cohort) Dietary folate Higher dietary folate was associated with a non-significant decreased risk of ovarian cancer (RR= 0.67, 95% CI= 0.43-1.04). For women consuming more than 20 g per week of alcohol, the risk was significantly decreased (RR= 0.26, 95% CI= 0.11-0.60), while in women consuming 20 g or less per week, there was no association (RR= 1.00, 95% CI= 0.59-1.70).
Tworoger et al. (2006)[20] Cohort study (Nurses Health Study) Dietary folate A non-significant decreased risk of ovarian cancer was associated with dietary folate intake (RR= 0.66, 95% CI= 0.43-1.03). However there was no association between total folate intake and ovarian cancer risk (RR= 1.21, 95% CI= 0.92-1.60).

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Pancreatic cancer

Author & Date Study Type Form of Folate Key Results
Larsson et al. (2006)[21] Meta-analysis Dietary folate Meta-analysis on four cohort studies found that dietary folate intake was associated with a significantly reduced risk of pancreatic cancer (RR= 0.52, 95% CI= 0.36-0.75).
Larsson et al. (2006)[15] Cohort study (using data from the Swedish Mammography Study and Cohort of Swedish Men) Dietary folate, total folate and folic acid from supplements The risk of pancreatic cancer was significantly decreased in those with a higher dietary folate (RR= 0.25, 95% CI= 0.11-0.59) and total folate intake (RR= 0.33, 95% CI= 0.15-0.72). However there was no association between pancreatic cancer risk and folic acid from supplements (RR= 1.02, 95% CI= 0.56-1.88).
Skinner et al. (2004)[22] Cohort study (using data from the Nurses Health Study and Health Professionals Health Study) Dietary folate and total folate There was no association between total folate intake and pancreatic cancer risk (RR= 1.03, 95% CI= 0.74-1.43) or folate from supplements (RR= 1.17, 95% CI= 0.81-1.69). However there was a non-significant decreased risk for dietary folate intake and pancreatic cancer risk (RR= 0.66, 95% CI= 0.42-1.03).
Schernhammer et al. (2007)[23] Nested case control study (using data from four cohort studies) Plasma folate No association was found between plasma folate levels (highest versus lowest quartiles) and pancreatic cancer risk (OR= 1.22, 95% CI= 0.77-1.95). When the analysis was restricted to nonusers of multi-vitamin supplements, there was a non-significant decreased risk of pancreatic cancer (OR= 0.54, 95% CI= 0.23-1.30).

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Gastric cancer

Author & Date Study Type Form of Folate Key Results
Larsson et al (2006)[15] Meta-analysis Dietary folate Meta-analysis on two cohort studies found there was no association between higher dietary folate intake and stomach cancer risk (RR= 1.01, 95% CI= 0.72-1.42).
Vollset et al. (2007)[24] Nested case control study (within the European Prospective Investigation into Cancer and Nutrition) Plasma folate No association was found between higher plasma folate levels and stomach cancer risk (RR= 0.92, 95% CI= 0.56-1.50)

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Prostate cancer

Author & Date Study Type Form of Folate Key Results
Mackerras et al. (2014)[2] Meta-analysis Folic acid supplementation Meta-analysis of five randomised controlled trials showed that folic acid was not associated with prostate cancer incidence (RR= 1.16, 95% CI= 0.85-1.60).
Stevens et al. (2006)[25] Cohort study (American Cancer Society Prevention Study II Nutrition Cohort) Dietary folate and total folate No association was found between dietary folate (RR= 1.03, 95% CI= 0.94-1.13) or total folate intake (RR= 1.11, 95% CI= 1.01-1.22) and prostate cancer risk. A higher intake of dietary folate was associated with a non-significant decreased risk of advanced prostate cancer (RR= 0.78, 95% CI= 0.53-1.15) as was the case for total folate (RR= 0.79, 95% CI= 0.54-1.17).
Hultdin et al. (2005)[26] Nested case control study (within the Northern Swedish Disease Cohort) Plasma folate No association was found between plasma folate levels and prostate cancer risk (OR= 1.30, 95% CI= 0.74-2.24). However participants who were followed up after 4.9 years or more had a significantly increased risk of prostate cancer with higher plasma folate levels (RR= 2.0, 95% CI= 1.1-3.7).
Johansson et al. (2008)[27] Nested case control study (within the European Prospective Investigation into Cancer and Nutrition) Plasma folate Higher plasma folate levels were associated with a non-significant increased risk of prostate cancer (RR= 1.30, 95% CI= 0.88-1.93).

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Abbreviations used in tables

CI Confidence interval
HR Hazard ratio
OR Odds ratio
RR Relative risk

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References

  1. World Cancer Research Fund, American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington DC: AICR; 2007.
  2. 2.0 2.1 2.2 2.3 2.4 Mackerras D, Tan J, Larter C. Folic acid, selected cancers and all-cause mortality: a meta-analysis. IFRAJ 2014;4(11) 1-27.
  3. 3.0 3.1 Kennedy DA, Stern SJ, Moretti M, Matok I, Sarkar M, Nickel C, et al. Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis. Cancer Epidemiol 2011 Feb;35(1):2-10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21177150.
  4. Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 2005 Feb 20;113(5):825-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15499620.
  5. Polyp Prevention Study Group, Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007 Jun 6;297(21):2351-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17551129.
  6. Figueiredo JC, Levine AJ, Grau MV, Barry EL, Ueland PM, Ahnen DJ, et al. Colorectal adenomas in a randomized folate trial: the role of baseline dietary and circulating folate levels. Cancer Epidemiol Biomarkers Prev 2008 Oct;17(10):2625-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18843003.
  7. F, Grainge MJ, Shepherd VC, Armitage NC, Muir KR. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 2008;134(1): 29-38.
  8. Martínez ME, Giovannucci E, Jiang R, Henning SM, Jacobs ET, Thompson P, et al. Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence. Int J Cancer 2006 Sep 15;119(6):1440-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16615116.
  9. Martínez ME, Henning SM, Alberts DS. Folate and colorectal neoplasia: relation between plasma and dietary markers of folate and adenoma recurrence. Am J Clin Nutr 2004 Apr;79(4):691-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15051616.
  10. Murphy G, Sansbury LB, Cross AJ, Stolzenberg-Solomon R, Laiyemo A, Albert PS, et al. Folate and MTHFR: risk of adenoma recurrence in the Polyp Prevention Trial. Cancer Causes Control 2008 Sep;19(7):751-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18322814.
  11. Cho E, Hunter DJ, Spiegelman D, Albanes D, Beeson WL, van den Brandt PA, et al. Intakes of vitamins A, C and E and folate and multivitamins and lung cancer: a pooled analysis of 8 prospective studies. Int J Cancer 2006 Feb 15;118(4):970-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16152626.
  12. Ericson U, Sonestedt E, Gullberg B, Olsson H, Wirfält E. High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmö Diet and Cancer cohort. Am J Clin Nutr 2007 Aug;86(2):434-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17684216.
  13. Lajous M, Romieu I, Sabia S, Boutron-Ruault MC, Clavel-Chapelon F. Folate, vitamin B12 and postmenopausal breast cancer in a prospective study of French women. Cancer Causes Control 2006 Nov;17(9):1209-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17006726.
  14. Sellers TA, Grabrick DM, Vierkant RA, Harnack L, Olson JE, Vachon CM, et al. Does folate intake decrease risk of postmenopausal breast cancer among women with a family history? Cancer Causes Control 2004 Mar;15(2):113-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15017123.
  15. 15.0 15.1 15.2 Larsson SC, Håkansson N, Giovannucci E, Wolk A. Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men. J Natl Cancer Inst 2006 Mar 15;98(6):407-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16537833.
  16. Lewis SJ, Harbord RM, Harris R, Smith GD. Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk. J Natl Cancer Inst 2006 Nov 15;98(22):1607-22 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17105984.
  17. Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA 2008 Nov 5;300(17):2012-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18984888.
  18. Navarro Silvera SA, Jain M, Howe GR, Miller AB, Rohan TE. Dietary folate consumption and risk of ovarian cancer: a prospective cohort study. Eur J Cancer Prev 2006 Dec;15(6):511-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17106331.
  19. Larsson SC, Giovannucci E, Wolk A. Dietary folate intake and incidence of ovarian cancer: the Swedish Mammography Cohort. J Natl Cancer Inst 2004 Mar 3;96(5):396-402 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14996861.
  20. Tworoger SS, Hecht JL, Giovannucci E, Hankinson SE. Intake of folate and related nutrients in relation to risk of epithelial ovarian cancer. Am J Epidemiol 2006 Jun 15;163(12):1101-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16554344.
  21. Larsson SC, Giovannucci E, Wolk A. Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology 2006 Oct;131(4):1271-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17030196.
  22. Skinner HG, Michaud DS, Giovannucci EL, Rimm EB, Stampfer MJ, Willett WC, et al. A prospective study of folate intake and the risk of pancreatic cancer in men and women. Am J Epidemiol 2004 Aug 1;160(3):248-58 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15257998.
  23. Schernhammer E, Wolpin B, Rifai N, Cochrane B, Manson JA, Ma J, et al. Plasma folate, vitamin B6, vitamin B12, and homocysteine and pancreatic cancer risk in four large cohorts. Cancer Res 2007 Jun 1;67(11):5553-60 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17545639.
  24. Vollset SE, Igland J, Jenab M, Fredriksen A, Meyer K, Eussen S, et al. The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev 2007 Nov;16(11):2416-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18006931.
  25. Stevens VL, Rodriguez C, Pavluck AL, McCullough ML, Thun MJ, Calle EE. Folate nutrition and prostate cancer incidence in a large cohort of US men. Am J Epidemiol 2006 Jun 1;163(11):989-96 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16554345.
  26. Hultdin J, Van Guelpen B, Bergh A, Hallmans G, Stattin P. Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study. Int J Cancer 2005 Feb 20;113(5):819-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15499634.
  27. Johansson M, Appleby PN, Allen NE, Travis RC, Roddam AW, Egevad L, et al. Circulating concentrations of folate and vitamin B12 in relation to prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition study. Cancer Epidemiol Biomarkers Prev 2008 Feb;17(2):279-85 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18268110.

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