Is folic acid (folate) supplementation linked to an increased risk of cancer?

Folic Acid Supplementation and Cancer Risk

The relationship between folic acid supplementation and cancer is complex and context-dependent: while folic acid deficiency may increase cancer risk, high-dose supplementation appears to promote progression of existing precancerous lesions, particularly in colorectal cancer, and should generally be avoided outside of specific indications like pregnancy.

The Dual Nature of Folate in Cancer

The evidence reveals a critical "timing paradox" with folic acid and cancer:

• Deficiency increases risk: Folic acid deficiency may increase the risk of colorectal and breast cancer, as folate is crucial for DNA synthesis, repair, and proper methylation 1
• Supplementation may promote existing lesions: Once carcinogenic processes have been initiated, folic acid supplementation may foster progression of pre-malignant lesions 1

Colorectal Cancer: The Strongest Evidence

High-Quality Trial Data Shows Harm

The most recent NCCN guidelines (2024) provide the clearest evidence of risk:

• The Aspirin/Folate Polyp Prevention Study found that 1 mg/day folic acid supplementation did NOT reduce colorectal adenoma risk (RR 1.04,95% CI 0.90-1.20) 1
• Advanced lesions increased: Risk of advanced lesions was higher with folic acid (11.4% vs 8.6%, RR 1.32) 1
• Serrated polyp risk significantly increased: Extended folic acid supplementation showed a statistically significant increased risk of sessile serrated lesions (RR 1.94,95% CI 1.02-3.68, P=0.04) during the second surveillance interval 1

Current Guideline Recommendations

The American Gastroenterological Association (2021) states definitively: "There is no clear role for folic acid supplementation in colorectal neoplasia prevention" 1

• Multiple meta-analyses of randomized trials show folic acid has no effect on colorectal cancer or adenoma incidence 1
• The NCCN (2024) added a cautionary statement that although folate has been linked to decreased risk of conventional adenomas, evidence suggests these agents may increase the risk of serrated polyps 1

Other Cancer Types: Limited Evidence

General Cancer Risk

• A 2012 meta-analysis of six large prospective folic acid supplementation trials found higher cancer incidence in folic acid-supplemented groups (RR 1.21,95% CI 1.05-1.39) 2
• The Aspirin/Folate Polyp Prevention Study noted increased numbers of non-colorectal cancers, particularly prostate cancer, in the folic acid arm 1

Maternal Cancer Risk

• A large Norwegian cohort study (429,004 women, average 7-year follow-up) found no overall effect on maternal cancer risk from folic acid supplementation during pregnancy (HR 1.08,95% CI 1.00-1.18 for one pregnancy) 3

Childhood Cancer

• Initial reports suggest folate fortification has led to reduction in incidence of certain childhood cancers such as neuroblastoma, Wilms tumor, and leukemias 4

Mechanism: Why Timing Matters

The biological explanation for this dual effect:

• Early/prevention phase: Folate deficiency causes DNA instability, uracil misincorporation, and chromosome breakage that can initiate cancer 5
• Promotion phase: Once precancerous lesions exist, folic acid supports nucleotide synthesis and cell proliferation, potentially accelerating progression 1, 6
• Mathematical modeling suggests folic acid supplementation started late in life (after age 20) mostly increases colorectal cancer risk, while early initiation may be protective 6

Clinical Implications and Recommendations

When to Avoid Supplementation

• Patients with history of colorectal polyps: Folic acid supplementation may increase advanced adenoma and serrated polyp risk 1
• Cancer survivors: Folic acid may promote recurrences and metastases in those with established cancer 1
• General population without deficiency: No clear benefit and potential harm 1

When Supplementation is Appropriate

• Pregnancy/preconception: Continue recommended 400 mcg daily for neural tube defect prevention, as maternal cancer risk is not increased 3
• Documented deficiency: Treat deficiency through food sources primarily (vegetables, fruits, enriched grain products) 1

Important Caveats

• Food sources are preferred: The American Cancer Society recommends obtaining folic acid through eating vegetables, fruits, and enriched grain products rather than supplements 1
• Post-fortification era: Since mandatory fortification began, most people receive adequate folate without supplementation 1
• Dose considerations: The tolerable upper limit is 300 mcg/day for children 1-3 years and 400 mcg/day for children 4-8 years; actual fortified food content may be 50% higher than labeled 1

Communication with Patients

• 31-68% of cancer patients using supplements do not discuss this with physicians 1
• Healthcare providers must actively ask about supplement use, as patients may not volunteer this information 1

Bottom Line for Clinical Practice

Do not recommend folic acid supplementation for cancer prevention in adults. For patients with prior colorectal polyps or cancer, actively discourage high-dose folic acid supplementation due to evidence of harm. Emphasize obtaining folate through dietary sources (vegetables, fruits, whole grains) rather than supplements, except during pregnancy where the neural tube defect prevention benefit clearly outweighs any theoretical cancer risk 1.