Circulating Folate and Folic Acid Concentrations: Associations With Colorectal Cancer Recurrence and Survival

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate (pABG) and p-acetamidobenzoylglutamate (apABG) were measured by liquid chromatography–tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and U.S. patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall and disease-free survival.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>No statistically significant associations were observed between folate, pABG, and apABG concentrations and recurrence, overall and disease-free survival, with hazard ratios (HRs) ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes/no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n = 296), a higher risk of recurrence was observed for each two-fold increase in folic acid (HR (95% confidence interval (95%CI): 1.31 (1.02 to 1.58)). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Circulating folate and folate catabolites concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid as they may increase the risk of colorectal cancer recurrence.</jats:p> </jats:sec>

The relationship between folic acid and colorectal cancer; a literature review

“…According to Ting PC, Lee WR [ 18 ] study; patients who take folic acid had a significant improve in CRC survival, that was attributed to its role in inhibiting colorectal cancer cell proliferation and migration. However, a different result was observed in Focus consortium [ 19 ] study as folic acid levels and its derivatives were not associated with neither CRC survival nor CRC recurrence. In 2003, a cohort study found that CRC patients who took both 5FU and folinic acid had less survival rate than those who took 5FU alone [ 20 ].…”

Colorectal Cancer Study of Austria (CORSA): A Population-Based Multicenter Study

“…Therefore, CORSA represents an active and leading player in cooperation, support actions, and consortia. So far, CORSA contributed to multiple international consortia such as Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], COlorectal cancer GENeTics (COGENT) and COnsortium of METabolomics Studies (COMETS) [ 13 ]. Furthermore, CORSA was a partner in two ERANET-TRANSCAN-funded projects: MetaboCCC [ 11 , 12 , 44 , 45 , 46 , 50 , 51 ], and “Biomarkers related to folate-dependent metabolism in colorectal cancer recurrence and survival” (FOCUS) [ 35 , 36 ].…”

Higher vitamin B6 status is associated with improved survival among patients with stage I–III colorectal cancer

“…With FOCUS, we study associations between folate and folate-mediated 1-carbon metabolism biomarkers and patient-reported outcomes such as quality of life (17) as well as clinical outcomes among patients aged 18 y and older diagnosed with primary CRC. The FOCUS Consortium has been previously described (11,18 Detailed data on clinical and sociodemographic features, including CRC treatment regimens, disease stage/site, and follow-up were prospectively captured. Comprehensive data on lifestyle features [including BMI (in kg/m 2 ) and smoking history] were also collected when available and harmonized across all study sites.…”

“…Baseline blood samples from CRC patients were processed in identical settings across all study centers as previously described (11,18), and metabolic profiling of biomarkers for all patients in the FOCUS Consortium was performed at BEVITAL AS (www.bevital.no). B6 vitamins and functional markers of vitamin B6 status (23), reflecting the metabolic effects of vitamin B6 serving as an enzyme cofactor, including the following: PLP (nmol/L), pyridoxal (PL) (nmol/L), 4-pyridoxic acid (PA) (nmol/L), 3 -hydroxykynurenine (HK) (nmol/L), kynurenic acid (KA) (nmol/L), 3 -hydroxyanthranilic acid (HAA) (nmol/L), anthranilic acid (AA) (nmol/L), xanthurenic acid (XA) (nmol/L), and creatinine (umol/L) were analyzed by LC-MS. PLP is the biologically active form of vitamin B6, PL is the 4-carboxyaldehyde form of vitamin B6, and PA is the end product of vitamin B6 catabolism.…”