Open Access

Anne J. M. R. Geijsen, Arve Ulvik, Biljana Gigic, Dieuwertje E. Kok, Fränzel J. B. van Duijnhoven, Andreana N. Holowatyj, Stefanie Brezina, Eline H. van Roekel, Andreas Baierl, Michael M. Bergmann, Jürgen Böhm, Martijn J. L. Bours, Hermann Brenner, Stéphanie O. Breukink, Mary P. Bronner, Jenny Chang-Claude, Johannes H. W. de Wilt, William M. Grady, Thomas Grünberger, Tanja Gumpenberger, Esther Herpel, Michael Hoffmeister, Lyen C. Huang, Jolanta D. Jedrzkiewicz, Eric T. P. Keulen, Rama Kiblawi, Torsten Kölsch, Janna L. Koole, Katharina Kosma, Ewout A. Kouwenhoven, Flip M. Kruyt, Gry Kvalheim, Christopher I. Li, Tengda Lin, Jennifer Ose, T. Bartley Pickron, Courtney L. Scaife, Peter Schirmacher, Martin A. Schneider, Petra Schrotz-King, Marie C. Singer, Eric R. Swanson, Peter van Duijvendijk, Henk K. van Halteren, Moniek van Zutphen, Kathy Vickers, F. Jeroen Vogelaar, Evertine Wesselink, Nina Habermann, Alexis B. Ulrich, Per M. Ueland, Matty P. Weijenberg, Andrea Gsur, Cornelia M. Ulrich, Ellen Kampman

• Background: 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. Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US 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 survival, and disease-free survival. Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or 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 twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival. Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.