Colorectal cancer is the second most common cause of cancer‐related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I–IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography‐mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I–IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (p_FDR < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl‐alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (p_FDR < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.

Supplement use among colorectal cancer (CRC) survivors is common, yet evidence supporting its beneficial health effects is mostly lacking and cancer-specific lifestyle guidelines advise against the use of supplements. We aimed to describe the use of supplements by CRC survivors from diagnosis to 2 years post-treatment and investigate how overall supplement use is longitudinally associated with fatigue. In a prospective cohort study of stage I-III CRC survivors (n = 325), information on supplement use was collected during repeated home visits at diagnosis and at 6 weeks, 6, 12, and 24 months post-treatment. Fatigue was assessed using the Checklist Individual Strength (score range 20-140) at all post-treatment time points. Linear mixed-models were applied to analyze longitudinal associations of overall supplement use with fatigue, adjusted for sex, age, comorbidities, chemotherapy, and physical activity. At all time points, about 40% of participants used supplements. Multivitamins/multiminerals were the most frequently used supplements at all time points. Of participants with at least two available measurements, 28% were consistent users, 45% consistent nonusers, and 27% inconsistent users (i.e. reported both use and nonuse). Reported fatigue levels declined significantly after treatment. Overall, no statistically significant differences in fatigue score over time were observed between supplement users and nonusers. Likewise, no intra-individual associations of supplement use and fatigue were found. However, in inter-individual analyses, supplement users reported to experience more fatigue compared to nonusers (β 7.0, 95% CI 0.3; 13.7). No overall association between supplement use and fatigue was found. Results of the current study do therefore not imply that supplement use alleviates complaints of fatigue among CRC survivors. However, increased levels of fatigue may be a reason for supplement use among CRC survivors.

Background: Vitamin D status may be an important determinant of health-related quality of life of colorectal cancer survivors. The current study investigated longitudinal associations between serum 25-hydroxyvitamin D3 (25OHD3) concentrations and quality of life in stage I–III colorectal cancer survivors up to 2 years after treatment. Methods: Patients with colorectal cancer (n = 261) were included upon diagnosis. Home visits (including blood sampling) were performed at diagnosis and at 6 weeks, 6 months, 1 year, and 2 years after treatment. Serum 25OHD3 concentrations were measured using LC/MS-MS and adjusted for season. Validated questionnaires were used to assess global quality of life and cognitive functioning (EORTC-QLQ-C30), fatigue (EORTC-QLQ-C30 and Checklist Individual Strength, CIS), and depression and anxiety (Hospital Anxiety and Depression Scale). Statistical analyses were performed using linear mixed models and adjusted for sex, age, time since diagnosis, therapy, comorbidities, physical activity, and body mass index. Results: At diagnosis, 45% of patients were vitamin D deficient (<50 nmol/L). After treatment, 25OHD3 concentrations increased on average with 3.1 nmol/L every 6 months. In confounder-adjusted models, 20 nmol/L increments in 25OHD3 were longitudinally associated with increased global quality of life [β 2.9; 95% confidence interval (CI), 1.5–4.3] and reduced fatigue (EORTC-QLQ-C30 subscale: β −3.5; 95% CI, −5.3 to −1.8 and CIS: β −2.8; 95% CI, −4.7 to −0.9). Observed associations were present both within and between individuals over time. Conclusions: Higher concentrations of 25OHD3 were longitudinally associated with better global quality of life and less fatigue in colorectal cancer survivors. Impact: This study suggests that higher 25OHD3 concentrations may be beneficial for colorectal cancer survivors. Future intervention studies are needed to corroborate these findings.

Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. A total of 2031 patients with stage I–III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5′-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3′-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3′-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16–32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HR_OS, 0.68; 95% CI: 0.59, 0.79; HR_DFS, 0.84; 95% CI: 0.75, 0.94; HR_Recurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HR_OS, 2.04; 95% CI: 1.67, 2.49; HR_DFS, 1.56; 95% CI: 1.31, 1.85; HR_Recurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HR_OS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HR_OS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HR_OS, 0.61; 95% CI: 0.47, 0.78). Higher preoperative vitamin B6 status is associated with improved OS among stage I–III CRC patients.

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.