Pre-to-post diagnosis weight trajectories in colorectal cancer patients with non-metastatic disease

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Metabolites across the colorectal cancer continuum : A clinical and nutritional perspective

Colorectal cancer is one of the most prevalent cancers worldwide. Genetic, environmental, nutritional, and other lifestyle factors play a large role in the development of colorectal cancer, but the role in colorectal cancer recurrence and survival is largely unknown. Measuring metabolites, i.e. molecules present in biospecimens, such as blood and tissue samples, can help to unravel the underlying biology of the colorectal cancer continuum. The colorectal cancer continuum reflects the process in which normal cells progress into colorectal cancer cells. Therefore, the overall aim of this thesis is to better understand the association between circulating metabolites and the colorectal cancer continuum from a clinical and nutritional perspective in two international consortia.In Chapter 2, the association between plasma metabolites and colorectal cancer occurrence is studied using an untargeted metabolomics approach. Data of 268 stage I-IV colorectal cancer patients and 353 colorectal cancer-free individuals of an international consortium are included. Data are split into an independent discovery and replication set. After replication, 28 molecules are associated with colorectal cancer, including 15 molecules that could be identified as known metabolites. Levels of taurine, hypoxanthine, lysophosphatidylethanolamines (LysoPEs) (20:4) and (22:6) are shown to be higher among colorectal cancer patients compared to the colorectal cancer-free individuals. The opposite is observed for valine, leucine, bilirubin, 1-methylnicotinamide, and seven phosphatidylcholines (LysoPCs), namely LysoPC(15:0), LysoPC(16:0), LysoPC(16:0) isomer, LysoPC(P-16:0), LysoPC(16:1), LysoPC(17:0), and  LysoPC(18:0), which show lower levels among colorectal cancer patients compared to colorectal cancer-free individuals.The association between plasma metabolites at diagnosis and colorectal cancer stage is investigated using a targeted metabolomics approach in Chapter 3. In total, 744 patients with stage I-IV colorectal cancer from an international consortium are included in the analysis. Sphingomyelin (SM) C26:0 show lower concentrations among patients with stage III compared to stage I colorectal cancer. SM C18:0 and phosphatidylcholine diacyl (PC aa) C32:0 concentrations are higher, whereas citrulline, histidine, PC aa C34:4, PC acyl-alkyl (ae) C40:1 and LysoPC a C16:0 and C17:0 are lower among stage IV compared to stage I colorectal cancer patients. No differences in plasma metabolite concentrations are observed between stage II and stage I colorectal cancer patients.In Chapter 4, two diet quality indices and three dietary patterns, and their associations with plasma metabolites in colorectal cancer patients are shown. Plasma metabolites of 195 stage I-IV colorectal cancer patients are quantified using a targeted metabolomics approach. Two widely acknowledged diet quality indices are used, the 2018 dietary cancer prevention recommendations of the World Cancer Research Fund (WCRF), i.e. the WCRF dietary score, and the Dutch Healthy Diet Index (DHD15-index), based on the Dutch dietary guidelines of 2015. A higher intake of a healthier diet is reflected by a higher WCRF score and DHD15-index. The three dietary patterns are identified based on the reported habitual dietary intake of the colorectal cancer patients by Food Frequency Questionnaire at cancer diagnosis, i.e. a Western, Carnivore and Prudent pattern. The Western and Carnivore pattern reflect high intake of items usually present in an unhealthier diet. The Western dietary pattern is characterized by a high intake of snacks, savory sauces and spreads, refined grains, pizza, high and medium-fat dairy, nuts and seeds, beer, and hard fats, and a low intake of whole grain products and potatoes. The Carnivore pattern is characterized by a high intake of red and processed meat, poultry, fish, eggs, and potatoes, and a low intake of soy and vegetarian products, and medium and high-fat dairy. The Prudent pattern reflects a healthy diet, with high consumptions of vegetables, fruits, fish, nuts and seeds, and low-fat dairy and low intakes of pastry and biscuits, and beer. Better adherence to healthier diets is associated with lower concentrations of plasma phosphatidylcholines (Chapter 4). More specifically, patients with better adherence to the WCRF dietary score, DHD guidelines and higher consumptions of the Prudent pattern show lower concentrations of plasma phosphatidylcholines. Contrary, patients with higher intakes of the Western and Carnivore patterns show higher concentrations of plasma phosphatidylcholines.Chapter 5 describes the associations between circulating concentrations of folate species at diagnosis and colorectal cancer recurrence and survival. The folate species folate, folic acid, and folate catabolites p-aminobenzoylglutamate (pABG) and p-acetamidobenzoylglutamate (apABG) are quantified using a targeted metabolomics approach in blood samples of 2024 stage I-III colorectal cancer patients within an international consortium. Circulating concentrations of folate, pABG and apABG are not associated with colorectal cancer recurrence and survival. Higher compared to lower concentrations of folic acid are associated with an increased risk of recurrences, but folic acid concentrations are not associated with colorectal cancer survival.The findings of this thesis suggest that amino acid and lipid metabolism may play important roles in the colorectal cancer continuum. In addition, higher circulating concentrations of folic acid may be associated with an increased risk of colorectal cancer recurrence. Based on the observations in this thesis, investigating metabolite concentrations across the colorectal cancer continuum may provide important leads to further study the underlying biology of colorectal cancer development and progression.This thesis also showed that national and international collaborations are valuable because of the availability of data from colorectal cancer patients from several countries and the availability of a wide variability in exposures and outcomes. Future national and international collaborations are, therefore, encouraged to further study the underlying biology of the complex interplay between metabolites, nutrition, and the colorectal cancer continuum from a clinical and nutritional perspective

Dietary intake of magnesium or calcium and chemotherapy-induced peripheral neuropathy in colorectal cancer patients

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe side-effect in colorectal cancer (CRC) patients. This study assessed the association between habitual dietary intake of magnesium or calcium and prevalence and severity of chronic CIPN in CRC patients receiving adjuvant chemotherapy. For this prospective cohort study, 196 CRC patients were considered. Magnesium and calcium intake was determined using a food frequency questionnaire at diagnosis, during and after chemotherapy. Chronic CIPN was assessed 12 months after diagnosis using the quality of life questionnaire CIPN20. Prevalence ratios were calculated to assess the association between magnesium or calcium intake and the prevalence of CIPN. Multivariable linear regression analysis was used to assess the association between magnesium or calcium intake and severity of CIPN. CIPN was reported by 160 (82%) patients. Magnesium intake during chemotherapy was statistically significantly associated with lower prevalence of CIPN (prevalence ratio (PR) 0.53, 95% confidence interval (CI) 0.32, 0.92). Furthermore, higher dietary intake of magnesium during (β-1.08, 95% CI -1.95, -0.22) and after chemotherapy (β-0.93, 95% CI -1.81, -0.06) was associated with less severe CIPN. No associations were found for calcium intake and the prevalence and severity of CIPN. To conclude, we observed an association between higher dietary magnesium intake and lower prevalence and severity of CIPN in CRC patients

The association between the adapted dietary inflammatory index and colorectal cancer recurrence and all-cause mortality

Background & aims: The inflammatory potential of the diet has been linked to colorectal cancer (CRC) development and mortality. However, it is unknown whether it is also associated with CRC recurrence. Therefore, the aim of this study was to investigate the associations between the inflammatory potential of the diet and plasma inflammation markers as well as recurrence and all-cause mortality in CRC patients. Methods: Data of the Colorectal cancer, Observational, LONgitudinal (COLON) study, a prospective cohort study, was used. Dietary intake, assessed using a semi-quantitative food frequency questionnaire, was available for 1478 patients at diagnosis and for 1334 patients six months after diagnosis. Dietary intake data were used to calculate the adapted dietary inflammatory index (ADII). Data about cancer recurrence and all-cause mortality, were assessed through linkage with the Netherlands Cancer Registry and the Municipal Personal Records Database, respectively. The association between the ADII (continuous) and inflammation markers (Interleukin (IL)6, IL8, IL10, Tumor Necrosis Factor (TNF)α, high sensitivity C-reactive protein (hsCRP) and a summary inflammatory z-score), measured with a multiplex assay using electrochemiluminiscence detection, was assessed using quantile regression analyses. Restricted cubic splines (RCS) analyses and multivariable Cox proportional hazard models were used to explore the relationship between the ADII and CRC outcomes. Results: During a median follow-up time of 3.2 years (Interquartile range (IQR) 2.0–4.1) for recurrence and 4.8 years (IQR 3.5–5.9) for all-cause mortality, 228 recurrences and 279 deaths occurred. A more pro-inflammatory diet at diagnosis as well as six months after diagnosis was associated with higher levels of TNFα, hsCRP and the summary inflammatory z-score. Results of RCS showed no relationship between the ADII and CRC outcomes at both time points. Also results of the Cox proportional hazard models showed no associations between the ADII at both time points and recurrence (HR (95%CI) 0.98 (0.94–1.04) & 0.96 (0.91–1.02) or all-cause mortality (HR (95%CI) 1.03 (0.98–1.07) & 1.00 (0.95–1.05)). Conclusion: Our study did not show an association between the ADII and recurrence and all-cause mortality in CRC patients. Further research should also take into account molecular tumor subtypes, as the effect of the inflammatory potential of the diet on cancer recurrence and mortality is more likely to be present in tumors with an inflammatory signature. Clinical Trial Registry numbers and website: The colon study: NCT03191110; clinical trials.gov.</p

Colorectal cancer survivors only marginally change their overall lifestyle in the first 2 years following diagnosis

Purpose: A healthy lifestyle after colorectal cancer (CRC) diagnosis may improve prognosis. Data related to lifestyle change in CRC survivors are inconsistent and potential interrelated changes are unknown. Methods: We assessed dietary intake, physical activity, body mass index (BMI), waist circumference, and smoking among 1072 patients diagnosed with stages I–III CRC at diagnosis, 6 months and 2 years post-diagnosis. An overall lifestyle score was constructed based on the 2018 World Cancer Research Fund/American Institute of Cancer Research recommendations (range 0–7). We used linear mixed models to analyze changes in lifestyle over time. Results: Participants had a mean (± SD) age of 65 ± 9 years and 43% had stage III disease. In the 2 years following CRC diagnosis, largest changes were noted for sugary drinks (− 45 g/day) and red and processed meat intake (− 62 g/week). BMI (+ 0.4 kg/m2), waist circumference (+ 2 cm), and dietary fiber intake (− 1 g/day) changed slightly. CRC survivors did not statistically significant change their mean intake of fruits and vegetables, alcohol, or ultra-processed foods nor did they change their physical activity or smoking behavior. Half of participants made simultaneous changes that resulted in improved concordance with one component as well as deteriorated concordance with another component of the lifestyle score. Overall lifestyle score changed from a mean 3.4 ± 0.9 at diagnosis to 3.5 ± 0.9 2 years post-diagnosis. Conclusions: CRC survivors hardly improve their overall lifestyle after diagnosis. Implications for Cancer Survivors: Given the importance of a healthy lifestyle, strategies to effectively support behavior changes in CRC survivors need to be identified.</p

Diet quality indices and dietary patterns are associated with plasma metabolites in colorectal cancer patients

Purpose: Emerging evidence suggests that diet is linked to survival in colorectal cancer patients, although underlying mechanisms are not fully understood. The aim of this study was to evaluate whether dietary exposures are associated with metabolite concentrations in colorectal cancer patients. Methods: Concentrations of 134 metabolites of the Biocrates AbsoluteIDQ p180 kit were quantified in plasma samples collected at diagnosis from 195 stage I-IV colorectal cancer patients. Food frequency questionnaires were used to calculate adherence to the World Cancer Research Fund (WCRF) dietary recommendations and the Dutch Healthy Diet (DHD15) index as well as to construct dietary patterns using Principal Component Analysis. Multivariable linear regression models were used to determine associations between dietary exposures and metabolite concentrations. All models were adjusted for age, sex, body mass index, smoking status, analytical batch, cancer stage, and multiple testing using false discovery rate. Results: Participants had a mean (SD) age of 66 (9) years, were mostly men (60%), and mostly diagnosed with stage II and III cancer. For the dietary pattern analyses, Western, Carnivore, and Prudent patterns were identified. Better adherence to the WCRF dietary recommendations was associated with lower concentrations of ten phosphatidylcholines. Higher intake of the Carnivore pattern was associated with higher concentrations of two phosphatidylcholines. The DHD15-index, Western pattern, or Prudent pattern were not associated with metabolite concentrations. Conclusion: In the current study, the WCRF dietary score and the Carnivore pattern are associated with phosphatidylcholines. Future research should elucidate the potential relevance of phosphatidylcholine metabolism in the colorectal cancer continuum. Clinical trial registry: ClinicalTrials.gov Identifier: NCT03191110.</p

Pre-to-post diagnosis weight trajectories in colorectal cancer patients with non-metastatic disease

Purpose: Previous studies have shown that > 50% of colorectal cancer (CRC) patients treated with adjuvant chemotherapy gain weight after diagnosis. This may affect long-term health. Therefore, prevention of weight gain has been incorporated in oncological guidelines for CRC with a focus on patients that undergo adjuvant chemotherapy treatment. It is, however, unknown how changes in weight after diagnosis relate to weight before diagnosis and whether weight changes from pre-to-post diagnosis are restricted to chemotherapy treatment. We therefore examined pre-to-post diagnosis weight trajectories and compared them between those treated with and without adjuvant chemotherapy. Methods: We included 1184 patients diagnosed with stages I–III CRC between 2010 and 2015 from an ongoing observational prospective study. At diagnosis, patients reported current weight and usual weight 2 years before diagnosis. In the 2 years following diagnosis, weight was self-reported repeatedly. We used linear mixed models to analyse weight trajectories. Results: Mean pre-to-post diagnosis weight change was −0.8 (95% CI −1.1, −0.4) kg. Post-diagnosis weight gain was + 3.5 (95% CI 2.7, 4.3) kg in patients who had lost ≥ 5% weight before diagnosis, while on average clinically relevant weight gain after diagnosis was absent in the groups without pre-diagnosis weight loss. Pre-to-post diagnosis weight change was similar in patients treated with (−0.1 kg (95%CI −0.8, 0.6)) and without adjuvant chemotherapy (−0.9 kg (95%CI −1.4, −0.5)). Conclusions: Overall, hardly any pre-to-post diagnosis weight change was observed among CRC patients, because post-diagnosis weight gain was mainly observed in patients who lost weight before diagnosis. This was observed independent of treatment with adjuvant chemotherapy

Pre-to-post diagnosis weight trajectories in colorectal cancer patients with non-metastatic disease

Purpose: Previous studies have shown that > 50% of colorectal cancer (CRC) patients treated with adjuvant chemotherapy gain weight after diagnosis. This may affect long-term health. Therefore, prevention of weight gain has been incorporated in oncological guidelines for CRC with a focus on patients that undergo adjuvant chemotherapy treatment. It is, however, unknown how changes in weight after diagnosis relate to weight before diagnosis and whether weight changes from pre-to-post diagnosis are restricted to chemotherapy treatment. We therefore examined pre-to-post diagnosis weight trajectories and compared them between those treated with and without adjuvant chemotherapy. Methods: We included 1184 patients diagnosed with stages I–III CRC between 2010 and 2015 from an ongoing observational prospective study. At diagnosis, patients reported current weight and usual weight 2 years before diagnosis. In the 2 years following diagnosis, weight was self-reported repeatedly. We used linear mixed models to analyse weight trajectories. Results: Mean pre-to-post diagnosis weight change was −0.8 (95% CI −1.1, −0.4) kg. Post-diagnosis weight gain was + 3.5 (95% CI 2.7, 4.3) kg in patients who had lost ≥ 5% weight before diagnosis, while on average clinically relevant weight gain after diagnosis was absent in the groups without pre-diagnosis weight loss. Pre-to-post diagnosis weight change was similar in patients treated with (−0.1 kg (95%CI −0.8, 0.6)) and without adjuvant chemotherapy (−0.9 kg (95%CI −1.4, −0.5)). Conclusions: Overall, hardly any pre-to-post diagnosis weight change was observed among CRC patients, because post-diagnosis weight gain was mainly observed in patients who lost weight before diagnosis. This was observed independent of treatment with adjuvant chemotherapy.</p

Targeted plasma metabolic profiles and risk of recurrence in stage ii and iii colorectal cancer patients : Results from an international cohort consortium

The identification of patients at high‐risk for colorectal cancer (CRC) recurrence remains an unmet clinical need. The aim of this study was to investigate associations of metabolites with risk of recurrence in stage II/III CRC patients. A targeted metabolomics assay (128 metabolites measured) was performed on pre‐surgery collected EDTA plasma samples from n = 440 newly diagnosed stage II/III CRC patients. Patients have been recruited from four prospective cohort studies as part of an international consortium: Metabolomic profiles throughout the continuum of CRC (MetaboCCC). Cox proportional hazard models were computed to investigate associations of metabolites with recurrence, adjusted for age, sex, tumor stage, tumor site, body mass index, and cohort; false discovery rate (FDR) was used to account for multiple testing. Sixty‐nine patients (15%) had a recurrence after a median follow‐up time of 20 months. We identified 13 metabolites that were nominally associated with a reduced risk of recurrence. None of the associations were statistically significant after controlling for multiple testing. Pathway topology analyses did not reveal statistically significant associations between recurrence and alterations in metabolic pathways (e.g., sphingolipid metabolism p = 0.04; pFDR = 1.00). To conclude, we did not observe statistically significant associations between metabolites and CRC recurrence using a well‐established metabolomics assay. The observed results require follow‐up in larger studies.</p

Cohort profile : Biomarkers related to folate-dependent one-carbon metabolism in colorectal cancer recurrence and survival - The FOCUS Consortium

Purpose The overarching goal of the FOCUS (biomarkers related to folate-dependent one-carbon metabolism in colorectal cancer (CRC) recurrence and survival) Consortium is to unravel the effect of folate and folate-mediated one-carbon metabolism (FOCM) biomarkers on CRC prognosis to provide clinically relevant advice on folate intake to cancer patients and define future tertiary prevention strategies. Participants The FOCUS Consortium is an international, prospective cohort of 2401 women and men above 18 years of age who were diagnosed with a primary invasive non-metastatic (stages I-III) CRC. The consortium comprises patients from Austria, two sites from the Netherlands, Germany and two sites from the USA. Patients are recruited after CRC diagnosis and followed at 6 and 12 months after enrolment. At each time point, sociodemographic data, data on health behaviour and clinical data are collected, blood samples are drawn. Findings to date An increased risk of cancer recurrences was observed among patients with higher compared with lower circulating folic acid concentrations. Furthermore, specific folate species within the FOCM pathway were associated with both inflammation and angiogenesis pathways among patients with CRC. In addition, higher vitamin B 6 status was associated with better quality of life at 6 months post-treatment. Future plans Better insights into the research on associations between folate and FOCM biomarkers and clinical outcomes in patients with CRC will facilitate the development of guidelines regarding folate intake in order to provide clinically relevant advice to patients with cancer, health professionals involved in patient care, and ultimately further tertiary prevention strategies in the future. The FOCUS Consortium offers an excellent infrastructure for short-term and long-term research projects and for combining additional biomarkers and data resulting from the individual cohorts within the next years, for example, microbiome data, omics and multiomics data or CT-quantified body composition data