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Self-reported type 2 diabetes mellitus (T2DM) is a risk factor for many cancers, suggesting its pathology relates to carcinogenesis. We conducted a case-cohort study to examine associations of hemoglobin A1c (HbA1c) and c-peptide with cancers associated with self-reported T2DM. This study was drawn from a prospective cohort of 32,383 women and men who provided blood specimens at baseline: c-peptide and HbA1c were assessed in 3,000 randomly selected participants who were cancer-free-at-baseline and an additional 2,281 participants who were cancer-free-at-baseline and subsequently diagnosed with incident colorectal, liver, pancreatic, female breast, endometrial, ovarian, bladder, or kidney cancers. Weighted Cox regression models estimated HRs and 95% confidence intervals (CI), adjusted for covariates. c-peptide was associated with higher risk of liver cancer [per SD HR: 1.80; 95% CI: 1.32–2.46]. HbA1c was associated with higher risk of pancreatic cancer (per SD HR: 1.21; 95% CI: 1.05–1.40) and with some suggestion of higher risks for all-cancers-of-interest (per SD HR: 1.05; 95% CI: 0.99–1.11) and colorectal (per SD HR: 1.09; 95% CI: 0.98–1.20), ovarian (per SD HR: 1.18; 95% CI: 0.96–1.45) and bladder (per SD HR: 1.08; 95% CI: 0.96–1.21) cancers. Compared with no self-reported T2DM and HbA1c < 6.5% (reference group), self-reported T2DM and HbA1c < 6.5% (i.e., T2DM in good glycemic control) was not associated with risk of colorectal cancer, whereas it was associated with higher risks of all-cancers-of-interest combined (HR: 1.28; 95% CI: 1.01–1.62), especially for breast and endometrial cancers. Additional large, prospective studies are needed to further explore the roles of hyperglycemia, hyperinsulinemia, and related metabolic traits with T2DM-associated cancers to better understand the mechanisms underlying the self-reported T2DM-cancer association and to identify persons at higher cancer risk. Significance: The results from this study suggest that HbA1c and c-peptide, markers of hyperglycemia and hyperinsulinemia respectively, are associated with certain cancers, though people with diabetes may be at increased risk of these cancers, perhaps other than colorectal, even when their glucose is well controlled.

Whole grain and fiber intakes may decrease the risk of colorectal cancer. The interplay between host genetic factors, colonization of specific bacteria, production of short-chain fatty acids (SCFA), and intake of whole grains and fiber could alter the protective role of carbohydrates against colorectal cancer. Here, we assessed intakes of types and sources of carbohydrates in 114,217 UK Biobank participants with detailed dietary data (2-5 24-hour dietary assessments), and a host polygenic score (PGS) was applied to categorize participants as high or low for intra-luminal microbial SCFA production, namely butyrate and propionate. Multivariable Cox proportional hazards models were used to determine the associations of carbohydrates and SCFA with colorectal cancer incidence. During a median follow-up of 9.4 years, 1,193 participants were diagnosed with colorectal cancer. Risk was inversely associated with intakes of non-free sugar and whole grain fiber. Evidence of heterogeneity was observed by the butyrate PGS; consuming higher amounts of whole grain starch was only associated with a lower risk of colorectal cancer in those with predicted high SCFA production. Similarly, in additional analyses utilizing the larger UK Biobank cohort (N=343,621) with less detailed dietary assessment, only individuals with a high genetically predicted butyrate production had a lower risk of colorectal cancer per 5 g/day intake of bread and cereal fiber. This study suggests that colorectal cancer risk varies by intake of carbohydrate types and sources, and the impact of whole grain intake may be modified by SCFA production.

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Self-reported type 2 diabetes mellitus (T2DM) is a risk factor for many cancers, suggesting its pathology relates to carcinogenesis. We conducted a case-cohort study to examine associations of hemoglobin A1c (HbA1c) and c-peptide with cancers associated with self-reported T2DM. This study was drawn from a prospective cohort of 32,383 women and men who provided blood specimens at baseline: c-peptide and HbA1c were assessed in 3,000 randomly selected participants who were cancer-free-at-baseline and an additional 2,281 participants who were cancer-free-at-baseline and subsequently diagnosed with incident colorectal, liver, pancreatic, female breast, endometrial, ovarian, bladder, or kidney cancers. Weighted Cox regression models estimated HRs and 95% confidence intervals (CI), adjusted for covariates. c-peptide was associated with higher risk of liver cancer [per SD HR: 1.80; 95% CI: 1.32–2.46]. HbA1c was associated with higher risk of pancreatic cancer (per SD HR: 1.21; 95% CI: 1.05–1.40) and with some suggestion of higher risks for all-cancers-of-interest (per SD HR: 1.05; 95% CI: 0.99–1.11) and colorectal (per SD HR: 1.09; 95% CI: 0.98–1.20), ovarian (per SD HR: 1.18; 95% CI: 0.96–1.45) and bladder (per SD HR: 1.08; 95% CI: 0.96–1.21) cancers. Compared with no self-reported T2DM and HbA1c < 6.5% (reference group), self-reported T2DM and HbA1c < 6.5% (i.e., T2DM in good glycemic control) was not associated with risk of colorectal cancer, whereas it was associated with higher risks of all-cancers-of-interest combined (HR: 1.28; 95% CI: 1.01–1.62), especially for breast and endometrial cancers. Additional large, prospective studies are needed to further explore the roles of hyperglycemia, hyperinsulinemia, and related metabolic traits with T2DM-associated cancers to better understand the mechanisms underlying the self-reported T2DM-cancer association and to identify persons at higher cancer risk.Significance:The results from this study suggest that HbA1c and c-peptide, markers of hyperglycemia and hyperinsulinemia respectively, are associated with certain cancers, though people with diabetes may be at increased risk of these cancers, perhaps other than colorectal, even when their glucose is well controlled.

Supplemental Table 1 - Association of self-reported T2DM at blood draw with risk of all-cancers combined and separately in CPS-II LifeLink participants; Supplemental Table 2 - Association BMI per 5 kg/m2 at blood draw with risk of all-cancers combined and separately in CPS-II LifeLink participants. Excludes those with BMI

Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ∼550,000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52,775 cases and 45,940 controls) using Mendelian randomization (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4,043 incident CRC cases and 332,773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, CI(95%): 0.78-0.99,P=0.04; OR: 0.93, CI(95%): 0.88-0.98,P=0.01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, CI(95%): 0.80-0.97,P=0.01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, CI(95%): 0.76-0.93,P=6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, CI(95%): 0.93-0.99,P=0.02] and following adjustment for the other WBC subtypes [RR: 0.96, CI(95%): 0.93-0.99,P=0.001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.What is already known of this topicWhile previous observational studies have suggested a protective role for eosinophils in colorectal cancer development and implicated neutrophils, whether changes in the levels of circulating white blood cells causes colorectal cancer has not been explored.What this study addsOur study is the first to use Mendelian randomization (MR) to investigate this relationship. In parallel, for comparison, we also conduct the largest cohort study to date on the topic. We found evidence to suggest that elevated eosinophil and lymphocyte count may have a protective effect on CRC risk, adding new insights into the pathogenesis of CRC.How this study might affect research, practice or policyOur findings will encourage further mechanistic exploration to understand the biological mechanisms underpinning our findings, which may lead to new therapeutic approaches or risk reduction strategies.

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and East Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions, and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Cross-tissue analyses indicated that over a third of effector genes most likely act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis, and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article.

It is unclear whether diet, and in particular certain foods or nutrients, are associated with lung cancer risk. We assessed associations of 92 dietary factors with lung cancer risk in 327,790 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) per standard deviation (SD) higher intake/day of each food/nutrient. Correction for multiple comparisons was performed using the false discovery rate and identified associations were evaluated in the Netherlands Cohort Study (NLCS). In EPIC, 2,420 incident lung cancer cases were identified during a median of 15 years of follow-up. Higher intakes of fibre (HR per 1 SD higher intake/day=0.91, 95%CI 0.87-0.96), fruit (HR=0.91, 95%CI 0.86-0.96), and vitamin C (HR=0.91, 95%CI 0.86-0.96) were associated with a lower risk of lung cancer, whereas offal (HR=1.08, 95%CI 1.03-1.14), retinol (HR=1.06, 95%CI 1.03-1.10), and beer/cider (HR=1.04, 95%CI 1.02-1.07) intakes were positively associated with lung cancer risk. Associations did not differ by sex and there was less evidence for associations among never smokers. None of the six associations with overall lung cancer risk identified in EPIC were replicated in the NLCS (2,861 cases), however in analyses of histological subtypes, inverse associations of fruit and vitamin C with squamous cell carcinoma were replicated in the NLCS. Overall, there is little evidence that intakes of specific foods and nutrients play a major role in primary lung cancer risk, but fruit and vitamin C intakes seem to be inversely associated with squamous cell lung cancer. This article is protected by copyright. All rights reserved.

Background: Excess body fatness, approximated by body mass index (BMI), is associated with higher risk of at least 13 cancer types and is the second-largest avoidable cause of cancer in many populations. Current epidemiologic evidence linking body fatness with cancer risk is largely based on a ‘once-only’ BMI measure which may fail to capture the life-course exposure to body fatness. Here, we test whether a novel metric that combines repeated BMI measures over an individual’s adult lifetime, the overweight-years metric, improves the performance characteristics for associations with cancer compared with a ‘once-only’ BMI measure. Methods: Within the ABACus 2 Consortium (4 US cohorts; 1 European cohort), we derived the overweight-years metric - a product of the degree of overweight (BMI minus 24.9 kg/m2) and the duration of overweight (in years). Using a random effects two-stage meta-analysis, we calculated the association between the overweight-years metric, and separately the cumulative degree and cumulative duration of overweight exposure with incident cancer by fitting multivariable-adjusted Cox proportional hazards models and comparing each metrics performance with BMI measured at a single time using Harrell’s C-statistic. Results: Out of 1,419,850 participants in the ABACus 2 consortium, 716,909 participants were included. Per standard deviation overweight-years, the multivariable-adjusted hazard ratio for obesity-related cancers in men was 1.15 (95% CI: 1.13, 1.17, I2: 0) and for women was 1.11 (95% CI: 1.04, 1.18, I2: 0.94). For ‘once-only’ BMI, the per standard deviation multivariable-adjusted hazard ratio for obesity-related cancers in men was 1.16 (95% CI: 1.15,1.18, I2: 0) and for women was 1.13 (95% CI: 1.09,1.18, I2: 0.82). For most obesity-related cancers, both degree and duration of overweight were significantly associated with risk. The overweight-years metric had a C-statistic of 0.610 (95% CI: 0.569, 0.649) and once-only BMI had a C-statistic of 0.608 (95% CI: 0.566, 0.648) for combined obesity-related cancers in men. In women, the C-statistic for overweight-years was 0.562 (95% CI: 0.537, 0.587) and once-only BMI had a C-statistic of 0.566 (95% CI: 0.544, 0.588) for combined obesity-related cancers. The C-statistic of the overweight-years metric and BMI measured at a single time combined was 0.609 (95% CI: 0.567, 0.650) in men and 0.573 (95% CI: 0.546, 0.600) in women for combined obesity-related cancers. Conclusion: Overall, there were marginal differences in the predictive performance between the overweight-years metric and a ‘once-only’ baseline-BMI measure. These findings show that excess weight throughout adulthood is important in cancer development. Funding: CRUK, NIHR, NHLBI, NCI, NPCR. Citation Format: Nadin Hawwash, Matthew Sperrin, Glen P. Martin, Michael Cook, Charles E. Matthews, Marian L. Neuhouser, Corinne E. Joshu, Elizabeth A. Platz, Heinz Freisling, Marc Gunter, Rob Bristow, Andrew G. Renehan. Excess weight by degree and duration and cancer risk: an individual participant data (IPD) meta - analyses of over 1.4 million participants (ABACus2 consortium) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3034.

Background: Statins and low-dose aspirin have been associated with a reduced breast cancer (BC) incidence, but results are inconsistent. Based on emerging evidence that parity, a protective factor for breast cancer, and these drugs modulate immunity, we hypothesized that the association between drug use and breast cancer risk may differ by parity. Objectives: To assess the associations of statin and low-dose aspirin use with BC incidence according to parity in French and Danish cohorts. Methods: We conducted two cohort studies, using data from the French E3N study and a Danish nationwide population-based cohort, respectively. From E3N, 51,482 women, mean age 65.5 years, were enrolled in 2005 and followed until 2014. Data on parity (here full-term pregnancies), drug use, and incident BC were acquired from questionnaires, a drug reimbursement database, pathology verified self-reports and the national cause-of-death registry, respectively. From nationwide health registries, we included all Danish women free of BC and aged 45 years in 2000-2005 (n=198,575), with follow-up to 2014. Use of the exposure drugs were defined as at least two reimbursements/filled prescriptions. In both cohorts, multivariable-adjusted Cox regression was used to compute hazard ratios (HR) for drug exposure, treated as time-varying lagged variables, and BC risk stratified by parity (0, 1, 2, 3+). Results: In E3N and Denmark, 1,878 and 5,436 incident BC cases occurred in a mean follow-up of 8.5 and 11.5 years, respectively. At the end of follow-up, 35% and 19% of E3N and 16% and 8% of the Danish cohort had been exposed to statins and low-dose aspirin, respectively. In E3N, effect modification was observed between parity and statins, but not low-dose aspirin. For statins, the HRs for use vs no use were 1.29 (0.97-1.72), 1.27 (0.99-1.65), 1.08 (0.91-1.27), and 0.76 (0.61-0.95) among women with 0, 1, 2, and 3+ full-term pregnancies, respectively (p-het=0.005). The corresponding estimates for low-dose aspirin were: 1.17 (0.80-1.71), 0.81 (0.54-1.20), 1.13 (0.90-1.43), and 1.22 (0.93-1.61; p-het=0.6). In contrast, the Danish data did not suggest any effect modification. HRs for use vs no use of statins were 0.82 (0.60-1.13), 1.05 (0.80-1.37), 0.91 (0.75-1.10), and 1.09 (0.83-1.44) among women with parity of 0, 1, 2, and 3+, respectively (p-het=0.3). For low-dose aspirin HRs were: 1.09 (0.75-1.59), 0.79 (0.54-1.15), 1.04 (0.82-1.32), and 0.99 (0.71-1.40; p-het=0.8). Conclusions: We observed effect modification by parity for the association between statins and breast cancer risk in the French but not the Danish cohort. Whether the age difference between the cohorts explains the inconsistent results should be explored. Citation Format: Julie A. Schmidt, Agnès Fournier, Manon Cairat, Aurélie Mailhac, Henrik Sørensen, Marc Gunter, Deirdre Cronin-Fenton. Parity, Use of Statins and Low-dose Aspirin, and Breast Cancer Risk – data from two large cohort studies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-17.

The metabolic dysfunction driven by obesity, including hyperglycemia and dyslipidemia, increases risk for developing at least 13 cancer types. The concept of "metabolic dysfunction" is often defined by meeting various combinations of criteria for metabolic syndrome. However, the lack of a unified definition of metabolic dysfunction makes it difficult to compare findings across studies. This review summarizes 129 studies that evaluated variable definitions of metabolic dysfunction in relation to obesity-related cancer risk and mortality after a cancer diagnosis. Strategies for metabolic dysfunction management are also discussed.A comprehensive search of relevant publications in MEDLINE (PubMed) and Google Scholar with review of references was conducted.Metabolic dysfunction, defined as metabolic syndrome diagnosis or any number of metabolic syndrome criteria out of clinical range, inflammatory biomarkers, or markers of metabolic organ function, has been associated with risk for, and mortality from, colorectal, pancreatic, postmenopausal breast, and bladder cancers. Metabolic dysfunction associations with breast and colorectal cancer risk have been observed independently of BMI, with increased risk in individuals with metabolically unhealthy normal weight or overweight/obesity compared with metabolically healthy normal weight.Metabolic dysfunction is a key risk factor for obesity-related cancer, regardless of obesity status. Nonetheless, a harmonized definition of metabolic dysfunction will further clarify the magnitude of the relationship across cancer types, enable better comparisons across studies, and further guide criteria for obesity-related cancer risk stratification.

Previous studies have suggested that components of one-carbon metabolism, particularly circulating vitamin B6, have an etiological role in renal cell carcinoma (RCC). Vitamin B6 is a cofactor in the transsulfuration pathway. We sought to holistically investigate the role of the transsulfuration pathway in RCC risk. We conducted a nested case-control study (455 RCC cases and 455 matched controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Plasma samples from the baseline visit were analyzed for metabolites of the transsulfuration pathway, including pyridoxal 5'-phosphate (PLP, the biologically active form of vitamin B6), homocysteine, serine, cystathionine, and cysteine, in addition to folate. Bayesian conditional logistic regression was used to estimate associations of metabolites with RCC risk as well as interactions with established RCC risk factors. Circulating PLP and cysteine were inversely associated with RCC risk, and these associations were not attenuated after adjustment for other transsulfuration metabolites (odds ratio (OR) and 90% credible interval (CrI) per 1 SD increase in log concentration: 0.76 [0.66, 0.87]; 0.81 [0.66, 0.96], respectively). A comparison of joint metabolite profiles suggested substantially greater RCC risk for the profile representative of low overall transsulfuration function compared to high function (OR 2.70 [90% CrI 1.26, 5.70]). We found some statistical evidence of interactions of cysteine with body mass index, and PLP and homocysteine with smoking status, on their associations with RCC risk. In conclusion, we found evidence suggesting that the transsulfuration pathway may play a role in metabolic dysregulation leading to RCC development. ispartof: INTERNATIONAL JOURNAL OF CANCER vol:151 issue:5 pages:708-716 ispartof: location:United States status: published

Background Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts. Objective To investigate the association between plasma concentrations of selected POPs and pancreatic cancer risk. Methods Prospective case-control study nested within the EPIC cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs (organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers) were measured in plasma collected at baseline by GC-MS/MS. Results Some, generally moderate effects were observed at higher concentrations of p,p’-DDT, trans-nonachlor, β-hexachlorocyclohexane, and the sum of 6 organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06 to 2.26; P for trend=0.025). Associations were stronger in the groups predefined as most valid or relevant. Among participants having fasted >6 hours at blood collection, the ORs were significant for 10 of 11 exposure categories. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis. Higher ORs were also observed among normal-weight participants, with relevant estimates for all 11 exposure categories. Among participants with a follow-up ≥10 years, estimates were also higher (e.g., for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend=0.035). Overall, trans-nonachlor, 3 PCBs, and the 2 sums of POPs were the exposures more clearly associated with pancreatic cancer risk. Conclusions A few moderately increased risks were apparent for the highest concentrations of certain POPs, sometimes with a dose-response relationship.

Type 2 diabetes is linked to higher risk of many non-metabolic conditions (e.g. cancers, neuropsychiatric and musculoskeletal disease) which all share a common risk factor: obesity. The causal pathways from excess weight to disease are unknown. We aimed to use specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects. Using metabolic biomarkers from 442,278 UK Biobank individuals, we identified two clusters of body fat % increasing alleles: a) 36 “favourable adiposity” (FA) alleles associated with a favourable metabolic profile (higher HDL and SHBG and lower triglyceride and liver enzymes); b) 38 “unfavourable adiposity” (UFA) alleles associated with an unfavourable profile (lower HDL and SHBG and higher triglyceride and liver enzymes). We used two-sample Mendelian randomization with 43 diseases from non-UK Biobank GWASs. We identified two sets of diseases. 1) Those where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here the FA and UFA clusters had an opposing effect on the risk of disease: type 2 diabetes (FA: 0.11 OR per 1 standard deviation higher body fat % [95%CI: 0.08, 0.16] vs. UFA: 5.50 [4.29, 7.05]), stroke (0.65 [0.52, 0.83] vs. 1.43 [1.23, 1.67]), gout (0.44 [0.29, 0.68] vs. 2.49 [1.88, 3.29]), breast cancer (1.12 [0.64, 1.94] vs. 0.52 [0.39, 0.68]) and colorectal cancer (0.67 [0.52, 0.85] vs. 1.20 [1, 1.50]). 2) Those where the mechanical excess weight (or other non-metabolic effects) is likely a cause of the disease. Here the FA cluster, despite having lower metabolic risk, and the UFA cluster were both associated with higher disease risk: venous thromboembolism (2.52 [1.82, 3.47] vs. 1.63 [1.25, 2.13]), osteoarthritis (1.45 [1.19, 1.76] vs. 2.20 [1.64, 2.95]), depression (2.85 [1.38, 5.89] vs. 2.59 [1.60, 4.21]). Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects in non-metabolic diseases pathophysiological mechanisms. Disclosure S. Martin: None. J. D. Bell: None. T. M. Frayling: None. H. Yaghootkar: None. J. Tyrrell: None. E. L. Thomas: None. M. Bown: None. J. T. Elder: None. C. Kabrhel: Research Support; Self; Diagnostica Stago, Grifols. N. Papadimitriou: None. M. Gunter: None. E. E. Vincent: None. Funding Diabetes UK (17/0005594)

Background: An improved understanding of the etiology of colorectal cancer is needed to allow more accurate disease prediction. This study will use a state-of-the-art metabolomics strategy leveraging existing data from 8 prospective cohort studies to discover and validate novel blood-based biomarkers that are associated with colorectal cancer risk. This project is in its early phase and the abstract is focusing on describing the study design. Methods: We will perform a meta-analysis using data from 8 large-scale prospective cohort studies that are part of the Consortium of Metabolomics Studies (COMETS): European Prospective Investigation into Cancer and Nutrition, Estonian Biobank, Women Health Study – Observational Study, Prostate, Lung, Colorectal and Ovarian Cancer Observational Study, Nurses’ Health Study, Health Professional Follow-up Study, Shanghai Women’s and Men’s Health Studies. All studies used a nested case-control study design (1:1 matching at a minimum by age and sex). Prediagnostic plasma and serum samples were analyzed using state-of-the art metabolomics platforms: Metabolon, Inc., Broad Institute and Biocrates. We expect n~150 overlapping identified metabolites across platforms. Data will be split into discovery and validation set. We will investigate associations of metabolites with colorectal cancer risk using multivariable conditional logistic regression models and random effects meta-analysis. Analyses will be stratified by age ( Results: The present study includes n=2,093 case-control pairs in the discovery dataset and n=1,082 case-control pairs in the validation dataset. Demographic data such as age at blood draw and age at diagnosis, race, body mass index, smoking, and dietary intake at baseline (red meat, vegetables, fruits, fat, and fiber) are collected. Data on tumor site are >95% complete. Tumor stage is available for >85% of patients and is expected to increase substantially since medical data abstraction is under way in some cohorts. Conclusions: This is the largest study, to our knowledge, investigating the associations of prediagnosis metabolomic profiles with colorectal cancer risk. The proposed analyses have the potential to identify biomarkers that may enhance population-wide and tailored screening of colorectal cancer risk. Citation Format: Jennifer Ose, Cornelia M. Ulrich, Mary Playdon, Ken Boucher, A. Heather Elisassen, Xia-Ou Shu, Wei Zheng, Andres Metspalu, Tonu Esku, Jessica Lasky-Su, Steve Moore, Marc Gunter. Associations of prediagnostic metabolomic profiles with colorectal cancer risk—a collaborative reanalysis within the COnsortium of METabolomic Studies (COMETS) [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr A06.

Colorectal cancer (CRC) is the third most common cancer worldwide and its incidence is rising. Identifying etiologic pathways and early detection for CRC are key to prevention and reducing mortality as the prognosis for advanced CRC, despite recent improvements in therapy, remains poor. One area of potentially measurable CRC risk factors, that is still relatively unexplored, are circulating levels of endogenous sex hormones. The incidence of CRC is greater in men than in women and a proposed hypothesis for this sex disparity is that higher levels of endogenous estrogens found in women may be protective against CRC. In addition, androgens, including testosterone, have been hypothesized to confer protective effects for CRC in men. However, few studies have evaluated the association between testosterone and CRC in men, and the limited available data suggest that any observed protective association is likely confined to colon rather than rectal cancer. The aim of this study was therefore to evaluate the relation of colon cancer risk with circulating levels of sex hormones and sex hormone binding globulin (SHBG) in a male population. Preliminary analyses included data from 461 cases of incident colon cancer and 461 matched controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Sex hormones (estradiol, estrone, testosterone, androstenedione, dehydroepiandrosterone, and progesterone) were measured in prediagnostic plasma samples using liquid chromatography-tandem /mass spectrometry (LC/-MS/MS), and SHBG was measured using a solid phase “sandwich” immunoradiometric assay. To test potential associations between circulating levels of sex hormones and SHBG with the risk of developing colon cancer, conditional logistic regression models were applied to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Multivariable models were adjusted for colon cancer risk factors, including anthropometric parameters, alcohol consumption, physical activity and smoking status. In addition, models including estrone, estradiol and testosterone were adjusted for SHBG and vice versa. Preliminary results indicated an inverse association for testosterone (multivariable OR per SD: 0.80 95% CI: 0.69 - 0.93) and SHBG (multivariable OR per SD: 0.84 95% CI: 0.72 - 0.99) with CRC risk. However, after additional adjustments to SHBG and sex hormone models respectively these associations were attenuated towards the null. No associations were identified for estradiol, estrone, androstenedione, dehydroepiandrosterone, and progesterone. These preliminary results do not support an association between endogenous estrogen and colon cancer in men, while a potential association between testosterone and SHBG and colon cancer will need to be further evaluated. Citation Format: Justin Harbs, Sabina Rinaldi, Audrey Gicquiau, Xijia Liu, Marc Gunter, Bethany Van Guelpen, Neil Murphy, Sophia Harlid, Epic Network. Associations between circulating sex hormone levels and risk of colon cancer among men from six European countries [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-152.

In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma, however epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption and risk of melanoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multi-centre prospective study that enrolled over 500,000 participants aged 25-70 years from ten European countries in 1992-2000. Information on coffee and tea drinking was collected at baseline using validated country-specific dietary questionnaires. We used adjusted Cox proportional hazards regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between coffee and tea consumption and melanoma risk. Overall, 2,712 melanoma cases were identified during a median follow-up of 14.9 years among 476,160 study participants. Consumption of caffeinated coffee was inversely associated with melanoma risk among men (HR for highest quartile of consumption vs. non-consumers 0.31, 95% CI 0.14-0.69) but not among women (HR 0.96, 95% CI 0.62-1.47). There were no statistically significant associations between consumption of decaffeinated coffee or tea and the risk of melanoma among both men and women. The consumption of caffeinated coffee was inversely associated with melanoma risk among men in this large cohort study. Further investigations are warranted to confirm our findings and clarify the possible role of caffeine and other coffee compounds in reducing the risk of melanoma., In France, the E3N study was financially supported by the Mutuelle Générale de l'Education Nationale (MGEN), the European Community, the French League Against Cancer (LNCC); Gustave Roussy; and the French Institute of Health and Medical research (INSERM). EPIC-Greece was supported by the Hellenic Health Foundation. Support for EPIC Norfolk is from Medical Research Council UK and Cancer Research UK. EPIC-Italy was supported by the Italian Association for Cancer Research (AIRC).

Background Folate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear. Objective To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade. Design, setting, and participants A study was performed with a nested case–control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression. Outcome measurements and statistical analysis Incident PCa and subtype by stage and grade. Results and limitations Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02–1.26], ptrend = 0.018, for folate and 1.12 [95% CI, 1.01–1.25], ptrend = 0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity 0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation. Conclusions The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation. Patient summary Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease., Take Home Message Higher folate concentration was associated with an increased risk of high-grade disease that was not evident for low-grade disease. This finding suggests a possible role for folate in the progression of clinically relevant prostate cancer and warrants further investigation.

BACKGROUND: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. METHODS: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. RESULTS: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, Pheterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, Ptrend < .001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, Pheterogeneity = .08). CONCLUSIONS: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.

Inverse associations of coffee and/or tea in relation to hepatocellular carcinoma (HCC) risk have been consistently identified in studies conducted mostly in Asia where consumption patterns of such beverages differ from Europe. In the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 201 HCC cases among 486,799 men/women, after a median follow-up of 11 years. We calculated adjusted hazard ratios (HRs) for HCC incidence in relation to quintiles/categories of coffee/tea intakes. We found that increased coffee and tea intakes were consistently associated with lower HCC risk. The inverse associations were substantial, monotonic and statistically significant. Coffee consumers in the highest compared to the lowest quintile had lower HCC risk by 72% [HR: 0.28; 95% confidence intervals (CIs): 0.16-0.50, p-trend

Objective: To determine side effect profiles and cure rates of azithromycin compared with erythromycin in the treatment of chlamydial cervicitis complicating pregnancy. Methods: Pregnant patients with positive DNA antigen assays for Chlamydia trachomatis were randomized to either azithromycin, 1 g oral slurry in a single dose, or erythromycin, 500 mg every 6 hours for 7 days. Repeat assays were planned for 3 weeks after therapy. Side effects, compliance, and treatment efficacy were assessed. Results: One hundred six women were enrolled, and eighty-five women completed the protocol. Significantly fewer gastrointestinal side effects were noted in the azithromycin group than in the erythromycin group (11.9% versus 58.1%, P ≤ .01). Enhanced compliance was noted with azithromycin, because it was given in a single observed dose. Similar treatment efficacy was noted between azithromycin and erythromycin (88.1% versus 93.0%, P > .05). Conclusion: Compared with erythromycin, azithromycin is associated with significantly fewer gastrointestinal side effects in pregnancy. This association, along with the ease of administration and similar efficacy, suggests that azithromycin should be considered for the initial treatment of chlamydial cervicitis in pregnancy.

International audience; Epidemiologic studies examining the association between specific fatty acids and colorectal cancer (CRC) risk are inconclusive. We investigated the association between dietary estimates and plasma levels of individual and total saturated (SFA), monounsaturated (MUFA), industrial-processed trans (iTFA), and ruminant-sourced trans (rTFA) fatty acids, and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Baseline fatty acid intakes were estimated in 450 112 participants (6162 developed CRC, median follow-up = 15 years). In a nested case-control study, plasma phospholipid fatty acids were determined by gas chromatography in 433 colon cancer cases and 433 matched controls. Multivariable-adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed using Cox and conditional logistic regression, respectively. Dietary total SFA (highest vs lowest quintile, HRQ5vsQ1 = 0.80; 95%CI:0.69-0.92), myristic acid (HRQ5vsQ1 = 0.83, 95%CI:0.74-0.93) and palmitic acid (HRQ5vsQ1 = 0.81, 95%CI:0.70-0.93) were inversely associated with CRC risk. Plasma myristic acid was also inversely associated with colon cancer risk (highest vs lowest quartile, ORQ4vsQ1 = 0.51; 95%CI:0.32-0.83), whereas a borderline positive association was found for plasma stearic acid (ORQ4vsQ1 = 1.63; 95%CI:1.00-2.64). Dietary total MUFA was inversely associated with colon cancer (per 1-SD increment, HR1-SD = 0.92, 95%CI: 0.85-0.98), but not rectal cancer (HR1-SD = 1.04, 95%CI:0.95-1.15, Pheterogeneity = 0.027). Dietary iTFA, and particularly elaidic acid, was positively associated with rectal cancer (HR1-SD = 1.07, 95%CI:1.02-1.13). Our results suggest that total and individual saturated fatty acids and fatty acids of industrial origin may be relevant to the aetiology of CRC. Both dietary and plasma myristic acid levels were inversely associated with colon cancer risk, which warrants further investigation.

Background & Aims There is an unclear association between intake of fish and long-chain n-3 polyunsaturated fatty acids (n-3 LC-PUFAs) and colorectal cancer (CRC). We examined the association between fish consumption, dietary and circulating levels of n-3 LC-PUFAs, and ratio of n-6:n-3 LC-PUFA with CRC using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods Dietary intake of fish (total, fatty/oily, lean/white) and n-3 LC-PUFA were estimated by food frequency questionnaires given to 521,324 participants in the EPIC study; among these, 6291 individuals developed CRC (median follow up, 14.9 years). Levels of phospholipid LC-PUFA were measured by gas chromatography in plasma samples from a sub-group of 461 CRC cases and 461 matched individuals without CRC (controls). Multivariable Cox proportional hazards and conditional logistic regression models were used to calculate hazard ratios (HRs) and odds ratios (ORs), respectively, with 95% CIs. Results Total intake of fish (HR for quintile 5 vs 1, 0.88; 95% CI, 0.80–0.96; Ptrend = .005), fatty fish (HR for quintile 5 vs 1, 0.90; 95% CI, 0.82–0.98; Ptrend = .009), and lean fish (HR for quintile 5 vs 1, 0.91; 95% CI, 0.83–1.00; Ptrend = .016) were inversely associated with CRC incidence. Intake of total n-3 LC-PUFA (HR for quintile 5 vs 1, 0.86; 95% CI, 0.78–0.95; Ptrend = .010) was also associated with reduced risk of CRC, whereas dietary ratio of n-6:n-3 LC-PUFA was associated with increased risk of CRC (HR for quintile 5 vs 1, 1.31; 95% CI, 1.18–1.45; Ptrend < .001). Plasma levels of phospholipid n-3 LC-PUFA was not associated with overall CRC risk, but an inverse trend was observed for proximal compared with distal colon cancer (Pheterogeneity = .026). Conclusions In an analysis of dietary patterns of participants in the EPIC study, we found regular consumption of fish, at recommended levels, to be associated with a lower risk of CRC, possibly through exposure to n-3 LC-PUFA. Levels of n-3 LC-PUFA in plasma were not associated with CRC risk, but there may be differences in risk at different regions of the colon.