Impact of cumulative body mass index and cardiometabolic diseases on survival among patients with colorectal and breast cancer: a multi-centre cohort study

BACKGROUND: Body mass index (BMI) and cardiometabolic comorbidities such as cardiovascular disease and type 2 diabetes have been studied as negative prognostic factors in cancer survival, but possible dependencies in the mechanisms underlying these associations remain largely unexplored. We analysed these associations in colorectal and breast cancer patients. METHODS: Based on repeated BMI assessments of cancer-free participants from four European countries in the European Prospective Investigation into Cancer and nutrition (EPIC) study, individual BMI-trajectories reflecting predicted mean BMI between ages 20 to 50 years were estimated using a growth curve model. Participants with incident colorectal or breast cancer after the age of 50 years were included in the survival analysis to study the prognostic effect of mean BMI and cardiometabolic diseases (CMD) prior to cancer. CMD were defined as one or more chronic conditions among stroke, myocardial infarction, and type 2 diabetes. Hazard ratios (HRs) and confidence intervals (CIs) of mean BMI and CMD were derived using multivariable-adjusted Cox proportional hazard regression for mean BMI and CMD separately and both exposures combined, in subgroups of localised and advanced disease. RESULTS: In the total cohort of 159,045 participants, there were 1,045 and 1,620 eligible patients of colorectal and breast cancer. In colorectal cancer patients, a higher BMI (by 1 kg/m2) was associated with a 6% increase in risk of death (95% CI of HR: 1.02-1.10). The HR for CMD was 1.25 (95% CI: 0.97-1.61). The associations for both exposures were stronger in patients with localised colorectal cancer. In breast cancer patients, a higher BMI was associated with a 4% increase in risk of death (95% CI: 1.00-1.08). CMDs were associated with a 46% increase in risk of death (95% CI: 1.01-2.09). The estimates and CIs for BMI remained similar after adjustment for CMD and vice versa. CONCLUSIONS: Our results suggest that cumulative exposure to higher BMI during early to mid-adulthood was associated with poorer survival in patients with breast and colorectal cancer, independent of CMD prior to cancer diagnosis. The association between a CMD diagnosis prior to cancer and survival in patients with breast and colorectal cancer was independent of BMI

Nutrient-wide association study of 92 foods and nutrients and breast cancer risk

Background:&nbsp;Several dietary factors have been reported to be associated with risk of breast cancer, but to date, unequivocal evidence only exists for alcohol consumption. We sought to systematically assess the association between intake of 92 foods and nutrients and breast cancer risk using a nutrient-wide association study. Methods:&nbsp;Using data from 272,098 women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we assessed dietary intake of 92 foods and nutrients estimated by dietary questionnaires. Cox regression was used to quantify the association between each food/nutrient and risk of breast cancer. A false discovery rate (FDR) of 0.05 was used to select the set of foods and nutrients to be replicated in the independent Netherlands Cohort Study (NLCS). Results:&nbsp;Six foods and nutrients were identified as associated with risk of breast cancer in the EPIC study (10,979 cases). Higher intake of alcohol overall was associated with a higher risk of breast cancer (hazard ratio (HR) for a 1 SD increment in intake&thinsp;=&thinsp;1.05, 95% CI 1.03&ndash;1.07), as was beer/cider intake and wine intake (HRs per 1 SD increment&thinsp;=&thinsp;1.05, 95% CI 1.03&ndash;1.06 and 1.04, 95% CI 1.02&ndash;1.06, respectively), whereas higher intakes of fibre, apple/pear, and carbohydrates were associated with a lower risk of breast cancer (HRs per 1 SD increment&thinsp;=&thinsp;0.96, 95% CI 0.94&ndash;0.98; 0.96, 95% CI 0.94&ndash;0.99; and 0.96, 95% CI 0.95&ndash;0.98, respectively). When evaluated in the NLCS (2368 cases), estimates for each of these foods and nutrients were similar in magnitude and direction, with the exception of beer/cider intake, which was not associated with risk in the NLCS. Conclusions:&nbsp;Our findings confirm a positive association of alcohol consumption and suggest an inverse association of dietary fibre and possibly fruit intake with breast cancer risk.</p

Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition

BACKGROUND: Diet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: This analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons. RESULTS: Consumption of n-6 γ-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintile Q5-Q1=0.77, 95% CI = 0.64; 0.92, p trend=0.01, q-value = 0.15). This association was mainly driven by γ-linolenic acid derived from plant sources (HR per unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HR per unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 α-linolenic acid from vegetable sources and endometrial cancer risk (HR per unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk. CONCLUSION: Our results suggest that higher consumption of γ-linolenic acid and α-linoleic acid from plant sources may be associated with lower risk of endometrial cancer

The association between adult attained height and sitting height with mortality in the European prospective investigation into cancer and nutrition (EPIC)

Adult height and sitting height may reflect genetic and environmental factors, including early life nutrition, physical and social environments. Previous studies have reported divergent associations for height and chronic disease mortality, with positive associations observed for cancer mortality but inverse associations for circulatory disease mortality. Sitting height might be more strongly associated with insulin resistance; however, data on sitting height and mortality is sparse. Using the European Prospective Investigation into Cancer and Nutrition study, a prospective cohort of 409,748 individuals, we examined adult height and sitting height in relation to all-cause and cause-specific mortality. Height was measured in the majority of participants; sitting height was measured in ~253,000 participants. During an average of 12.5 years of follow-up, 29,810 deaths (11,931 from cancer and 7,346 from circulatory disease) were identified. Hazard ratios (HR) with 95% confidence intervals (CI) for death were calculated using multivariable Cox regression within quintiles of height. Height was positively associated with cancer mortality (men: HRQ5 vs. Q1=1.11, 95%CI=1.00-1.24; women: HRQ5 vs. Q1=1.17, 95%CI=1.07-1.28). In contrast, height was inversely associated with circulatory disease mortality (men: HRQ5 vs. Q1=0.63, 95%CI=0.56-0.71; women: HRQ5 vs. Q1=0.81, 95%CI=0.70-0.93). Although sitting height was not associated with cancer mortality, it was inversely associated with circulatory disease (men: HRQ5 vs. Q1=0.64, 95%CI=0.55-0.75; women: HRQ5 vs. Q1=0.60, 95%CI=0.49-0.74) and respiratory disease mortality (men: HRQ5 vs. Q1=0.45, 95%CI=0.28-0.71; women: HRQ5 vs. Q1=0.60, 95%CI=0.40-0.89). We observed opposing effects of height on cancer and circulatory disease mortality. Sitting height was inversely associated with circulatory disease and respiratory disease mortality

Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population

We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between pre-diagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested-case control study was conducted within the EPIC cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function and alpha-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95%CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable=1.30; 95%CI:1.14-1.48). The association was stronger among cases diagnosed within two years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC=0.86). For cases diagnosed within two years, the combination of OPN and AFP was best able to predict HCC risk (AUC=0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within two years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis

Association of Pre-diagnostic Antibody Responses to Escherichia coli and Bacteroides fragilis Toxin Proteins with Colorectal Cancer in a European Cohort

The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); the Sicilian Government, AIRE ONLUS Ragusa, AVIS Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), and Statistics Netherlands (the Netherlands); Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona), Spain; Swedish Cancer Society, Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (C864/A14136 to EPIC-Norfolk; C8221/A19170, C570/A16491 and C8221/ A290170 to EPIC-Oxford), Medical Research Council (MR/ N003284/1 and MC-UU_12015/1 to EPIC-Norfolk, MR/ M012190/1 to EPIC-Oxford (UK). The funding sources had no influence on the design of the study; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication.Support for this study was also provided by the COST Action CA17118 supported by COST (European Cooperation in Science and Technology, www.cost.eu) to DJH.Experimental evidence has implicated genotoxic Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of E. coli and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study. Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven E. coli proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to E. coli and ETBF with CRC. The IgA-positivity of any of the tested E. coli antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05–1.91). Dual-positivity for both IgA and IgG to E. coli and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (pheterogeneity = 0.095). Sero-positivity to E. coli and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups.European Commission (DG-SANCO)International Agency for Research on CancerDanish Cancer Society (Denmark)Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France)Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany)Hellenic Health Foundation (Greece)Sicilian Government, AIRE ONLUS Ragusa, AVIS Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, and National Research Council (Italy)Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), and Statistics Netherlands (the Netherlands)Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway)Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona), SpainSwedish Cancer Society, Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden)Cancer Research UK (C864/A14136 to EPIC-Norfolk; C8221/A19170, C570/A16491 and C8221/ A290170 to EPIC-Oxford), Medical Research Council (MR/ N003284/1 and MC-UU_12015/1 to EPIC-Norfolk, MR/ M012190/1 to EPIC-Oxford (UK)COST Action CA17118 supported by COST (European Cooperation in Science and Technology

Acrylamide and glycidamide hemoglobin adduct levels and endometrial cancer risk: A nested case-control study in nonsmoking postmenopausal women from the EPIC cohort

Acrylamide, classified in 1994 by IARC as “probably carcinogenic to humans,” was discovered in 2002 in some heat-treated, carbohydrate-rich foods. Four prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The purpose of this nested case-control study, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, was to evaluate, for the first time, the association between hemoglobin adducts of acrylamide (HbAA) and glycidamide (HbGA) and the risk of developing EC in non-smoking postmenopausal women. Hemoglobin adducts were measured in red blood cells by HPLC/MS/MS. Four exposure variables were evaluated: HbAA, HbGA, their sum (HbAA+HbGA), and their ratio (HbGA/HbAA). The association between hemoglobin adducts and EC was evaluated using unconditional multivariable logistic regression models, and included 383 EC cases (171 were type-I EC), and 385 controls. Exposure variables were analyzed in quintiles based on control distributions. None of the biomarker variables had an effect on overall EC (HRHbAA;Q5vsQ1: 0.84, 95%CI: 0.49–1.48; HRHbGA;Q5vsQ1: 0.94, 95%CI: 0.54–1.63) or type-I EC risk. Additionally, none of the subgroups investigated (BMI < 25 vs. ≥25 kg m−2, alcohol drinkers vs. never drinkers, oral contraceptive users vs. non-users) demonstrated effect measure modification. Hemoglobin adducts of acrylamide or glycidamide were not associated with EC or type-I EC risk in 768 nonsmoking postmenopausal women from the EPIC cohort

Causal effects of lifetime smoking on breast and colorectal cancer risk: Mendelian randomization study

International audienceBackground: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer. Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking (n ¼ 126 variants) and ever having smoked regularly (n ¼ 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/ 105,974 controls) and colorectal cancer (52,775 cases/45,940 controls). Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00–1.26; P ¼ 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor–positive and estrogen receptor–negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04–1.40; P ¼ 0.01), colon cancer (OR, 1.31; 95% CI, 1.11–1.55; P < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07–1.73; P ¼ 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90–1.14; P ¼ 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86–1.10; P ¼ 0.68). Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer. Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies

Mediation analysis of the alcohol‐postmenopausal breast cancer relationship by sex hormones in the EPIC cohort

Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex-hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol-consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol-related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor-positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1-standard deviation (1-SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol-related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1-SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol-BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association