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Background Classical anthropometric traits may fail to fully represent the relationship of weight, adiposity, and height with cancer risk. We investigated the associations of body shape phenotypes with the risk of overall and site-specific cancers. Methods We derived four distinct body shape phenotypes from principal component (PC) analysis on height, weight, body mass index (BMI), waist (WC) and hip circumferences (HC), and waist-to-hip ratio (WHR). The study included 340,152 men and women from 9 European countries, aged mostly 35–65 years at recruitment (1990–2000) in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results After a median follow-up of 15.3 years, 47,110 incident cancer cases were recorded. PC1 (overall adiposity) was positively associated with the risk of overall cancer, with a HR per 1 standard deviation (SD) increment equal to 1.07 (95% confidence interval 1.05 to 1.08). Positive associations were observed with 10 cancer types, with HRs (per 1 SD) ranging from 1.36 (1.30–1.42) for endometrial cancer to 1.08 (1.03–1.13) for rectal cancer. PC2 (tall stature with low WHR) was positively associated with the risk of overall cancer (1.03; 1.02–1.04) and five cancer types which were not associated with PC1. PC3 (tall stature with high WHR) was positively associated with the risk of overall cancer (1.04; 1.03–1.05) and 12 cancer types. PC4 (high BMI and weight with low WC and HC) was not associated with overall risk of cancer (1.00; 0.99–1.01). Conclusions In this multi-national study, distinct body shape phenotypes were positively associated with the incidence of 17 different cancers and overall cancer.

Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; Ptrend = .001), BCC (HR = 1.12, 95% CI = 1.01-1.23; Ptrend = .04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; Ptrend = .17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; Ptrend = .13; BCC: HR = 1.08, 95% CI = 1.00-1.17,Ptrend = .03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, Ptrend = .13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; Ptrend = .0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31;Ptrend = .14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer. What's new? Drinking alcohol can make the skin more sensitive to sunlight and vulnerable to skin cancer. Here, the authors conducted a large prospective cohort study to evaluate whether alcohol consumption correlates with skin cancer risk. Among the 450 112 participants, there were 2457 cases of melanoma, 8711 of basal cell carcinoma, and 1928 of squamous cell carcinoma. There was a positive association between alcohol and all three cancer types, stronger in men than in women. The association varied somewhat by beverage type.

Background Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. Methods We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses’ Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Results Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). Conclusions Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

PURPOSE Heart failure (HF) is a potentially life-threatening complication of treatment for childhood cancer. We evaluated the risk and risk factors for HF in a large European study of long-term survivors. Little is known of the effects of low doses of treatment, which is needed to improve current treatment protocols and surveillance guidelines. METHODS This study includes the PanCareSurFup and ProCardio cohort of ≥ 5-year childhood cancer survivors diagnosed between 1940 and 2009 in seven European countries (N = 42,361). We calculated the cumulative incidence of HF and conducted a nested case-control study to evaluate detailed treatment-related risk factors. RESULTS The cumulative incidence of HF was 2% (95% CI, 1.7 to 2.2) by age 50 years. The case-control study (n = 1,000) showed that survivors who received a mean heart radiation therapy (RT) dose of 5 to < 15 Gy have an increased risk of HF (odds ratio, 5.5; 95% CI, 2.5 to 12.3), when compared with no heart RT. The risk associated with doses 5 to < 15 Gy increased with exposure of a larger heart volume. In addition, the HF risk increased in a linear fashion with higher mean heart RT doses. Regarding total cumulative anthracycline dose, survivors who received ≥ 100 mg/m2 had a substantially increased risk of HF and survivors treated with a lower dose showed no significantly increased risk of HF. The dose-response relationship appeared quadratic with higher anthracycline doses. CONCLUSION Survivors who received a mean heart RT dose of ≥ 5 Gy have an increased risk of HF. The risk associated with RT increases with larger volumes exposed. Survivors treated with < 100 mg/m2 total cumulative anthracycline dose have no significantly increased risk of HF. These new findings might have consequences for new treatment protocols for children with cancer and for cardiomyopathy surveillance guidelines.

BACKGROUND: Epidemiological studies suggest that coffee consumption may be inversely associated with risk of endometrial cancer (EC), the most common gynecological malignancy in developed countries. Furthermore, coffee consumption may lower circulating levels of estrogen and insulin, hormones implicated in endometrial carcinogenesis. Antioxidants and other chemopreventive compounds in coffee may have anticarcinogenic effects. Based on available meta-analyses, the World Cancer Research Fund concluded that consumption of coffee probably protects against EC.OBJECTIVE: Our main aim was to examine the association between coffee consumption and EC risk by combining individual-level data in a pooled analysis. We also sought to evaluate potential effect modification by other risk factors of EC.PATIENTS AND METHODS: We combined individual-level data from 19 epidemiologic studies (6 cohort, 13 case-control) of 12,159 endometrial cancer cases and 27,479 controls from the Epidemiology of Endometrial Cancer Consortium (E2C2). Logistic regression was used to calculate odds ratios (OR) and their corresponding 95% confidence intervals (CI). All models were adjusted for potential confounders including age, race, body mass index, smoking status, diabetes status, study design and study site.RESULTS: Coffee drinkers had a lower risk of EC compared to non-coffee drinkers (multi-adjusted OR = 0.87, 95% CI = 0.79,0.95). There was a dose-response relationship between higher coffee consumption and lower risk of EC: compared to non-coffee drinkers, the adjusted pooled ORs for those who drank 1, 2-3 and more than 4 cups/day were 0.90 (95% CI = 0.82,1.00), 0.86 (95% CI = 0.78,0.95), and 0.76 (95% CI = 0.66,0.87), respectively (p for trend < 0.001). The inverse association between coffee consumption and EC risk was stronger in participants with body mass index (BMI) over 25 kg/m2.CONCLUSION: The results of the largest analysis to date pooling individual-level data further support the potentially beneficial health effects of coffee consumption in relation to EC, especially among females with higher BMI.

Peer reviewed: True, Funder: International Agency for Research on Cancer (IARC), Funder: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Funder: NIHR Imperial Biomedical Research Centre (BRC), Funder: Danish Cancer Society (Denmark), Funder: Ligue Contre le Cancer, Funder: Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Funder: Institut National de la Santé et de la Recherche Médicale (INSERM), Funder: German Cancer Aid, Funder: German Cancer Research Center (DKFZ), Funder: German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Funder: Federal Ministry of Education and Research (BMBF), Funder: Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Funder: Compagnia di San Paolo, Funder: National Research Council, Funder: Dutch Ministry of Public Health, Welfare and Sports (VWS), Funder: Netherlands Cancer Registry (NKR), Funder: LK Research Funds, Funder: Dutch Prevention Funds, Funder: Dutch ZON (Zorg Onderzoek Nederland), Funder: World Cancer Research Fund (WCRF), Funder: Statistics Netherlands, Funder: Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Funder: Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, Funder: Catalan Institute of Oncology—ICO, Funder: Swedish Cancer Society, Funder: Swedish Research Council, Funder: County Councils of Skåne and Västerbotten, Polyphenols are bioactive compounds from plants with antioxidant properties that may have a protective role against body weight gain, with adipose tissue and systemic oxidative stress as potential targets. We aimed to investigate the dietary intake of individual polyphenols and their association with 5-year body weight change in a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 349,165 adult participants from nine European countries. Polyphenol intake was estimated through country-specific validated dietary questionnaires and the Phenol-Explorer database. Body weight was obtained at recruitment and after a mean follow-up time of 5 years. Associations were estimated using multilevel mixed linear regression models. From 91 polyphenols included, the majority (n = 67) were inversely associated with 5-year body weight change after FDR-correction (q < 0.05). The greatest inverse associations were observed for quercetin 3-O-rhamnoside (change in weight for doubling in intake: -0.071 (95% CI: -0.085; -0.056) kg/5 years). Only 13 polyphenols showed positive associations with body weight gain, mainly from the subclass hydroxycinnamic acids (HCAs) with coffee as the main dietary source, such as 4-caffeoylquinic acid (0.029 (95% CI: 0.021; 0.038) kg/5 years). Individual polyphenols with fruit, tea, cocoa and whole grain cereals as the main dietary sources may contribute to body weight maintenance in adults. Individual HCAs may have different roles in body weight change depending on their dietary source.

BACKGROUND: The association between protein intake and prostate cancer risk remains unclear.AIMS: To prospectively investigate the associations of dietary intakes of total protein, protein from different dietary sources, and amino acids with prostate cancer risk and mortality.METHODS: In 131,425 men from the European Prospective Investigation into Cancer and Nutrition, protein and amino acid intakes were estimated using validated dietary questionnaires. Multivariable-adjusted Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).RESULTS: During a mean follow-up of 14.2 years, 6939 men were diagnosed with prostate cancer and 914 died of the disease. Dairy protein was positively associated with overall prostate cancer risk in the three highest fifths compared to the lowest (HR Q3 =1.14 (95% CI 1.05-1.23); HR Q 4=1.09 (1.01-1.18); HR Q5 =1.10 (1.02-1.19)); similar results were observed for yogurt protein (HR Q3 =1.14 (1.05-1.24); HR Q4 =1.09 (1.01-1.18); HR Q5 =1.12 (1.04-1.21)). For egg protein intake and prostate cancer mortality, no association was observed by fifths, but there was suggestive evidence of a positive association in the analysis per standard deviation increment. There was no strong evidence of associations with different tumour subtypes. DISCUSSION: Considering the weak associations and many tests, the results must be interpreted with caution.CONCLUSION: This study does not provide strong evidence for an association of intakes of total protein, protein from different dietary sources or amino acids with prostate cancer risk or mortality. However, our results may suggest some weak positive associations, which need to be confirmed in large-scale, pooled analyses of prospective data.

Despite high prices, many college students do not re-file the Free Application for Federal Student Aid (FAFSA) or file late, making college less affordable. Low-cost technological interventions delivering personalized information and/or advising may improve refiling and academic outcomes, but questions remain regarding the efficacy of this approach at scale. This multi-pronged randomized experiment tested informational and framing text message interventions for a national sample of approximately 10,000 undergraduates. The text outreach caused earlier FAFSA re-filing for some students. However, gains in re-filing during the active intervention period were not sustained after the intervention concluded and did not translate into additional federal financial aid or improved postsecondary persistence or attainment. Implications for the scaling and targeting of nudging are discussed.

PURPOSE Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation ( Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION To our knowledge, we demonstrate—for the first time—that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

Supplementary table 1. Correlations of sRANKL and the sRANKL/OPG ratio with select hormones among controls: EPIC cohort nested case-control study. Supplementary table 2. Distribution of covariates by quintiles of sRANKL. Supplementary table 3. Circulating concentrations of sRANKL and breast cancer risk by hormone-receptor subtype and menopausal status at blood collection. Supplementary table 4. The sRANKL/OPG ratio and breast cancer risk by hormone-receptor subtype and menopausal status at blood collection. Supplementary table 5. sRANKL additionally adjusted for continuous (log2) OPG and breast cancer risk by hormone-receptor subtype: EPIC nested case-control study. Supplementary table 6. sRANKL/OPG cross-classification based on median split of sRANKL and OPG and breast cancer risk by hormone-receptor subtype: EPIC nested case-control study.

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Perspective on This Article from Anthropometric Measures, Physical Activity, and Risk of Glioma and Meningioma in a Large Prospective Cohort Study

Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PR)] defined breast cancer. In a case–control study nested within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition), estradiol, testosterone, and sex hormone–binding globulin levels were measured in prediagnostic serum samples from postmenopausal women not using hormone replacement therapy at blood donation. A total of 554 women who developed invasive breast cancer with information on receptor status were matched with 821 control subjects. Conditional logistic regression models estimated breast cancer risk with hormone concentrations according to hormone receptor status of the tumor. Sex steroid hormones were associated with risks of not only ER+PR+ breast cancer [estradiol OR for highest vs. lowest tertile = 2.91 (95% CI: 1.62–5.23), Ptrend = 0.002; testosterone OR = 2.27 (95% CI: 1.35–3.81), Ptrend = 0.002] but also of ER-PR- breast cancer [estradiol OR = 2.11 (95% CI: 1.00–4.46), Ptrend = 0.05; testosterone OR = 2.06 (95% CI: 0.95–4.46), Ptrend = 0.03], with associations appearing somewhat stronger in the receptor-positive disease. Serum androgens and estrogens are associated with risks of both hormone receptor–negative as well as receptor–positive breast tumors. Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and -negative clinical breast tumors. Cancer Prev Res; 4(10); 1626–35. ©2011 AACR.

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As protection from COVID-19 following two doses of the BNT162b2 vaccine showed a time dependent waning, a third (booster) dose was administrated. This study aims to compare the antibody response following the third dose versus the second and to evaluate post-booster seroconversion.A prospective observational study conducted in Maccabi Healthcare Services. Serial SARS-CoV-2 Spike IgG tests, 1,2,3 and 6 months following the second vaccine dose and one month following the third were obtained. Neutralizing antibody levels were measured in a subset of participants. Per individual SARS-CoV-2 Spike IgG titer ratios were calculated one month after the booster administration compared to titers one month following the second dose and prior to booster.Among 110 participants,56 (51%) were women. Mean age was 61.7 ± 1.9 years and 66 (60%) were immunocompromised. One month after third dose, IgG titers were induced 7.83 (95 %CI 5.25-11.67) folds and 2.40 (95 %CI 1.90-3.03) folds compared to one month after the second, in the immunocompromised and immunocompetent groups, respectively. Of the 17 immunocompromised participants who were seronegative after the second dose, 4 (24%) became seropositive following the third. Comparing the titers prior to the third dose, an increase of 50.7 (95 %CI 32.5-79.1) fold in the immunocompromised group and 25.7 (95 %CI 19.1-34.7) fold in and immunocompetent group, was observed.A third BNT162b2 vaccine elicited robust humoral response, superior to the response observed following the second, among immunocompetent and immunocompromised individuals.

Aims This study aimed to evaluate the association between physical activity and the incidence of coronary heart disease (CHD) in individuals with and without CHD risk factors. Methods and results EPIC-CVD is a case-cohort study of 29 333 participants that included 13 582 incident CHD cases and a randomly selected sub-cohort nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Self-reported physical activity was summarized using the Cambridge physical activity index (inactive, moderately inactive, moderately active, and active). Participants were categorized into sub-groups based on the presence or the absence of the following risk factors: obesity (body mass index ≥30 kg/m2), hypercholesterolaemia (total cholesterol ≥6.2 mmol/L), history of diabetes, hypertension (self-reported or ≥140/90 mmHg), and current smoking. Prentice-weighted Cox regression was used to assess the association between physical activity and incident CHD events (non-fatal and fatal). Compared to inactive participants without the respective CHD risk factor (referent), excess CHD risk was highest in physically inactive and lowest in moderately active participants with CHD risk factors. Corresponding excess CHD risk estimates amongst those with obesity were 47% [95% confidence interval (CI) 32–64%] and 21% (95%CI 2–44%), with hypercholesterolaemia were 80% (95%CI 55–108%) and 48% (95%CI 22–81%), with hypertension were 80% (95%CI 65–96%) and 49% (95%CI 28–74%), with diabetes were 142% (95%CI 63–260%), and 100% (95%CI 32–204%), and amongst smokers were 152% (95%CI 122–186%) and 109% (95%CI 74–150%). Conclusions In people with CHD risk factors, moderate physical activity, equivalent to 40 mins of walking per day, attenuates but does not completely offset CHD risk.

There is existing evidence on the potential role of chronic inflammation in the pathogenesis of pancreatic cancer (PC) and on how risk may be modulated by dietary factors. Pro-inflammatory diets are suggested to be associated with increased risk of PC but, so far, evidence remains not conclusive. We examined the association between the dietary inflammatory potential and PC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which includes 450,112 participants.After a 14-year follow-up, a total of 1239 incident PC cases were included in this study. The inflammatory potential of the diet was estimated using an Inflammatory Score of the Diet (ISD). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between the ISD and PC were estimated using multivariable Cox regression models, adjusted for known risk factors for PC.Participants with higher ISDs had a higher risk of developing PCs. In the fully adjusted multivariate model, the risk of PC increased by 11% (HR 1.11, 95% CI 1.02-1.22) for 1 point each standard deviation increase in the ISD score. Neither obesity nor any other known risk factor for PC showed statistically significant interactions.To the best of our knowledge, this is the first prospective study reporting a positive relationship between the inflammatory potential of diet and PC. Since early diagnosis and treatment of pancreatic cancer might be challenging, prevention remains the major hope for reducing the burden of this disease.

Supplementary Table 1 from Eighteen Insulin-like Growth Factor Pathway Genes, Circulating Levels of IGF-I and Its Binding Protein, and Risk of Prostate and Breast Cancer

Data on the role of dietary factors in endometrial cancer development are limited and inconsistent. We applied a “nutrient-wide association study” approach to systematically evaluate dietary risk associations for endometrial cancer while controlling for multiple hypothesis tests using the false discovery rate (FDR) and validating the results in an independent cohort. We evaluated endometrial cancer risk associations for dietary intake of 84 foods and nutrients based on dietary questionnaires in three prospective studies, the European Prospective Investigation into Cancer and Nutrition (EPIC; N = 1,303 cases) followed by validation of nine foods/nutrients (FDR ≤ 0.10) in the Nurses' Health Studies (NHS/NHSII; N = 1,531 cases). Cox regression models were used to estimate HRs and 95% confidence intervals (CI). In multivariate adjusted comparisons of the extreme categories of intake at baseline, coffee was inversely associated with endometrial cancer risk (EPIC, median intake 750 g/day vs. 8.6; HR, 0.81; 95% CI, 0.68–0.97, Ptrend = 0.09; NHS/NHSII, median intake 1067 g/day vs. none; HR, 0.82; 95% CI, 0.70–0.96, Ptrend = 0.04). Eight other dietary factors that were associated with endometrial cancer risk in the EPIC study (total fat, monounsaturated fat, carbohydrates, phosphorus, butter, yogurt, cheese, and potatoes) were not confirmed in the NHS/NHSII. Our findings suggest that coffee intake may be inversely associated with endometrial cancer risk. Further data are needed to confirm these findings and to examine the mechanisms linking coffee intake to endometrial cancer risk to develop improved prevention strategies. Cancer Epidemiol Biomarkers Prev; 24(2); 466–71. ©2015 AACR.

Background: Experimental and epidemiologic data suggest that higher circulating prolactin is associated with breast cancer risk; however, how various risk factors for breast cancer influence prolactin levels in healthy women is not clear.Methods: We analyzed cross-sectional associations between several suggested reproductive and lifestyle risk factors for breast cancer and circulating prolactin among pre- and postmenopausal women, taking into account the use of current postmenopausal hormone therapy, among 2,560 controls from a breast cancer nested case–control study within the EPIC cohort.Results: Adjusted geometric mean prolactin levels were significantly higher among premenopausal women, and among postmenopausal women using hormone therapy compared with nonusers (8.2, 7.0, and 6.3 ng/mL, respectively; Pcat = Pcat = 0.001). Prolactin levels were lower among parous women compared with nulliparous women (8.61 vs. 10.95 ng/mL; Pcat = 0.0002, premenopausal women); the magnitude of this difference depended on the number of full-term pregnancies (22.1% lower, ≥3 vs. 1 pregnancy, Ptrend = 0.01). Results for parity were similar but lower in magnitude among postmenopausal women. Prolactin did not vary by other studied factors, with the exception of lower levels among postmenopausal smokers compared with never smokers.Conclusions: Our study shows that current hormone therapy use, especially the use of combined hormone therapy, is associated with higher circulating prolactin levels in postmenopausal women, and confirms prior findings of lower circulating prolactin in parous women.Impact: Our study extends the knowledge linking various breast cancer risk factors with circulating prolactin. Cancer Epidemiol Biomarkers Prev; 23(11); 2532–42. ©2014 AACR.

Supplementary Table S2. TL quartiles and OS association analysis (Crude Cox regression).

Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer–related dysregulation of CDCP1 expression years before diagnosis.Significance:Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms.See related commentary by Itzstein et al., p. 3441.

Supplemental tables 1 and 2. Supplementary Table 1. Odds ratios (95% CI) for ovarian cancer by tertile concentrations and for doubling in CRP and IL-6 by menopausal status, age at diagnosis and HRT use at blood donation. Supplementary Table 2. Odds ratios (95% CI) for ovarian cancer for doubling in CRP and IL-6 by BMI categories and waist circumference, mutual adjusted for IL-6 and CRP.

Supplementary Figure S1. Kaplan-Meier OS curves of bladder cancer patients stratified for TL quartiles. OS, overall survival; TL, telomere length.

Supplementary Table S1. Adjusteda geometric mean prolactin levels, ng/ml (95% CI) by established correlates at the time of blood donation. Supplementary Table S2. Adjusteda geometric mean prolactin levels, ng/ml (95% CI) depending on the anthropometric factors. Supplementary Table S3. Adjusteda geometric mean prolactin levels, ng/ml (95% CI) depending on the lifestyle factors.

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Supplemental Material and Methods, Tables S1-S6, Figure S1 Supplemental Table S1. Hazard Ratiosa and 95% CIs from analyses of nutrient and food intakes (FDR≤0.10) reported in the baseline dietary assessment in relation to endometrial cancer risk in the EPIC study. Supplemental Table S2. Hazard Ratiosa and 95% CIs from analyses of intake of nutrients/foods at baseline (FDR > 0.10) in relation to endometrial cancer risk in the EPIC study. Supplemental Table S3. Age-standardized dietary intake of selected foods/nutrients (FDR≤0.10 in the EPIC studya) at the study baseline in the EPIC, NHS and NHSII study populations. Supplemental Table S4. Hazard Ratiosa and 95% CIs from analyses of intake of selected nutrients/foods at baseline in relation to endometrial cancer risk in the Nurses’ Health Study (NHS) and NHSII. Supplemental Table S5. Hazard Ratiosa and 95% CIs from analyses of the cumulative average intake of selected nutrients/foods in relation to endometrial cancer risk in the Nurses’ Health Study (NHS) and NHSII. Supplemental Table S6. Hazard Ratiosa and 95% CIs from analyses of the cumulative average intake of selected nutrients/foods in relation to invasive endometrial adenocarcinoma risk in the Nurses’ Health Study (NHS) and NHSII. Supplemental Figure S1. Summary of NWAS analytical method to test associations between food and nutrient intake and risk of endometrial cancer (EC.

Backgrounds: Multiple polymorphisms affecting smoking behavior have been identified through genome-wide association studies. Circulating levels of the nicotine metabolite cotinine is a marker of recent smoking exposure. Hence, genetic variants influencing smoking behavior are expected to be associated with cotinine levels.Methods: We conducted an analysis in a lung cancer case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We investigated the effects of single-nucleotide polymorphisms (SNP) previously associated with smoking behavior on (i) circulating cotinine and (ii) lung cancer risk. A total of 894 cases and 1,805 controls were analyzed for cotinine and genotyped for 10 polymorphisms on 7p14, 8p11, 10q23, 15q25, and 19q13.Results: Two variants in the nicotinic acetylcholine receptor subunit genes CHRNA5 and CHRNA3 on 15q25, rs16969968 and rs578776, were associated with cotinine (P = 0.001 and 0.03, respectively) in current smokers and with lung cancer risk (P < 0.001 and P = 0.001, respectively). Two 19q13 variants, rs7937 and rs4105144, were associated with increased cotinine (P = 0.003 and P < 0.001, respectively) but decreased lung cancer risk (P = 0.01 for both, after adjusting for cotinine). Variants in 7p14, 8p11, and 10q23 were not associated with cotinine or lung cancer risk.Conclusions: 15q25 and 19q13 SNPs were associated with circulating cotinine. The directions of association for 15q25 variants with cotinine were in accordance with that expected of lung cancer risk, whereas SNPs on 19q13 displayed contrasting associations of cotinine and lung cancer that require further investigation.Impact: This study is the largest to date investigating the effects of polymorphisms affecting smoking behavior on lung cancer risk using circulating cotinine measures as proxies for recent smoking behavior. Cancer Epidemiol Biomarkers Prev; 20(10); 2250–61. ©2011 AACR.

Background: Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins.Methods: We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium.Results: After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 × 10−4); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R2 = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers.Conclusion: Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women.Impact: Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes. Cancer Epidemiol Biomarkers Prev; 19(11); 2877–87. ©2010 AACR.

Supplementary Table S3. Multivariate Cox regression survival analysis, including TL, age, TG, BCG, radical cystectomy, radiotherapy and chemotherapy. All cause of death.

Supplementary Table S1. Description of populations included and not included in the TL study and comparative analysis.

Supplementary Methods, Figures and Tables.

Background: Evidence suggests an etiologic role for inflammation in ovarian carcinogenesis and heterogeneity between tumor subtypes and anthropometric indices. Prospective studies on circulating inflammatory markers and epithelial invasive ovarian cancer (EOC) have predominantly investigated overall risk; data characterizing risk by tumor characteristics (histology, grade, stage, dualistic model of ovarian carcinogenesis) and anthropometric indices are sparse.Methods: We conducted a nested case–control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate C-reactive protein (CRP), IL6, and EOC risk by tumor characteristics. A total of 754 eligible EOC cases were identified; two controls (n = 1,497) were matched per case. We used multivariable conditional logistic regression to assess associations.Results: CRP and IL6 were not associated with overall EOC risk. However, consistent with prior research, CRP >10 versus CRP ≤1 mg/L was associated with higher overall EOC risk [OR, 1.67 (1.03–2.70)]. We did not observe significant associations or heterogeneity in analyses by tumor characteristics. In analyses stratified by waist circumference, inflammatory markers were associated with higher risk among women with higher waist circumference; no association was observed for women with normal waist circumference [e.g., IL6: waist ≤80: ORlog2, 0.97 (0.81–1.16); waist >88: ORlog2, 1.78 (1.28–2.48), Pheterogeneity ≤ 0.01].Conclusions: Our data suggest that high CRP is associated with increased risk of overall EOC, and that IL6 and CRP may be associated with EOC risk among women with higher adiposity.Impact: Our data add to global evidence that ovarian carcinogenesis may be promoted by an inflammatory milieu. Cancer Epidemiol Biomarkers Prev; 24(6); 951–61. ©2015 AACR.

Background: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival.Methods: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years.Results: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non–muscle-invasive tumor/high-grade and with non–muscle-invasive tumor/non–high-grade (TL reference 0.7 ± 0.2; vs. respectively, 0.8 ± 0.2, P = 3.4 × 10−2 and 0.8 ± 0.2, P = 3.6 × 10−2). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 × 10−4). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Guérin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7–9.1; P = 1.2 × 10−3).Conclusions: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade.Impact: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2439–46. ©2014 AACR.

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01–1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01–1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00–1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. [Cancer Res 2009;69(17):6857–64]

Supplementary Tables 1-8 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Supplementary Figure Legend from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Supplementary Figure 1 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Background Breast Cancer (BC) is a leading public-health issue affecting women on a global scale, accounting for about 500,000 new cases every year in Europe. Thanks to the widespread implementation of screening programs and the improvement in therapies, women with BC live longer but they also are more likely to experience an increased risk of other diseases, including second primary cancer, cardiovascular, and metabolic diseases. Reasons for this increased risk include genetics, shared risk factors, and adverse effects from BC treatment. Methods To analyse the risk of myocardial infarction (MI) and stroke in women with BC considering the potential side effects of treatments, we used data from the Piedmont Longitudinal Study, an administrative cohort based on the record-linkage among census data and several health-administrative databases to include than 4 million inhabitants of an Italian region. Results Among 1,342,333 women ranging from 30 to 75 years old 19,203 had a BC diagnosis in the follow-up period, of whom 206 experienced a subsequent MI and 203 a stroke. Women with BC showed an increased risk for MI (HR: 1.20; 95%CI: 1.05–1.38) and for stroke (HR: 1.58; 95%CI: 1.38–1.82). Chemotherapy seemed to be the major risk factor for MI in BC women, while no different risk by therapy was found for stroke. Conclusion The results of this study supported the hypothesis about the toxic effect of therapies, suggesting both clinicians to routinely and actively screen for these treatment-related toxicities in women with BC and researchers to prioritize personalized treatments in order to minimize potentially devastating side effects.

Introdução: Mulheres com autoimagem genital negativa podem apresentar disfunções sexuais (DS). Ainda, as DS podem estar relacionadas a desconfortos no assoalho pélvico. Objetivo: Investigar a relação entre autoimagem genital, função sexual e desconforto no assoalho pélvico em mulheres jovens universitárias. Métodos: Estudo observacional e transversal com 102 acadêmicas de graduação e pós-graduação entre 18 a 29 anos, sexualmente ativas. Foram aplicadas uma ficha de identificação, os questionários Female Sexual Function Index (FSFI), Pelvic Floor Distress Inventory (PFDI-SF-20) e Female Genital Self-Image Scale (FGSIS). Resultados: O escore total do FGSIS indicou autoimagem genital positiva, FSFI boa função sexual e o PFDI-20 desconforto no assoalho pélvico baixo. Observou-se relação positiva entre autoimagem genital e função sexual e relação inversa com o desconforto no assoalho pélvico. Conclusão: As mulheres apresentaram autoimagem genital positiva, boa função sexual e baixo desconforto no assoalho pélvico, e as variáveis se relacionavam entre si.

Background: Evidence is accumulating that immune cells play a prominent role in pancreatic cancer etiology but prospective investigations are missing. Methods: We conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study with 502 pairs of incident pancreatic cancer cases and matched controls. Relative counts of circulating immune cells (neutrophils and lymphocyte sublineages: total CD3+, CD8+, CD4+, and FOXP3+ regulatory T cells (Tregs) relative to nucleated cells, (white blood cells) were measured by qRT-PCR. ORs with 95% confidence intervals were estimated using logistic regressions, modeling relative counts of immune cells on a continuous scale. Results: Neither relative counts of immune cell types taken individually, nor mutually adjusted for each other were associated with pancreatic cancer risks. However, in subgroup analyses by strata of lag-time, higher relative counts of Tregs and lower relative counts of CD8+ were significantly associated with an increased pancreatic cancer risks in participants diagnosed within the first 5 years of follow-up. Conclusions: These results might reflect reverse causation, due to higher relative counts of Tregs and lower counts of CD8+ cells among individuals with more advanced stages of latent pancreatic cancer, who are closer to the point of developing clinical manifest disease. Impact: We have shown, for the first time, that increased relative counts of regulatory T cells and lower relative counts of CD8+, cytotoxic T cells may be associated with pancreatic cancer risk or relatively late-stage tumor development. See related commentary by Michaud and Kelsey, p. 2176

The objective of this article was to assess the cost-effectiveness of screening strategies for cardiovascular diseases (CVD). A decision analytic model was constructed to estimate the costs and benefits of one-off screening strategies differentiated by screening age, sex and the threshold for initiating statin therapy ("uniform" or "age-adjusted") from the Spanish NHS perspective. The age-adjusted thresholds were configured so that the same number of people at high risk would be treated as under the uniform threshold. Health benefit was measured in quality-adjusted life years (QALY). Transition rates were estimated from the European Prospective Investigation into Cancer and Nutrition (EPIC-CVD), a large multicentre nested case-cohort study with 12 years of follow-up. Unit costs of primary care, hospitalizations and CVD care were taken from the Spanish health system. Univariate and probabilistic sensitivity analyses were employed. The comparator was no systematic screening program. The base case model showed that the most efficient one-off strategy is to screen both men and women at 40 years old using a uniform risk threshold for initiating statin treatment (Incremental Cost-Effectiveness Ratio of €3,274/QALY and €6,085/QALY for men and women, respectively). Re-allocating statin treatment towards younger individuals at high risk for their age and sex would not offset the benefit obtained using those same resources to treat older individuals. Results are sensitive to assumptions about CVD incidence rates. To conclude, one-off screening for CVD using a uniform risk threshold appears cost-effective compared with no systematic screening. These results should be evaluated in clinical studies.

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

For an $${\text {L}}_2$$ -bounded martingale starting at 0 and having final variance $$\sigma ^2$$ , the expected local time at $$a \in \text {R}$$ is at most $$\sqrt{\sigma ^2+a^2}-|a|$$ . This sharp bound is attained by Standard Brownian Motion stopped at the first exit time from the interval $$(a-\sqrt{\sigma ^2+a^2},a+\sqrt{\sigma ^2+a^2})$$ . In particular, the maximal expected local time anywhere is at most $$\sigma $$ , and this bound is sharp. Sharp bounds for the expected maximum, maximal absolute value, maximal diameter and maximal number of upcrossings of intervals have been established by Dubins and Schwarz (Societe Mathematique de France, Asterisque 157(8), 129–145 1988), by Dubins et al. (Ann Probab 37(1), 393–402 2009) and by the authors (2018).

Background DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer. Methods Using data from four prospective case–control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage. Results None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath ‘age acceleration’ (AA): OR per SD = 1.02, 95%CI: 0.95–1.10; AA-Hannum: OR = 1.03, 95%CI:0.95–1.12; PhenoAge: OR = 1.01, 95%CI: 0.94–1.09 and GrimAge: OR = 1.03, 95%CI: 0.94–1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01–1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics. Conclusion We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.

Review question / Objective: What is the potential role of microRNAs as biomarkers of colorectal cancer. Eligibility criteria: Studies were considered eligible for the systematic review if they met the following criteria: 1) study patients have been diagnosed with CRC; 2) healthy individuals were used as controls; 3) biological samples were plasma or serum or blood; 4) results included any of AUC, sensitivity, and specificity and/or fold change values. Studies were excluded if they were: 1) reviews, meta-analyses, conference abstracts, letters; 2) animals or cells experiments; 3) studies that investigated prognosis, survival, or metastatic cancers only; 4) studies that investigated toxicity or therapy efficacy; 5) studies with insufficient data; 6) studies not published in English language.