• Added Value of Serum Hormone Measurements in Risk Prediction Models for Breast Cancer for Women Not Using Exogenous Hormones: Results from the EPIC Cohort.

      Hüsing, Anika; Fortner, Renée T; Kühn, Tilman; Overvad, Kim; Tjønneland, Anne; Olsen, Anja; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Fournier, Agnes; Boeing, Heiner; Trichopoulou, Antonia; Benetou, Vassiliki; Orfanos, Philippos; Masala, Giovanna; Pala, Valeria; Tumino, Rosario; Fasanelli, Francesca; Panico, Salvatore; Bueno de Mesquita, H Bas; Peeters, Petra H; van Gills, Carla H; Quirós, J Ramón; Agudo, Antonio; Sánchez, Maria-Jose; Chirlaque, Maria-Dolores; Barricarte, Aurelio; Amiano, Pilar; Khaw, Kay-Tee; Travis, Ruth C; Dossus, Laure; Li, Kuanrong; Ferrari, Pietro; Merritt, Melissa A; Tzoulaki, Ioanna; Riboli, Elio; Kaaks, Rudolf (2017-08-01)
      Purpose: Circulating hormone concentrations are associated with breast cancer risk, with well-established associations for postmenopausal women. Biomarkers may represent minimally invasive measures to improve risk prediction models.Experimental Design: We evaluated improvements in discrimination gained by adding serum biomarker concentrations to risk estimates derived from risk prediction models developed by Gail and colleagues and Pfeiffer and colleagues using a nested case-control study within the EPIC cohort, including 1,217 breast cancer cases and 1,976 matched controls. Participants were pre- or postmenopausal at blood collection. Circulating sex steroids, prolactin, insulin-like growth factor (IGF) I, IGF-binding protein 3, and sex hormone-binding globulin (SHBG) were evaluated using backward elimination separately in women pre- and postmenopausal at blood collection. Improvement in discrimination was evaluated as the change in concordance statistic (C-statistic) from a modified Gail or Pfeiffer risk score alone versus models, including the biomarkers and risk score. Internal validation with bootstrapping (1,000-fold) was used to adjust for overfitting.Results: Among women postmenopausal at blood collection, estradiol, testosterone, and SHBG were selected into the prediction models. For breast cancer overall, model discrimination after including biomarkers was 5.3 percentage points higher than the modified Gail model alone, and 3.4 percentage points higher than the Pfeiffer model alone, after accounting for overfitting. Discrimination was more markedly improved for estrogen receptor-positive disease (percentage point change in C-statistic: 7.2, Gail; 4.8, Pfeiffer). We observed no improvement in discrimination among women premenopausal at blood collection.Conclusions: Integration of hormone measurements in clinical risk prediction models may represent a strategy to improve breast cancer risk stratification. Clin Cancer Res; 23(15); 4181-9. ©2017 AACR.
    • Anthropometry, physical activity, and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition.

      Berrington de González, Amy; Spencer, Elizabeth A; Bueno-de-Mesquita, H Bas; Roddam, Andrew; Stolzenberg-Solomon, Rachel; Halkjaer, Jytte; Tjønneland, Anne; Overvad, Kim; Clavel-Chapelon, Francoise; Boutron-Ruault, Marie-Christine; Boeing, Heiner; Pischon, Tobias; Linseisen, Jakob; Rohrmann, Sabine; Trichopoulou, Antonia; Benetou, Vassiliki; Papadimitriou, Aristoteles; Pala, Valeria; Palli, Domenico; Panico, Salvatore; Tumino, Rosario; Vineis, Paolo; Boshuizen, Hendriek C; Ocké, Marga C; Peeters, Petra H; Lund, Eiliv; Gonzalez, Carlos A; Larrañaga, Nerea; Martinez-Garcia, Carmen; Mendez, Michelle; Navarro, Carmen; Quirós, J Ramón; Tormo, María-José; Hallmans, Göran; Ye, Weimin; Bingham, Sheila A; Khaw, Kay-Tee; Allen, Naomi; Key, Tim J; Jenab, Mazda; Norat, Teresa; Ferrari, Pietro; Riboli, Elio (2006-05-01)
      Tobacco smoking is the only established risk factor for pancreatic cancer. Results from several epidemiologic studies have suggested that increased body mass index and/or lack of physical activity may be associated with an increased risk of this disease. We examined the relationship between anthropometry and physical activity recorded at baseline and the risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition (n = 438,405 males and females age 19-84 years and followed for a total of 2,826,070 person-years). Relative risks (RR) were calculated using Cox proportional hazards models stratified by age, sex, and country and adjusted for smoking and self-reported diabetes and, where appropriate, height. In total, there were 324 incident cases of pancreatic cancer diagnosed in the cohort over an average of 6 years of follow-up. There was evidence that the RR of pancreatic cancer was associated with increased height [RR, 1.74; 95% confidence interval (95% CI), 1.20-2.52] for highest quartile compared with lowest quartile (P(trend) = 0.001). However, this trend was primarily due to a low risk in the lowest quartile, as when this group was excluded, the trend was no longer statistically significant (P = 0.27). A larger waist-to-hip ratio and waist circumference were both associated with an increased risk of developing the disease (RR per 0.1, 1.24; 95% CI, 1.04-1.48; P(trend) = 0.02 and RR per 10 cm, 1.13; 95% CI, 1.01-1.26; P(trend) = 0.03, respectively). There was a nonsignificant increased risk of pancreatic cancer with increasing body mass index (RR, 1.09; 95% CI, 0.95-1.24 per 5 kg/m(2)), and a nonsignificant decreased risk with total physical activity (RR, 0.82; 95% CI, 0.50-1.35 for most active versus inactive). Future studies should consider including measurements of waist and hip circumference, to further investigate the relationship between central adiposity and the risk of pancreatic cancer.
    • Circulating RANKL and RANKL/OPG and Breast Cancer Risk by ER and PR Subtype: Results from the EPIC Cohort.

      Sarink, Danja; Schock, Helena; Johnson, Theron; Overvad, Kim; Holm, Marianne; Tjønneland, Anne; Boutron-Ruault, Marie-Christine; His, Mathilde; Kvaskoff, Marina; Boeing, Heiner; Lagiou, Pagona; Papatesta, Eleni-Maria; Trichopoulou, Antonia; Palli, Domenico; Pala, Valeria; Mattiello, Amalia; Tumino, Rosario; Sacerdote, Carlotta; Bueno-de-Mesquita, H B As; van Gils, Carla H; Peeters, Petra H; Weiderpass, Elisabete; Agudo, Antonio; Sánchez, Maria-José; Chirlaque, Maria-Dolores; Ardanaz, Eva; Amiano, Pilar; Khaw, Kay Tee; Travis, Ruth; Dossus, Laure; Gunter, Mark; Rinaldi, Sabina; Merritt, Melissa; Riboli, Elio; Kaaks, Rudolf; Fortner, Renée T (2017-09)
      Receptor activator of nuclear factor-kappa B (RANK)-RANK ligand (RANKL) signaling promotes mammary tumor development in experimental models. Circulating concentrations of soluble RANKL (sRANKL) may influence breast cancer risk via activation of RANK signaling; this may be modulated by osteoprotegerin (OPG), the decoy receptor for RANKL. sRANKL and breast cancer risk by hormone receptor subtype has not previously been investigated. A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. This study included 1,976 incident invasive breast cancer cases [estrogen receptor positive (ER+),n= 1,598], matched 1:1 to controls. Women were pre- or postmenopausal at blood collection. Serum sRANKL was quantified using an ELISA, serum OPG using an electrochemiluminescent assay. Risk ratios (RR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status (Phet= 0.05). Higher concentrations of sRANKL were positively associated with risk of ER+ breast cancer [5th vs. 1st quintile RR 1.28 (95% CI, 1.01-1.63);Ptrend= 0.20], but not ER- disease. For both ER+ and estrogen and progesterone receptor positive (ER+PR+) breast cancer, results considering the sRANKL/OPG ratio were similar to those for sRANKL; we observed a suggestive inverse association between the ratio and ER-PR- disease [5th vs. 1st quintile RR = 0.60 (0.31-1.14);Ptrend= 0.03]. This study provides the first large-scale prospective data on circulating sRANKL and breast cancer. We observed limited evidence for an association between sRANKL and breast cancer risk.Cancer Prev Res; 10(9); 525-34. ©2017 AACR.
    • Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies.

      Smith, Todd; Muller, David C; Moons, Karel G M; Cross, Amanda J; Johansson, Mattias; Ferrari, Pietro; Fagherazzi, Guy; Peeters, Petra H M; Severi, Gianluca; Hüsing, Anika; Kaaks, Rudolf; Tjonneland, Anne; Olsen, Anja; Overvad, Kim; Bonet, Catalina; Rodriguez-Barranco, Miguel; Huerta, Jose Maria; Barricarte Gurrea, Aurelio; Bradbury, Kathryn E; Trichopoulou, Antonia; Bamia, Christina; Orfanos, Philippos; Palli, Domenico; Pala, Valeria; Vineis, Paolo; Bueno-de-Mesquita, Bas; Ohlsson, Bodil; Harlid, Sophia; Van Guelpen, Bethany; Skeie, Guri; Weiderpass, Elisabete; Jenab, Mazda; Murphy, Neil; Riboli, Elio; Gunter, Marc J; Aleksandrova, Krasimira Jekova; Tzoulaki, Ioanna (2018-04-03)
      To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts.
    • Dairy Product Intake and Risk of Type 2 Diabetes in EPIC-InterAct: A Mendelian Randomization Study.

      Vissers, Linda E T; Sluijs, Ivonne; van der Schouw, Yvonne T; Forouhi, Nita G; Imamura, Fumiaki; Burgess, Stephen; Barricarte, Aurelio; Boeing, Heiner; Bonet, Catalina; Chirlaque, Maria-Dolores; Fagherazzi, Guy; Franks, Paul W; Freisling, Heinz; Gunter, Marc J; Quirós, J Ramón; Ibsen, Daniel B; Kaaks, Rudolf; Key, Timothy; Khaw, Kay T; Kühn, Tilman; Mokoroa, Olatz; Nilsson, Peter M; Overvad, Kim; Pala, Valeria; Palli, Domenico; Panico, Salvatore; Sacerdote, Carlotta; Spijkerman, Annemieke M W; Tjonneland, Anne; Tumino, Rosario; Rodríguez-Barranco, Miguel; Rolandsson, Olov; Riboli, Elio; Sharp, Stephen J; Langenberg, Claudia; Wareham, Nicholas J (2019-02-06)
      To estimate the causal association between intake of dairy products and incident type 2 diabetes. The analysis included 21,820 European individuals (9,686 diabetes cases) of the EPIC-InterAct case-cohort study. Participants were genotyped, and rs4988235 (LCT-12910C>T), a SNP for lactase persistence (LP) which enables digestion of dairy sugar, i.e., lactose, was imputed. Baseline dietary intakes were assessed with diet questionnaires. We investigated the associations between imputed SNP dosage for rs4988235 and intake of dairy products and other foods through linear regression. Mendelian randomization (MR) estimates for the milk-diabetes relationship were obtained through a two-stage least squares regression. Each additional LP allele was associated with a higher intake of milk (β 17.1 g/day, 95% CI 10.6-23.6) and milk beverages (β 2.8 g/day, 95% CI 1.0-4.5) but not with intake of other dairy products. Other dietary intakes associated with rs4988235 included fruits (β -7.0 g/day, 95% CI -12.4 to -1.7 per additional LP allele), nonalcoholic beverages (β -18.0 g/day, 95% CI -34.4 to -1.6), and wine (β -4.8 g/day, 95% CI -9.1 to -0.6). In instrumental variable analysis, LP-associated milk intake was not associated with diabetes (hazard ratio 0.99 rs4988235 was associated with milk intake but not with intake of other dairy products. This MR study does not suggest that milk intake is associated with diabetes, which is consistent with previous observational and genetic associations. LP may be associated with intake of other foods as well, but owing to the modest associations we consider it unlikely that this has caused the observed null result.
    • Dietary folate intake and pancreatic cancer risk: Results from the European Prospective Investigation into Cancer and Nutrition.

      Park, Jin Young; Bueno-de-Mesquita, H Bas; Ferrari, Pietro; Weiderpass, Elisabete; de Batlle, Jordi; Tjønneland, Anne; Kyro, Cecilie; Rebours, Vinciane; Boutron-Ruault, Marie-Christine; Mancini, Francesca Romana; Katzke, Verena; Kühn, Tilman; Boeing, Heiner; Trichopoulou, Antonia; La Vecchia, Carlo; Kritikou, Maria; Masala, Giovanna; Pala, Valeria; Tumino, Rosario; Panico, Salvatore; Peeters, Petra H; Skeie, Guri; Merino, Susana; Duell, Eric J; Rodríguez-Barranco, Miguel; Dorronsoro, Miren; Chirlaque, Maria-Dolores; Ardanaz, Eva; Gylling, Björn; Schneede, Jörn; Ericson, Ulrika; Sternby, Hanna; Khaw, Kay-Tee; Bradbury, Kathryn E; Huybrechts, Inge; Aune, Dagfinn; Vineis, Paolo; Slimani, Nadia (2018-09-04)
      Pancreatic cancer (PC) has an exceptionally low survival rate and primary prevention strategies are limited. Folate plays an important role in one-carbon metabolism and has been associated with the risk of several cancers, but not consistently with PC risk. We aimed to investigate the association between dietary folate intake and PC risk, using the standardised folate database across 10 European countries. A total of 477,206 participants were followed up for 11 years, during which 865 incident primary PC cases were recorded. Folate intake was energy-adjusted using the residual method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In multivariable analyses stratified by age, sex, study centre and adjusted for energy intake, smoking status, BMI, educational level, diabetes status, supplement use and dietary fibre intake, we found no significant association between folate intake and PC risk: the HR of PC risk for those in the highest quartile of folate intake (≥353 μg/d) compared with the lowest (<241 μg/d) was 0.81 (95% CI: 0.51, 1.31; Ptrend = 0.38). In current smokers, a positive trend was observed in PC risk across folate quartiles (HR=4.42 (95% CI: 1.05, 18.62) for ≥353 μg/d vs. <241 μg/d, Ptrend = 0.01). Nonetheless, there was no significant interaction between smoking and dietary folate intake (Pinteraction = 0.99). We found no association between dietary folate intake and PC risk in this large European study. This article is protected by copyright. All rights reserved.
    • Dietary intake of different types and characteristics of processed meat which might be associated with cancer risk--results from the 24-hour diet recalls in the European Prospective Investigation into Cancer and Nutrition (EPIC).

      Linseisen, Jakob; Rohrmann, Sabine; Norat, Teresa; González, Carlos Alberto; Dorronsoro Iraeta, Miren; Morote Gómez, Patrocinio; Chirlaque, María-Dolores; Pozo, Basilio G; Ardanaz, Eva; Mattisson, Irene; Pettersson, Ulrika; Palmqvist, Richard; Guelpen, Bethany van; Bingham, Sheila A; McTaggart, Alison; Spencer, Elizabeth A; Overvad, Kim; Tjønneland, Anne; Stripp, Connie; Clavel-Chapelon, Françoise; Kesse, Emmanuelle; Boeing, Heiner; Klipstein-Grobusch, Kerstin; Trichopoulou, Antonia; Vasilopoulou, Effie; Bellos, George; Pala, Valeria; Masala, Giovanna; Tumino, Rosario; Sacerdote, Carlotta; Pezzo, Mariarosaria Del; Bueno-de-Mesquita, H Bas; Ocké, Marga C; Peeters, Petra H M; Engeset, Dagrun; Skeie, Guri; Slimani, Nadia; Riboli, Elio (2006-06-01)
      OBJECTIVE: There is increasing evidence for a significant effect of processed meat (PM) intake on cancer risk. However, refined knowledge on how components of this heterogeneous food group are associated with cancer risk is still missing. Here, actual data on the intake of PM subcategories is given; within a food-based approach we considered preservation methods, cooking methods and nutrient content for stratification, in order to address most of the aetiologically relevant hypotheses. DESIGN AND SETTING: Standardised computerised 24-hour diet recall interviews were collected within the framework of the European Prospective Investigation into Cancer and Nutrition (EPIC), a prospective cohort study in 27 centres across 10 European countries. SUBJECTS: Subjects were 22,924 women and 13,031 men aged 35-74 years. RESULTS: Except for the so-called 'health-conscious' cohort in the UK, energy-adjusted total PM intake ranged between 11.1 and 47.9 g day(-1) in women and 18.8 and 88.5 g day(-1) in men. Ham, salami-type sausages and heated sausages contributed most to the overall PM intake. The intake of cured (addition of nitrate/nitrite) PM was highest in the German, Dutch and northern European EPIC centres, with up to 68.8 g day(-1) in men. The same was true for smoked PM (up to 51.8 g day(-1)). However, due to the different manufacturing practice, the highest average intake of NaNO2 through PM consumption was found for the Spanish centres (5.4 mg day(-1) in men) as compared with German and British centres. Spanish centres also showed the highest intake of NaCl-rich types of PM; most cholesterol- and iron-rich PM was consumed in central and northern European centres. Possibly hazardous cooking methods were more often used for PM preparation in central and northern European centres. CONCLUSIONS: We applied a food-based categorisation of PM that addresses aetiologically relevant mechanisms for cancer development and found distinct differences in dietary intake of these categories of PM across European cohorts. This predisposes EPIC to further investigate the role of PM in cancer aetiology.
    • Dietary intake of total polyphenol and polyphenol classes and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

      Zamora-Ros, Raul; Cayssials, Valerie; Jenab, Mazda; Rothwell, Joseph A; Fedirko, Veronika; Aleksandrova, Krasimira; Tjønneland, Anne; Kyrø, Cecilie; Overvad, Kim; Boutron-Ruault, Marie-Christine; Carbonnel, Franck; Mahamat-Saleh, Yahya; Kaaks, Rudolf; Kühn, Tilman; Boeing, Heiner; Trichopoulou, Antonia; Valanou, Elissavet; Vasilopoulou, Effie; Masala, Giovanna; Pala, Valeria; Panico, Salvatore; Tumino, Rosario; Ricceri, Fulvio; Weiderpass, Elisabete; Lukic, Marko; Sandanger, Torkjel M; Lasheras, Cristina; Agudo, Antonio; Sánchez, Maria-Jose; Amiano, Pilar; Navarro, Carmen; Ardanaz, Eva; Sonestedt, Emily; Ohlsson, Bodil; Nilsson, Lena Maria; Rutegård, Martin; Bueno-de-Mesquita, Bas; Peeters, Petra H; Khaw, Kay-Thee; Wareham, Nicholas J; Bradbury, Kathryn; Freisling, Heinz; Romieu, Isabelle; Cross, Amanda J; Vineis, Paolo; Scalbert, Augustin (2018-05-15)
      Polyphenols may play a chemopreventive role in colorectal cancer (CRC); however, epidemiological evidence supporting a role for intake of individual polyphenol classes, other than flavonoids is insufficient. We evaluated the association between dietary intakes of total and individual classes and subclasses of polyphenols and CRC risk and its main subsites, colon and rectum, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The cohort included 476,160 men and women from 10 European countries. During a mean follow-up of 14 years, there were 5991 incident CRC cases, of which 3897 were in the colon and 2094 were in the rectum. Polyphenol intake was estimated using validated centre/country specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, a doubling in total dietary polyphenol intake was not associated with CRC risk in women (HRlog2 = 1.06, 95% CI 0.99-1.14) or in men (HRlog2 = 0.97, 95% CI 0.90-1.05), respectively. Phenolic acid intake, highly correlated with coffee consumption, was inversely associated with colon cancer in men (HRlog2 = 0.91, 95% CI 0.85-0.97) and positively associated with rectal cancer in women (HRlog2 = 1.10, 95% CI 1.02-1.19); although associations did not exceed the Bonferroni threshold for significance. Intake of other polyphenol classes was not related to colorectal, colon or rectal cancer risks. Our study suggests a possible inverse association between phenolic acid intake and colon cancer risk in men and positive with rectal cancer risk in women.
    • Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort.

      Gasull, Magda; Pumarega, José; Kiviranta, Hannu; Rantakokko, Panu; Raaschou-Nielsen, Ole; Bergdahl, Ingvar A; Sandanger, Torkjel Manning; Goñi, Fernando; Cirera, Lluís; Donat-Vargas, Carolina; Alguacil, Juan; Iglesias, Mar; Tjønneland, Anne; Overvad, Kim; Mancini, Francesca Romana; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Johnson, Theron; Kühn, Tilman; Trichopoulou, Antonia; Karakatsani, Anna; Peppa, Eleni; Palli, Domenico; Pala, Valeria; Tumino, Rosario; Naccarati, Alessio; Panico, Salvatore; Verschuren, Monique; Vermeulen, Roel; Rylander, Charlotta; Nøst, Therese Haugdahl; Rodríguez-Barranco, Miguel; Molinuevo, Amaia; Chirlaque, María-Dolores; Ardanaz, Eva; Sund, Malin; Key, Tim; Ye, Weimin; Jenab, Mazda; Michaud, Dominique; Matullo, Giuseppe; Canzian, Federico; Kaaks, Rudolf; Nieters, Alexandra; Nöthlings, Ute; Jeurnink, Suzanne; Chajes, Veronique; Matejcic, Marco; Gunter, Marc; Aune, Dagfinn; Riboli, Elio; Agudo, Antoni; Gonzalez, Carlos Alberto; Weiderpass, Elisabete; Bueno-de-Mesquita, Bas; Duell, Eric J; Vineis, Paolo; Porta, Miquel (2019-02-01)
      The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases. First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles. Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models. There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p'-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB.