Meat, fish, poultry and egg consumption in relation to risk of pancreatic cancer: A prospective study

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1 Int. J. Cancer: 118, (2006) ' 2005 Wiley-Liss, Inc. Meat, fish, poultry and egg consumption in relation to risk of pancreatic cancer: A prospective study Susanna C. Larsson 1 *, Niclas Hakanson 1, Johan Permert 2 and Alicja Wolk 1 1 Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 2 Department for Clinical Sciences, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden High meat consumption has been associated with increased risk of pancreatic cancer in several, although not all, case-control studies. However, prospective data on this relationship are sparse, and the results have been inconsistent. We prospectively evaluated meat, fish, poultry, and egg consumption in relation to pancreatic cancer incidence in a population-based cohort of 61,433 Swedish women. Diet was assessed with a food-frequency questionnaire at baseline ( ) and again in Pancreatic cancers were ascertained through linkage to the Swedish Cancer Register. Cox proportional hazards models were used to estimate multivariate hazard ratios with 95% confidence intervals (CI). During the 941,218 person-years of follow-up, from 1987 through 2004, 172 incident cases of pancreatic cancer were diagnosed. Long-term red meat consumption (using data from both dietary questionnaires) was positively associated with risk of pancreatic cancer (p-trend ), whereas long-term poultry consumption was inversely (p-trend ) associated with risk. The multivariate hazard ratios for the highest versus the lowest category of consumption were 1.73 (95% CI ) for red meat and 0.44 (95% CI ) for poultry. There were no significant associations with processed meat, fish or egg consumption. Findings from this prospective study suggest that substituting poultry for red meat might reduce the risk of pancreatic cancer. ' 2005 Wiley-Liss, Inc. Key words: cohort studies; egg; fish; meat; pancreatic cancer Diet is a potentially modifiable exposure that may play a role in the development of pancreatic cancer, the sixth leading cause of cancer death in the European Union. 1 In this regard, several casecontrol studies, 2 9 although not all, have reported increased risk of pancreatic cancer associated with high consumption of total meat, red meat or meat cooked at high temperatures. Consumption of poultry or fish has been inconsistently associated with higher 3,4 or lower risk 5,12,16 of pancreatic cancer in case-control studies; some studies 6,7,10,11,15 showed no substantial association. Similarly, findings on egg consumption in relation to pancreatic cancer risk have been mixed, with increased risk found in some case-control studies 3,16 but not in others. 4,5,11,13 Because pancreatic cancer is rapidly fatal, many case-control studies have relied on next-of-kin interviews to determine exposures, and they tend to have low participation rates among cases. Furthermore, in case-control studies, diet is assessed retrospectively; hence, such studies are susceptible to recall bias. For these reasons, the results from case-control studies should be interpreted cautiously. Prospective cohort studies, in which exposure data have been collected before the cancer diagnosis, are best suited to evaluate the role of dietary factors in the etiology of pancreatic cancer. To date, relatively few prospective studies have examined the association between consumption of meat, fish, poultry and egg and risk of pancreatic cancer, and the findings have been inconclusive. In all but one 21 of previous prospective studies, dietary data were collected at baseline only, which could lead to misclassification of long-term diet and attenuate potential relationships. We sought to prospectively examine long-term consumption of red meat, processed meat, fish, poultry and egg in relation to the risk of pancreatic cancer in the Swedish Mammography Cohort, a large population-based cohort with repeated assessments of diet. Material and methods Study population The Swedish Mammography Cohort is a population-based prospective cohort study established between 1987 and 1990, when all women born between 1914 and 1948 and residing in Uppsala and V astmanland counties, central Sweden, received a mailed questionnaire about diet, weight, height and education. 25 Of the 90,303 women, 66,651 returned a completed questionnaire. In the autumn of 1997, a follow-up questionnaire with about 350 items was mailed to participants to update dietary data and obtain information on other lifestyle factors. Of the 56,030 women who were still alive and living in the study area, 39,227 completed the 1997 questionnaire. To form the baseline cohort for our primary analyses, we excluded women with erroneous national registration number, those with implausible total energy intakes (i.e., 3 standard deviations from the mean value for log-transformed energy intake) and those with diagnosed cancer (except nonmelanoma skin cancer) at baseline. The final baseline cohort consisted of 61,433 women eligible for followed-up from 1987 through For secondary analyses with follow-up from 1998 through 2004, 36,616 cancer-free women with reasonable energy intake (i.e., less than 3 standard deviations from the mean value of log-transformed energy intake in the 1997 questionnaire) were included. This study was approved by the Regional Ethical Review Board in Stockholm. Assessment of diet At baseline, a 67-item food-frequency questionnaire (FFQ) was used to assess dietary intake. An expanded 96-item FFQ was used to update information on diet in In these FFQs, participants reported their average consumption of each food item over the past year with the use of 8 prespecified mutually exclusive frequency response categories. Questions about meat, poultry and fish, were similar in the 2 FFQs. We considered red meat to include minced meat (hamburgers, meatballs, meatloaf, etc); casserole with beef, pork or veal; and whole beef (steaks, roasts, etc). Processed meat included sausage or hotdogs; bacon; ham, salami or lunch meat and blood pudding/sausage. Poultry included chicken; hens and other poultry. Fish included lean fish (e.g., cod); fatty fish (e.g., salmon, herring, mackerel and sardines) and canned tuna. The baseline FFQ has been validated in a sample of 129 women randomly selected from the study population. The Spearman correlation coefficients between the FFQ and the average of 4 1-week weighted diet records ranged from 0.3 to 0.7 for red and processed Grant sponsor: Swedish Research Council/Longitudinal Studies; Grant sponsor: Swedish Cancer Foundation; Grant sponsor: V astmanland County Research Fund against Cancer. *Correspondence to: Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE Stockholm, Sweden. Fax: susanna.larsson@ki.se Received 28 August 2005; Accepted 9 November 2005 DOI /ijc Published online 29 December 2005 in Wiley InterScience (www. interscience.wiley.com). Publication of the International Union Against Cancer

2 MEAT, FISH, POULTRY AND EGG CONSUMPTION IN RELATION TO RISK OF PANCREATIC CANCER: A PROSPECTIVE STUDY 2867 TABLE I AGE-STANDARDIZED CHARACTERISTICS OF WOMEN IN THE SWEDISH MAMMOGRAPHY COHORT ACCORDING TO CONSUMPTION OF RED MEAT AND POULTRY AT BASELINE ( ) Red meat consumption, servings/week Poultry consumption, servings/week < < < < Age (years) Post-secondary education (%) Body mass index (kg/m 2 ) Ever smoker (%) Pack-years of smoking 1, Mean daily intake Energy intake (kcal) 1,400 1,512 1,597 1,760 1,539 1,580 1,637 Alcohol intake (g) Dietary folate intake (lg) Information from the 1997 questionnaire. 2 Among past and current smokers. Pack-years 5 average number of packs smoked per day multiplied by the number of years of smoking. meat items and from 0.4 to 0.5 for fish items; for poultry and egg, the correlation coefficients were 0.4 and 0.5, respectively (A. Wolk, unpublished data). Assessment of nondietary exposures The baseline questionnaire collected information on demographic characteristics, weight and height. We calculated body mass index (BMI) as weight in kilograms divided by the square of height in meters. Information on cigarette smoking history was obtained first in 1997 from the second questionnaire. Pack-years were estimated from smoking history by multiplying the average number of packs of cigarettes smoked per day by the number of years of smoking. Ascertainment of cases and follow-up Incident cases of pancreatic cancer were identified through computerized record linkage of the study population with the Swedish Cancer Register and the Regional Cancer Register covering the study area, both of which have been documented to be almost 100% complete. 26 Cases of pancreatic cancer were defined as malignant neoplasm of the exocrine pancreas [International Classification of Diseases, Ninth Revision (ICD-9), 157]. Islet-cell carcinomas (ICD-9, 157.4) were not included, as the etiology of these tumors may be different from that of the exocrine pancreas. Through linkage to the Swedish Death and Population registers at Statistics Sweden, we received information on dates of death and dates of migration. Statistical analysis Each woman accrued follow-up time beginning at the date of entry into the cohort and ending at the date of diagnosis of pancreatic cancer, death from any cause, migration or December 31, 2004, whichever came first. Red meat, processed meat and fish consumption was analyzed in 4 categories (approximate quartiles). The same cut points were applied to red meat and processed meat with the aim of estimating relative risks for comparable levels of intake. For poultry and egg consumption, we used 3 categories because of limited range of consumption. To account for changes in diet during follow-up and to better represent long-term dietary intake, we used a cumulative averaged approach. 27 Specifically, the incidence of pancreatic cancer from baseline through 1997 was related to meat, fish, poultry and egg consumption reported on the baseline dietary questionnaire, and the incidence of pancreatic cancer from 1998 through December 2004 was related to the average consumption at baseline and in 1997; for women who did not complete the 1997 questionnaire, data from the baseline questionnaire was used. We also related baseline dietary intake (without updating) to incidence of pancreatic cancer during the entire follow-up period. We used Cox proportional hazards models 28 (PROC PHREG in SAS version 9.1 software; SAS Institute, Inc., Cary, NC) to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Age in months and the year of entry into the cohort were used as stratification variables in the Cox model. In multivariate models, in addition to age, we simultaneously adjusted for education (less than high school, high school graduate, or more than high school), BMI (<23.0, , , or 30 kg/m 2 ), cigarette smoking (never smoker, past and smoked <20 pack-years, past and smoked 20 pack-years, current and smoked <20 pack-years, current and smoked 20 pack-years, missing) and intakes of total energy (continuous), alcohol (quartiles), and energy-adjusted dietary folate (quartiles). These covariates were either known or potential risk factors for pancreatic cancer or were associated with both the dietary exposures and risk of pancreatic cancer in the present cohort. To test for linear trends across categories, we assigned the median value to each category and treated this value as a continuous variable. All p-values are from 2-sided statistical tests. Results At baseline, women with higher consumption of red meat and poultry were younger and more likely to have a post-secondary education than women with a low consumption of these foods (Table I). Consumption of red meat and poultry was positively associated with intakes of alcohol and energy. In addition, women with higher consumption of poultry had a higher BMI, a higher dietary folate intake and were slightly less likely to smoke than women who did not consume poultry. Smoking was not clearly related to red meat consumption. We ascertained 172 incident cases of exocrine pancreatic cancer during 941,218 person-years of follow-up from 1987 through Table II shows HRs of pancreatic cancer according to baseline and updated average (long-term) consumption of red meat, fish, poultry and egg. After adjustment for potential confounders, risk of pancreatic cancer was positively associated with long-term red meat consumption (p-trend ) and inversely associated with long-term poultry consumption (p-trend ). Additional adjustment for consumption of fruits, vegetables and dairy foods did not essentially change the results (data not shown). Analyses based on dietary intake as measured on the baseline questionnaire only yielded a weaker (and not statistically significant) association between red meat consumption and pancreatic cancer risk, than analyses using updated measures of intake. Processed meat, fish or egg consumption was not significantly related to pancreatic cancer risk in analyses using baseline or updated average diet (Table II). Exclusion of cases diagnosed within the first 2 years of follow-up made no material difference to any of the results shown in Table II. We examined the risk of pancreatic cancer in relation to red meat and poultry consumption as measured on the 1997 follow-up questionnaire. Among the 36,616 women who completed this questionnaire and were cancer-free as of December 1997, 61 inci-

3 2868 LARSSON ET AL. TABLE II HAZARD RATIOS AND 95% CONFIDENCE INTERVALS OF PANCREATIC CANCER AMONG WOMEN BETWEEN 1987 AND 2004 ACCORDING TO BASELINE AND UPDATED AVERAGE (LONG-TERM) CONSUMPTION OF RED MEAT, PROCESSED MEAT, FISH, POULTRY, AND EGG Food item Baseline ( ) consumption Updated average consumption (servings/week) Cases Person-years Model 1 1 Model 2 2 Cases Person-years Model 1 1 Model 2 2 Red meat < , , < , ( ) 1.15 ( ) , ( ) 1.62 ( ) 2.5 < , ( ) 1.30 ( ) , ( ) 1.34 ( ) , ( ) 1.33 ( ) , ( ) 1.73 ( ) p-trend Processed meat < , , < , ( ) 0.70 ( ) , ( ) 0.80 ( ) 2.5 < , ( ) 0.74 ( ) , ( ) 0.77 ( ) , ( ) 1.00 ( ) , ( ) 0.94 ( ) p-trend Fish , , < , ( ) 0.90 ( ) , ( ) 0.88 ( ) 1.5 < , ( ) 1.48 ( ) , ( ) 1.52 ( ) , ( ) 1.11 ( ) , ( ) 1.22 ( ) p-trend Poultry , , < , ( ) 0.83 ( ) , ( ) 0.88 ( ) , ( ) 0.24 ( ) 8 819, ( ) 0.44 ( ) p-trend Egg < , , < , ( ) 1.07 ( ) , ( ) 1.22 ( ) , ( ) 0.87 ( ) , ( ) 0.83 ( ) p-trend Model 1 adjusted for age (in months) and total energy intake (continuous). 2 Model 2 adjusted for age (in months), education (less than high school, high school graduate, or more than high school), body mass index (<23.0, , , or 30 kg/m 2 ), smoking (never smoker, past and smoked <20 pack-years, past and smoked 20 pack-years, current and smoked <20 pack-years, current and smoked 20 pack-years, or missing) and intakes of total energy (continuous), alcohol (quartiles) and energy-adjusted folate (quartiles). Red meat, processed meat, fish, poultry and egg were included simultaneously in the model. dent cases of pancreatic were diagnosed during 249,593 personyears of follow-up. The multivariate HRs (adjusted for the same variables as in Table II) for the top compared with the bottom tertile of consumption were 1.26 (95% CI ; p-trend ) for red meat and 0.43 (95% CI ; p-trend ) for poultry. Processed meat, fish and egg consumption as reported on the 1997 questionnaire was not associated with pancreatic cancer risk (data not shown). We also examined consistent consumption of red meat and poultry over time in relation to risk of pancreatic cancer (Table III). Considering the cases that were diagnosed after the 1997 dietary assessments, women who consistently reported consuming 3 servings or more of red meat per week in the baseline and 1997 questionnaires had a 2.6-fold higher risk of pancreatic cancer compared with those who at baseline and in 1997 consistently reported consuming less than 2 servings per week. Similarly, compared with women who consistently reported that they never consumed poultry, women who consistently reported that they consumed poultry in the baseline and 1997 questionnaires had a 64% lower risk of pancreatic cancer. These results did not change after further adjustment for a history of diabetes and physical activity. Discussion In this large population-based prospective cohort of women, long-term red meat consumption was positively associated with pancreatic cancer risk, whereas long-term poultry consumption was inversely associated with risk. No appreciable associations of processed meat, fish or egg consumption with risk of pancreatic cancer were observed. A number of case-control studies, 2 9 but not all, have reported positive associations between consumption of total meat, red meat and processed meat and risk of pancreatic cancer. To TABLE III HAZARD RATIOS AND 95% CONFIDENCE INTERVALS OF STOMACH CANCER AMONG WOMEN BETWEEN 1998 AND 2004 ACCORDING TO LONG-TERM CONSISTENT CONSUMPTION OF RED MEAT AND POULTRY Food item Intake at baseline and in Low/Low All other combinations High/High Red meat No of cases Person-years 35, Model ( ) 2.18 ( ) Model ( ) 2.63 ( ) Poultry No of cases Person-years 24, Model ( ) 0.45 ( ) Model ( ) 0.36 ( ) 1 Red meat: Low/Low 5 <2 servings/week (median, 1.3 servings/ week) at baseline and in 1997, High/High 5 3 servings/week (median, 4.2 servings/week) at baseline and in 1997; Poultry: Low/ Low 5 never/seldom consumption at baseline and in 1997, High/ High servings/week (median, 0.5 serving/week) at baseline and in Model 1 adjusted for age (in months) and total energy intake (continuous). 3 Model 2 adjusted for age (in months), education (less than high school, high school graduate, or more than high school), body mass index (<23.0, , or 30 kg/m 2 ), smoking (never smoker, past and smoked <20 pack-years, past and smoked 20 pack-years, current and smoked <20 pack-years or current and smoked 20 pack-years) and intakes of total energy (continuous), alcohol (quartiles) and energy-adjusted folate (quartiles). date, 8 cohort studies have examined the association between consumption of various meats and risk of pancreatic cancer. In the largest of these studies, the Multiethnic Cohort Study, 18 consumption of red meat and processed meat was statistically significantly

4 MEAT, FISH, POULTRY AND EGG CONSUMPTION IN RELATION TO RISK OF PANCREATIC CANCER: A PROSPECTIVE STUDY 2869 positively associated with pancreatic cancer risk. Two other cohort studies 17,23 also showed a statistically significant positive association with meat consumption. A cohort of 7th-day Adventists 24 reported a nonsignificant 2.3-fold increase in risk for consumption of total meat. No appreciable associations between total or red meat consumption and pancreatic cancer risk was observed in 3 other cohort studies, 19,21,22 and 1 cohort of Swedish twins 20 found a reduced risk with pork and sausage consumption. In our study, we observed a lower risk of pancreatic cancer associated with poultry consumption. No association with consumption of chicken or poultry was reported in previous cohort 18,21 23 and case-control studies, 6,10,15 while 1 case-control study 4 showed an increased risk with higher consumption of chicken. Thus, our findings for poultry may be attributable to chance. Cooking of meat, poultry and fish at high temperatures, such as pan-frying, barbecuing or grilling, produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). These compounds may pose a potential risk of cancer to humans, 29 depending on to which extent they are activated in vivo by metabolic enzymes. Animal studies have shown that HCAs may promote pancreatic carcinogenesis. 30 A recent case-control study reported an increased risk of pancreatic cancer associated with high intakes of various HCAs. 31 Furthermore, several epidemiologic studies have observed positive associations with consumption of fried, grilled and barbecued meat 7,9 and other fried or grilled foods. 14,16,32 The findings of studies on polymorphisms in enzymes that metabolizes HCAs, PAHs and other carcinogens in relation to pancreatic cancer have been inconsistent Our data do not fully support a role of HCAs and PAHs in the development of pancreatic cancer because we found that only consumption of red meat, and not fish or poultry, was associated with elevated risk of pancreatic cancer. However, the cooking of red meat in Sweden typically involves high-temperature pan-frying, whereas fish and poultry are prepared also by stewing or baking, which does not produce HCAs and PAHs. Another possibility is that other factors present in fish and poultry are protective and counterbalance a positive association with consumption of these foods. For example, fatty fish (e.g. salmon, herring and mackerel) contains long-chain n-3 polyunsaturated fatty acids, which have been shown to inhibit carcinogenesis in animal models and in vitro studies. 37 This study has several major strengths: it had a populationbased and prospective design with 18 years of follow-up, included a large number of incident cases, follow-up of the study population was practically complete and it was not prone to the biases of case-control studies. We were also able to evaluate associations with baseline and long-term diet. Random error in measuring dietary intake is likely to have attenuated the associations. By updating and averaging food consumption during follow-up in the present study, we attempted to reduce random measurement error and to account for changes in food intake during follow-up. The observed positive association of red meat consumption with pancreatic cancer risk was stronger in analyses based on updated information than in analyses conducted using data from the baseline questionnaire only. Because our study was observational, we cannot rule out the possibility that the observed associations with red meat and poultry consumption were attributable to unmeasured dietary or behavioral factors, or to residual confounding by risk factors such as cigarette smoking. We did not have smoking data for all participants because information on smoking was first obtained in However, smoking was not appreciable related to consumption of red meat or poultry in our study population. Thus, any residual confounding due to inadequate smoking data would be small. 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