ARTICLE

Dietary Patterns and Pancreatic Cancer Risk in Men and Women

Dominique S. Michaud, Halcyon G. Skinner, Kana Wu, Frank Hu, Edward Giovannucci, Walter C. Willett, Graham A. Colditz, Charles S. Fuchs

Affiliations of authors: Departments of Epidemiology (DSM, FH, EG, WCW, GAC) and Nutrition (FH, KW, EG, WCW), Harvard School of Public Health, Boston, MA; Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA (EG, WCW, GAC, CSF); Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL (HGS); Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA (CSF)

Correspondence to: Dominique Michaud, ScD, Harvard School of Public Health, Kresge 920, 677 Huntington Ave., Boston, MA 02115. (e-mail address: dmichaud{at}hsph.harvard.edu).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Diabetes appears to be associated with the development of pancreatic cancer. Three large prospective cohort studies observed a statistically significant relationbetween obesity and pancreatic cancer risk. Dietary patterns have been associated with fasting insulin levels and risk of diabetes. To determine whether dietary patterns are associated with pancreatic cancer risk, we analyzed data from two large prospective cohort studies. Methods: We combined data for men and women to obtain a total of 366 cases of incident pancreatic cancer from a total of 124 672 eligible participants. Dietary data were obtained from food frequency questionnaires in 1986 for men and in 1984 for women. We identified two major dietary patterns, prudent and western, by factor analysis. The prudent pattern was characterized by high fruit and vegetable intake; the western pattern was characterized by high meat and high fat intakes. Multivariable relative risks (RRs) were adjusted for potential confounders, including smoking and body mass index. Results: In the pooled analysis of men and women, no associations were observed between the prudent pattern (RR = 1.32, 95% confidence interval [CI] = 0.66 to 2.63, for highest versus lowest quintile) or the western pattern (RR = 0.91, 95% CI = 0.57 to 1.47, for highest versus lowest quintile) and the risk of pancreatic cancer. Stratifying by body mass index or physical activity did not change the associations. Conclusion: Dietary patterns were not associated with the risk of pancreatic cancer in two large cohort studies of men and women.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Pancreatic cancer is the fourth leading cause of cancer mortality in the United States (1). Rates for this cancer are highest in developed countries (2) and have increased dramatically in countries such as Japan (3), where westernization has been taking place. Prevention could play an important role in reducing pancreatic cancer incidence and mortality, but few environmental risk factors have been identified. One such factor is cigarette smoking; in addition, diabetes has become a widely accepted risk factor of pancreatic cancer (4,5). Positive associations between obesity and pancreatic cancer risk have also been reported recently in three large prospective studies (6,7). Therefore, insulin resistance and elevated postload glucose levels might play a role in pancreatic cancer etiology.

Studying individual dietary components can provide insight into the mechanism of the disease and provide a basis for dietary recommendations. Alternatively, dietary patterns can provide useful information about the overall effect of consuming different combinations of food groups by accounting for complex interactions between foods. Consequently, in some cases, dietary patterns may be more strongly related to disease than individual foods and nutrients. Dietary patterns, especially the western pattern (characterized by a high consumption of red meat, high-fat dairy products, and refined grains), have been associated with fasting insulin levels (8) and risk of type 2 diabetes (9) and may be associated with the risk of pancreatic cancer.

Results on the association between food groups or individual nutrients and pancreatic cancer risk have been largely inconclusive (10). To date, no study has examined dietary patterns inrelation to pancreatic cancer risk. We therefore prospectively examined the association between major dietary patterns, identified by factor analysis, and the risk of pancreatic cancer in two cohort studies of men and women.


    PATIENTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Populations

The Health Professionals Follow-Up Study (HPFS) was initiated in 1986 when 51 529 U.S. men aged 40–75 years responded to a mailed questionnaire. Participants of the HPFS study are dentists, veterinarians, pharmacists, optometrists, osteopathic physicians, and podiatrists. The Nurses' Health Study (NHS) was established in 1976 when 121 700 female registered nurses aged 30–55 years responded to a mailed questionnaire. Both cohorts are active, and participants are contacted regularly. Individual characteristics and habits were obtained on the baseline questionnaires or on subsequent questionnaires mailed every 2 years. In addition, time-varying data, such as smoking status, are updated regularly. Deaths of most members of this cohort are reported by family members or by the postal service in response to questionnaire mailings. In addition, the National Death Index is searched biennially for nonrespondents; this method has been shown to have a sensitivity of 98% (11).

Detailed dietary data were obtained from all participants at baseline in the HPFS and from nurses who responded to the 1984 food frequency questionnaire. Although the NHS cohort did include a dietary questionnaire in 1980, we started follow-up for this analysis in 1984 (in NHS) because the 1984 dietary questionnaire included more food items and was similar to the baseline HPFS questionnaire. For these analyses, a total of 47 493 men (HPFS) and 77 179 women (NHS) were eligible after excluding participants diagnosed with cancer (other than nonmelanoma skin cancer) before 1986 (HPFS) or 1984 (NHS) or those with implausibly low or high daily energy intake (<800 or >4200 kcal/day for men; <500 or >3500 kcal/day for women).

Dietary Assessment

A food frequency questionnaire that included approximately 130 items was mailed to all NHS participants in 1984 and to HPFS participants in 1986. Participants were asked to report their average frequency of intake over the previous year for a specified serving size of each food.

To identify dietary patterns, we applied factor analysis to data from the food frequency questionnaires in each cohort. Food items on the food frequency questionnaires were grouped into 37 predefined food groups (see Table 1). Food items similar in nutrient profile were combined (e.g., spinach, iceberg or head lettuce, and romaine or leaf lettuce were combined into "green leafy vegetables"). Certain food items were not combined if their nutrient profile was unique (e.g., pizza).


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Table 1.  Pearson correlation coefficients for the relationship between food intake and factors representing dietary patterns in the Health Professionals Follow-Up Study (HPFS) (1986) and Nurses' Health Study (NHS) (1984)*

 
Factor analysis (principal component) was conducted using the factor procedure in SAS software (version 8.2, SAS Institute Inc., Cary, NC). The factors were rotated by an orthogonal transformation (Varimax rotation function in SAS). Factor analysis aggregates correlated variables. The obtained factors are linear combinations of the included variables, explaining as much variation in the original variables as possible. We retained two factors, based on an eigenvalue of more than 1.5 and the interpretability of the derived factors, and we labeled these two factors as the "prudent" and "western" patterns, as previously described (1214). The individual scores for the two patterns represent the values estimated for each participant based on their intake of foods and the factor loadings of the foods (i.e., correlations with the patterns). The two dietary patterns are not correlated with each other.

The validity and reproducibility of the dietary pattern scores were previously examined in a subgroup of 127 male participants (13). The Pearson correlation coefficient for a comparison between two food frequency questionnaires (administered 1 year apart) and diet records (corrected for week-to-week variation in the diet records) ranged from 0.45 to 0.74 for the prudent and western dietary patterns, respectively.

Smoking History and Other Risk Factors

Smoking status and history of smoking were obtained at baseline and in all subsequent questionnaires in both cohorts. Current smokers also reported intensity of smoking (average number of cigarettes smoked per day) on each questionnaire. Past smokers reported when they last smoked, and the time since quitting was also calculated for those who quit during follow-up. In a previous publication from these cohorts (15), we examined the relationship between smoking and pancreatic cancer risk in detail; the strongest associations were observed for pack-years smoked within the previous 15 years.

Height and current weight were reported by participants at baseline. Current weight was obtained biennially from the questionnaires (in both cohorts). We estimated body mass index from weight and height (i.e., kilograms/[height in meters]2) as a measure of total adiposity. In 1986, the questionnaires mailed to the two cohorts included a section assessing physical activity. Participants were asked to average the time spent per week in a total of eight different activities over the previous year. A weekly physical-activity score was derived by multiplying the time spent in each activity per week by its typical energy-expenditure requirements expressed in metabolic equivalents (METs) (16); this score was called the MET-hour score. Participants were also asked about history of diabetes at baseline and in all subsequent questionnaires.

Identification of Cases of Pancreatic Cancer

Participants in both cohorts were asked to report specified medical conditions including cancers that were diagnosed in the 2-year period between each follow-up questionnaire. Whenever a participant (or next-of-kin for decedents) reported a diagnosis of pancreatic cancer, we asked for permission to obtain related medical records or pathology reports. If permission to obtain records was denied, we attempted to confirm the self-reported cancer with an additional letter or phone call to the participant. If the primary cause of death as reported by a death certificate was a previously unreported case of pancreatic cancer, we contacted a family member to obtain permission to retrieve medical records or to confirm the diagnosis of pancreatic cancer. In the HPFS cohort, we were able to obtain pathology reports confirming the diagnosis of pancreatic cancer for 95% of cases. For the 5% cases for which we were not able to obtain pathology reports, we obtained confirmation of the self-reported cancer from a secondary source (e.g., death certificate, physician, or telephone interview of a family member). In the NHS cohort, we were able to obtain pathology reports confirming the diagnosis of pancreatic cancer for 85% of cases. For the 15% cases for which we were not able to obtain pathology reports, we obtained confirmation of the self-reported cancer from a secondary source (e.g., death certificate, physician, or telephone interview of a family member). All medical records in both cohorts had complete information on histology (because hospitals were re-contacted if the original information sent was incomplete). When we included or excluded cases with missing medical records in our analyses, no differences were observed between these two types of analyses, and thus we included cases without medical records.

In the HPFS cohort, 185 confirmed incident cases of pancreatic cancer, diagnosed between the return of the baseline (1986) dietary questionnaire and January 31, 2000, were available for analyses. In the NHS, 181 confirmed incident pancreatic cancer cases, diagnosed between the return of the 1984 dietary questionnaire and June 30, 2000, were available for the analyses. Thus, a total of 366 incident cases of pancreatic cancer were included in our analyses.

Statistical Analysis

We computed person-time of follow-up for each participant from the return date of the baseline questionnaire to the date of pancreatic cancer diagnosis, death from any cause, or the end of follow-up (January 31, 2000, for men and June 30, 2000, for women), whichever came first. Incidence rates of pancreatic cancer were calculated by dividing the number of incident cases by the number of person-years in each category of exposure. We computed the relative risk for each of the upper quintiles by dividing the rates in these categories by the rate in the lowest quintile. Our primary analyses were conducted by use of baseline diet; in addition, secondary analyses were conducted by use of dietary data collected in follow-up years [with cumulative updating methodology for exposure categorization (17)].

Relative risks (RRs) adjusted for potential confounders were approximated by Cox proportional hazards regression. Proportionality of hazard was evaluated by visual examination of associations across intervals of time. A new data record was created for every questionnaire cycle at which a participant was at risk, with covariates set to their values at the time that the questionnaire was returned. All models were stratified by age andcalendar time. To control for cigarette smoking, the following categories that were based on a previous analysis of the cohorts studied were used (15): never smoker, quit 15 years ago or longer, quit less than 15 years ago and smoked 25 pack-years or less in past 15 years, quit less than 15 years ago and smoked more than 25 pack-years in past 15 years, current smoker with 25 pack-years or less in past 15 years, and current smoker with more than 25 pack-years in past 15 years (age and smoking variables were updated biennially). In addition, we controlled for history of diabetes (updating these variables biennially in the analyses) (4). Body mass index was not updated in the main analyses because pancreatic cancer is frequently associated with profound weight loss, and our previous findings showed the strongest associations for baseline body mass index (data from the 1976 NHS questionnaire and from the 1986 HPFS questionnaire) (6). To control for physical activity, we used quintiles of physical activity in both cohorts and did not update these variables over time because preclinical symptoms could affect activity levels. In the final model, we included age, pack-years of smoking (as described above), body mass index (quintiles), total physical activity (quintiles), caloric intake (quintiles), height (as five categories), history of diabetes, and multivitamin use.

In addition, we performed analyses with a 2-year lag to exclude preclinical cases at baseline. All P values are based on two-sided statistical tests.

We pooled the data from the two cohorts by use of a random-effects model for the logarithm of the relative risks (18). Tests of heterogeneity using the Q statistic (18) were conducted for continuous variables to evaluate the overall trend before pooling.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Two major dietary patterns were identified by factor analysis that we labeled prudent and western to be consistent with previous publications describing these patterns (8,9,12,13). The prudent pattern is characterized by high consumption of vegetables, legumes, fruit, whole grains, fish, and poultry. The western pattern is characterized by high consumption of red meat, processed meat, refined grains, French fries, high-fat dairy products, sweets and desserts, and high-sugar drinks (Table 1). In our cohorts, these two patterns have been shown to be stable over time (9,12).

A higher compared with a lower (quintile 5 compared with quintiles 3 and 1) prudent pattern was associated with healthy behaviors, whereas a higher compared with a lower western pattern was associated with less healthy behaviors (Table 2). Men and women with a higher compared with a lower prudent pattern were less likely to be current smokers and to have smoked fewer packs of cigarettes in their lifetimes, to exercise more, and to consume more multivitamin supplements, less total fat, and less alcohol. Those with a higher compared with a lower prudent pattern were also more likely to have hypercholesterolemia, hypertension, or a history of diabetes; however, these correlations may reflect changes in diet after diagnosis of hypertension or high cholesterol. Men and women with a higher compared with a lower western pattern were more likely to be current smokers and to have smoked more packs of cigarettes in their lifetime, to weigh more, to exercise less, and to consume fewer multivitamin supplements, more total fat, and more alcohol. Hypercholesterolemia and hypertension were less frequent among those with a higher western pattern.


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Table 2.  Baseline characteristics among men in the Health Professionals Follow-Up Study (HPFS) (1986) and women in the Nurses' Health Study(NHS) (1984) by quintile of dietary pattern*

 
For the follow-up period of this analysis, the overall crude incidence rate was 15 pancreatic cancers per 100 000 person-years in the NHS cohort and 30 pancreatic cancers per 100 000 person-years in the HPFS cohort.

No associations were observed between the prudent or the western pattern and the risk of pancreatic cancer in women (Table 3). In men, the risk of pancreatic cancer was elevated in the top four quintiles of the prudent pattern, but a dose-response relationship was not observed. In addition, the linear test for trend was not statistically significant for the association between prudent dietary pattern and pancreatic cancer risk. After adjustment for potential confounders, including smoking, body mass index, physical activity, multivitamin use, height, history of diabetes, and caloric intake, the relative risks associated with a prudent pattern among the men increased slightly (RR = 1.88, 95% confidence interval [CI] = 1.06 to 3.32, for highest versus lowest quintile; Table 3); smoking and caloric intake accounted for most of the difference between age-adjusted and multivariable relative risks. No association was observed for the western pattern and pancreatic cancer risk in men.


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Table 3.  Relative risks (RRs)* (95% confidence intervals [CIs]) of pancreatic cancer according to major dietary patterns in the Health Professionals Follow-upStudy (HPFS) (1986–2000) and in the Nurses' Health Study (NHS) (1984–2000)

 
After the two cohorts were pooled, neither of the two dietary patterns was related to pancreatic cancer risk (RR = 1.32, 95% CI = 0.66 to 2.63, for highest versus lowest quintile of the prudent pattern; RR = 0.91, 95% CI = 0.57 to 1.47, for highest versus lowest quintile of the western pattern; Table 3). Additional adjustment for aspirin use, glycemic load intake, hypertension, hypercholesterolemia, or cholecystectomy resulted in similar associations in each cohort (data not shown). Removing men with high cholesterol (who might have recently changed their diet) led to similar associations with the prudent pattern among men (data not shown).

A secondary analysis using cumulative updating of dietary exposure from follow-up questionnaires (to minimize misclassification of exposure) yielded similar results overall, but relative risks with the prudent pattern in the HPFS cohort were attenuated (multivariable RR = 1.67, 95% CI = 0.98 to 2.86, for highest versus lowest quintile of the prudent pattern) compared with those observed with baseline diet (RR = 1.88, 95% CI = 1.06 to 3.32, for highest versus lowest quintile of the prudent pattern; Table 3).

To explore which food(s) may be responsible for the elevated risks observed with the prudent diet in the HPFS cohort, we examined the relation between specific foods that contributed substantially to the prudent dietary pattern and the risk of pancreatic cancer. No individual food was associated with a substantial increase in pancreatic cancer risk. The two strongest positive associations with pancreatic cancer risk observed were for intakes of fish and tomatoes (highest versus lowest quintiles, multivariable RR for fish = 1.46, 95% CI = 0.95 to 2.24; multivariable RR for tomatoes = 1.42, 95% CI = 0.87 to 2.32).

We stratified the dietary pattern analyses by body mass index and physical activity to examine whether dietary patterns may differentially affect those at higher risk. Associations in the separate strata were similar to those reported overall (e.g., for highest versus lowest prudent pattern quintile in HPFS: multivariable RR = 1.68, 95% CI = 0.70 to 4.05 for body mass index <25 kg/m2, and RR = 1.67, 95% CI = 0.75 to 3.71 for body mass index ≥25 kg/m2; other data not shown). Similarly, stratifying by smoking status did not change the associations observed for the two dietary patterns in either cohort.

Removing the first 2 years of follow-up from the analyses did not alter associations between dietary patterns and risk of pancreatic cancer (data not shown). Furthermore, removing individuals who were diabetic at baseline from the analyses did not change the associations.


    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The dominant dietary patterns in two United States cohorts were not associated with the risk of pancreatic cancer in this prospective study. Among men, a positive association was observed among those consuming a more prudent diet (the highest quintile) compared with those consuming a less prudent diet (the lowest quintile); however, the test for linear trend for this association was not statistically significant. Moreover, similar associations with the prudent dietary pattern were not observed among women. The results in each cohort and both cohorts combined were similar after removing the first 2 years of follow-up or after removing diabetic subjects at baseline and did not vary when stratifying by body mass index or physical activity.

Case-control studies of diet and risk of pancreatic cancer have reported consistent inverse associations for fruit and vegetable intake [for summary, see (10)]. In contrast, prospective studies have observed no associations for total fruit and/or vegetable intake (10,19), suggesting that findings from case-control studies may have been biased by differential recall of dietary intake or proxy interviews. In the present study, the overall null association between prudent diet and pancreatic cancer risk is consistent with findings for fruits and vegetables from previous cohort studies.

Reports of associations between meat intake and pancreatic cancer risk have been inconsistent. Although meat intake was associated with elevated risk of pancreatic cancer in sevencase-control studies (2026), no positive associations for meat items were found in six other case-control studies (2732).A statistically significant association between total meat intake and pancreatic cancer risk was reported in one prospective study (RR = 3.0, 95% CI = 1.2 to 7.5, for top to bottom quartile comparison) (33), but no association was reported in six other prospective studies, including the HPFS and NHS cohorts (3439). Our null finding for the western pattern, largely characterized by a diet high in meat and fat, therefore, is consistent with our previous observation that total meat, processed meat, and fat intakes are not associated with pancreatic cancer (39).

Previous studies using dietary patterns in the HPFS and NHS cohorts reported inverse associations between the prudent diet and risk of colon cancer (12) and between the prudent diet and risk of diabetes (9) and positive associations between the western diet and risk of colon cancer (12) and between the western diet and risk of diabetes (9). In addition, the western pattern was positively associated with insulin levels, and the prudent pattern was inversely associated with insulin levels among a subsample of men from the HPFS cohort (8). These findings suggest that dietary patterns may predict underlying hyperinsulinemia, which has been implicated in the development of pancreatic cancer (40). However, the lack of association between the prudent and western patterns and pancreatic cancer risk in the current analyses suggests that a different dietary model may be required to understand the underlying mechanism that ties diabetes to pancreatic cancer risk. For example, we previously demonstrated that a high glycemic load is positively associated with pancreatic cancer in women in the NHS (41). Alternatively, dietary patterns early in life, which we are not able to capture in these cohorts, may be a more relevant exposure.

One limitation to this study is the use of self-administered food frequency questionnaires to assess dietary intake. Measurement error in dietary variables can be both random andsystematic and may bias relative risks toward the null (whennondifferential, as would be expected in a prospective study). Adjusting for total energy intake reduces some of the systematic over- and under-reporting, which is common in food frequency questionnaires. Despite this correction, our null findings overall could hide a real association if measurement error in the dietary variables was substantial. Although we cannot exclude this possibility entirely, we believe that it is unlikely given previous positive findings between dietary patterns and both colon cancer and diabetes in the HPFS and NHS cohorts (9,12).

Several factors may explain the positive association of pancreatic cancer observed among men with a high prudent diet. Residual confounding or unmeasured confounding may have been responsible for the unexpected observation among men. Alternatively, the relatively small number of only 185 cases of pancreatic cancer in the HPFS cohort may have contributed to sample bias and a chance finding. Given that these findings are opposite to our hypothesis, did not follow a dose-response relationship, and were not reproduced in women, we view this finding with caution. In addition, we cannot rule out the possibility that measurement error in covariates included in the multivariable model was responsible for exacerbating the point estimates observed between prudent diet and pancreatic cancer.

The prospective design of this study avoids recall or selection bias and the use of proxy interviews. Other strengths include high follow-up response rates, detailed and updated information on potential confounding variables, and a relatively large number of cases of pancreatic cancer. In addition, the two major dietary patterns used in our analyses were previously validated with dietary records in the HPFS cohort (13), and similar dietary patterns have been reported in other populations (4244). Although dietary patterns change over time, the prudent and western patterns consistently emerge as the two factors explaining the most variation in the dietary variables when factor analysis with updated dietary food frequency questionnaires was used over the follow-up years in the NHS and HPFS cohorts (9,12). Therefore, although dietary patterns are not created a priori, they are robust across populations and over time.

In this study of two prospective cohorts that included men and women, we did not observe an overall association between dietary patterns and pancreatic cancer. Given the lack of biological plausibility, the positive association observed in men with a high prudent diet is likely to have resulted from bias or chance. Obesity and physical activity did not modify the associations with dietary patterns in either cohort. Although hyperinsulinemia and glucose intolerance may play a role in pancreatic cancer etiology, two major dietary patterns linked with fasting insulin levels and diabetes do not appear to be important predictors of pancreatic cancer risk.


    NOTES
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The work reported in this manuscript was supported by Public Health Service grants CA87969, CA55075, CA86102, and CA95589 from the National Institutes of Health.


    REFERENCES
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 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Manuscript received September 1, 2004; revised February 1, 2005; accepted February 15, 2005.



             
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