In this large population-based case-control study, our results provided evidence that the saturated fatty acids, monounsaturated palmitoleic and oleic fatty acids, and polyunsaturated linolenic acid may increase the risk of pancreatic cancer, whereas gadolic acid (monounsaturated) and high intake of omega-3 fatty acids (polyunsaturated) may decrease risk. Pancreatic cancer risk also was decreased with increased intake of vitamin C or vitamin E, and we uniquely showed that the effect was largely due to intake from supplements rather than from food. Our results also suggested that the decreased pancreatic cancer risk associated with high intake of total vitamin E may be limited to or greater among never smokers, but should be interpreted with caution.
In our study, all individual saturated fatty acids were associated with an increased risk of pancreatic cancer independent of total energy intake. In contrast, a Canadian case-control study reported a decreased risk with increased intake of palmitic acid and of stearic acid, and no association with butyric acid and lauric acid (17
). In the Nurses' Health Study cohort, no association was reported with stearic acid (19
). Palmitic acid is the most common saturated fatty acid in the U.S. diet and is largely from consumption of red meat or processed meat, whereas dietary stearic, butyric, and lauric acids are less common and come mainly from dairy sources. Our saturated fatty acid results are consistent with results from our earlier analyses that showed a positive association between pancreatic cancer and foods containing high amounts of saturated fat such as ice cream, cheese, butter, beef, lamb, or certain processed meat (e.g., sausage, bacon) (21
). Two cohort studies also reported increased risk with higher intake of saturated fat (20
), high-fat dairy products (20
), and with higher intake of saturated fat from red meat or processed meat (14
). However, cohort study results also have reported no association with dairy products (14
), or with any type of fat or meat (19
We found a modest increase in pancreatic cancer risk with higher intake of the monounsaturated palmitoleic acid and oleic acid, and with the polyunsaturated linolenic acid. Results from three case-control and two cohort studies that assessed fatty acid intake (17
) are somewhat inconsistent with our findings. Overall, these results are inconclusive showing decreased risk with higher intake of oleic acid (17
) and linoleic acid (22
), and no association with any individual polyunsaturated fatty acids (17
), or with oleic acid, linoleic acid, or α-linolenic acid (18
). It is possible that small sample size (19
) and use of proxy data (22
) in some studies contributed to the discrepant results. The inconsistency of our results with the two large case-control studies (17
) may be due to other study design-related differences including use of different measurement tools, unmeasured confounding, and differences in the range, average and median amount of fatty acid intake across the studied populations. For example, although vegetable oils and nuts have among the highest concentration of these fatty acids, the common sources for these fatty acids in European and U.S. populations are animal products (meat, dairy products) or foods prepared with cooking oils (e.g., potato chips, French fries) (55
). As these food sources of fatty acid have been associated with increased risk of cancer, it may be difficult to separate the fatty acid effects from effects of other food components in populations with high consumption of animal products or processed foods.
In our study, there was some evidence of a decreased pancreatic cancer risk with high intake of the monounsaturated gadolic acid and the polyunsaturated long-chain omega-3 fatty acid. The reported association between pancreatic cancer and gadolic acid intake is unique to our study and the association with the long-chain omega-3 fatty acid was limited to participants with the highest intake (≥0.85 g/day, n=98). The dietary sources of these fatty acids are mainly fish and other seafood, especially fatty cold-water fish. Evidence from experimental studies indicates that long-chain omega-3 fatty acids (e.g., eicosapentaenoic acid, docosahexaenoic acid), that are present in fatty cold-water fish and fish oils can inhibit pancreatic carcinogenesis (25
). Epidemiologic studies have shown mixed results for the association between fish intake and pancreatic cancer (14
), and no association was found in the one published study among smokers that investigated the relationship between intake of marine omega-3 fatty acids and pancreatic cancer risk (20
). The inconsistent or null findings in these studies could be related to the low intake of fish or long-chain omega-3 fatty acids in the studied populations. In our study, the inverse association was among participants who had the highest intake, suggesting that the low within-population variability in the intake of fish or long-chain omega-3 fatty acids also may contribute to the null findings. Although there are compelling data attributing positive health effects with intake of omega-3 fatty acids, the literature to support a chemopreventive effect in pancreatic cancer is limited. Further large studies or pooled studies that are designed to assess markers of nutrient intake, e.g. clinical, biological and epidemiological, are needed to confirm these findings and to elucidate the associated biologic mechanisms.
Results from our study provide support for the hypothesis that antioxidants may reduce the risk of pancreatic cancer. Total vitamin C or E intake was associated with a greater than 30% decreased risk of pancreatic cancer among those with the highest intake and was largely due to intake from supplements rather than from food. We found no association for vitamin C or E intake from food alone and the median values for the highest quartiles of total intake of vitamin C or E were increased ~5 to 40-fold over that from food alone. Our results showed that the decreased risk with total intake was driven by those with a high supplemental intake of these vitamins. Similar to our study, six case-control and three cohort studies reported no association with increased intake of vitamin C or E from food (18
). However, the overall results have been mixed, as five other case-control studies have reported a decreased risk with vitamin C intake (16
) and with vitamin E intake (44
). The two studies that have published results of supplemental vitamin C use and pancreatic cancer risk suggested that ever use of vitamin C supplements was associated with a decreased risk of pancreatic cancer (18
). Discrepancies in results may be partly explained by the narrow range of foods rich in dietary vitamin C (citrus fruits and drinks), and in vitamin E (vegetable oils and nuts), differences in the range, average and median amount of antioxidant nutrient intake across populations, use of inadequate dietary assessment tools and small sample size. It is also possible that unmeasured variation in vitamin E transport genes or other antioxidant metabolism genes (e.g. SOD2) could partially explain apparent discrepancies in results. Given our results and the increasing prevalence of supplement use in the U.S. population (64
), continued assessment of these nutrients is warranted and it will be important for future studies to collect supplement use data to clarify the association between these nutrients and pancreatic cancer risk.
Our results suggesting that the reduced risk of pancreatic cancer associated with high intake of total vitamin E may be limited to or greater among never smokers is somewhat supported by results from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study that showed no risk reduction with high intake of vitamin E among male smokers (62
), although this study recently reported that high serum α-tocopherol concentration was associated with a lower pancreatic cancer risk in this population (54
). There also is some evidence that smokers have lower plasma concentrations of vitamin E than nonsmokers due to the effect of oxidative stress from cigarette smoke (65
). Although intriguing and biologically plausible, the differences across smoking strata could be due to chance and continued investigation is needed to confirm and clarify our results.
The biologic mechanisms to explain how dietary fat may affect risk for pancreatic cancer remain to be elucidated. However, studies have shown that high fat and certain fatty acids can promote excretion of bile acids resulting in increased bile reflux into the head of the pancreas that then may act as a tumor promoter (67
). In addition, saturated fat and some monounsaturated fatty acids also can increase insulin resistance (23
), a suggested risk factor for the development of pancreatic cancer (8
). The association between pancreatic cancer and vitamins C and E is biologically plausible given their strong antioxidant properties that are known to have anti-carcinogenic effects. Vitamins C and E can block reactive oxygen species, reducing oxidative stress and thus reducing cancer-causing mutations (34
). Vitamins C and E also may alter pancreatic cancer risk through their ability to stimulate immune function (68
). Additional studies are needed to confirm and clarify these associations.
In this large population-based study, in-person interviews were conducted by trained and experienced interviewers. Rapid case ascertainment with a goal to identify eligible cases within one month of diagnosis was used to reduce selection bias and to minimize the effects of the short survival and high mortality rates on patient recruitment. No proxy interviews were conducted and props and photos were used for portion sizes to help reduce reporting and information bias. For most factors, participants were asked to report their exposure prior to the one year before their cancer diagnosis (cases) or interview (controls), to diminish potential effects related to reverse causation. Dietary data collected in the FFQ pertained to average intake of foods in the one year prior to diagnosis/interview. To assess whether cases were more likely to have recently changed their diets, possibly related to their cancer, we analyzed dietary changes over the past 10 years. We found that controls were more likely than cases to report dietary changes and these changes were toward ‘healthier diets’ e.g.
more fruits and vegetables, less red meat (45
). Our use of rapid case ascertainment to identify and interview patients shortly after diagnosis combined with few commonly known risk factors for pancreatic cancer, also would have helped to diminish recall bias and resultant misclassification of exposures. Any non-differential misclassification would have biased our results toward the null. However, if recall and thus misclassification of diet were related to case-control status in our study then the effect estimates may be biased either away from or toward the null. Also, given the high fatality rate of pancreatic cancer, if cases who were interviewed were healthier and more likely to have had better diets with resultant higher levels of nutrient intake compared with not interviewed cases, then our results may be biased toward the null. The large sample size and extensive dataset allowed us to assess multiple lifestyle factors and exposures as potential confounders and effect modifiers of diet. However, more than 80% of the study population was non-Hispanic white and our results may not be generalizable to non-white populations, especially blacks/African-Americans who have high pancreatic cancer incidence and mortality rates.
In conclusion, results from this large population-based case-control study provide additional evidence that dietary factors and use of supplements may affect risk of pancreatic cancer. Our results showing increased risk of pancreatic cancer with increased saturated fatty acid intake and decreased risk with high intake of long-chain omega-3 fatty acid and of vitamin C and E from supplements contribute new data to the epidemiologic literature on pancreatic cancer. Future large studies are needed to confirm our findings and to clarify the role of specific nutrients from food and from supplements in pancreatic cancer development.