Nitrosamines and Heme Iron and Risk of Prostate Cancer in the European Prospective Investigation into Cancer and Nutrition

Prostate cancer is the second most common cancer diagnosed in men, and it is the sixth most common cause of cancer mortality worldwide (1). It has been suggested that some aspect of a Western diet, such as a high meat intake, may increase prostate cancer risk (2, 3). There are various mechanisms by which meat could increase risk, one of which is via heme iron, which can promote endogenous production of NOCs (Nitrosocompounds; ref. 4); in addition, any sources of iron can also catalyze free radical formation leading to oxidative cell damage (5). Although a recent meta-analysis on cohort studies is not supportive of a positive association with red or processed meat (6), it does not preclude an association with certain aspects of meat intake, such as its content of heme iron, or nitrosamines. The aim of this study was to examine the association between dietary nitrosamines (endogenous and exogenous), heme iron intake and prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

The rationale and design of EPIC conducted in 23 centers in 10 European countries were described in detail elsewhere (7). A questionnaire collected information about sociodemographic and lifestyle characteristics and medical history. Dietary data were collected by validated country-specific questionnaires that recorded the usual dietary intake over the previous 12 months (7), and which were used to estimate preformed NDMA (N-Nitrosodimethylamine) from different food groups, predicted ENOC (endogenous NOCs; μg/d; ref. 8) and heme iron intake, as described elsewhere (9, 10).

Men were not eligible for this analysis if they had no dietary or nondietary data were missing (5,761 men). Individuals were also excluded if they were in the top or bottom 1% of the distribution of the ratio of reported energy intake to energy requirement (79 cases), to reduce the impact of implausible extreme values in the analysis (11). One male noncase from Athens, who was aged <30 at recruitment, was excluded. We also excluded subjects with an extreme heme iron intake (heme iron >4 mg/d; 2% of cases and noncases). Following these exclusions, complete data on diet and follow-up for cancer were available for 139,005 men of the 148,016 men in the original data set.

Prostate cancer case ascertainment was via cancer registries, active follow-up, and other methods as previously described (12). Proportional hazards models were used to estimate the association between nitrosamines (NDMA and ENOC) and heme iron and prostate cancer risk. Age was used as the underlying time scale, with entry time defined as age at recruitment and exit time defined as age at first prostate tumor (cases) and age at death or last complete follow-up (noncases). All models were stratified by age and center and adjusted for confounding variables (see Table 2). Subgroup analyses were also carried out according to stage and grade of the tumor, as previously described (12). Trend tests were done by assigning the median value for each quintile category and modeling this as a continuous variable. The Statistical Analysis System version 9 (SAS Institute) was used for analyses.

After a mean follow-up of 11 years, 4,606 prostate cancer cases were identified. The association of lifestyle characteristics by dietary intake of nitrosamine and heme iron is shown in Table 1. In multivariable models, prostate cancer risk was not associated with intake of nitrosamines (HR for the highest vs. lowest quintile: 0.91; 95% CI: 0.81–1.03 for ENOC, and 1.04; 95% CI: 0.95–1.18 for NDMA) or heme iron (HR for the highest vs. lowest quintile: 1.00; 95 CI: 0.88–1.39). This lack of association was supported by analyses of continuous variables (Table 2). Furthermore, similar findings were found when stratifying prostate cancer cases by grade and stage.

To our knowledge this is the first European prospective study of nitrosamines, heme iron intake, and prostate cancer risk. We found no overall association between intake of nitrosamines and heme iron and prostate cancer risk. One study reported that heme iron intake was associated with a 9% increased risk for total prostate cancer and 28% for advanced disease (3), but we did not find any associations of the dietary factors with risk regardless of stage or grade. One possible explanation for our null findings is that red meat intake (the most important source of heme iron) is also a source of selenium and zinc. The WCRF report (1) judges foods containing selenium as probably protective against prostate cancer. However, a previous analysis from our group did not find any association between plasma selenium and prostate cancer risk (13). The strengths of this study include its large size, prospective design, and adjustment of potential confounding variables.

In summary, our findings do not support the hypothesis that dietary nitrosamines and heme iron intakes are associated with the risk of developing prostate cancer.

No potential conflicts of interest were disclosed.