In our study, red meat, processed meat, heme iron, nitrite/nitrate from meat, grilled/barbecued meat, and B[a]P were associated with elevated risks of advanced prostate cancer. We observed similar but less strong associations for total prostate cancer but no association for nitrite/nitrate. For fatal prostate cancer, we observed a suggestive positive association for red meat but not for other meat-related variables.
In their 2007 report (5
), a World Cancer Research Fund expert panel concluded that the evidence for a role of processed meat in the etiology of prostate cancer was “limited—suggestive,” and for red meat the evidence was at an even lower level of “limited—no conclusion.” Similar conclusions were reached in a review (8
) and some recent cohort studies (49
), although a review of fat and meat intake in relation to prostate cancer found that 16 out of 22 case-control and cohort studies showed a positive risk of 1.3 or more with higher total meat intake (9
). Few studies disaggregated meat into red and processed meat (9
); the studies that did, however, found evidence that different subtypes of meat may be associated with an increased risk (14
). Our results provide evidence in support of the premise that analyzing meat by subgroup is important. We found risks around 1.3 among men consuming red and processed meat in the highest quintile, while associations for white meat were null. We also observed that red processed meat specifically may be related to increased risk, providing evidence that specific components of this type of meat may be important.
We observed an increased risk of prostate cancer with heme iron intake but not with total iron from the diet. To our knowledge, the relation between heme iron and prostate cancer has not been previously investigated. Kolonel (9
) suggested that red meat may exert its role via other trace minerals such as selenium and zinc (high in red meat), which are essential for testosterone synthesis, but did not specifically address the role of heme in red meat. Tappel (52
) suggested that heme iron may damage many organs, including the prostate, by catalyzing free radical formation. Once absorbed, heme iron is transported by the blood to every organ and tissue, where it can catalyze oxidative reactions, causing damage to lipids, proteins, DNA, and other nucleic acids. The level of free radical damage caused by heme-catalyzed oxidation can be of a magnitude similar to that resulting from ionizing radiation (52
Another mechanism related to red and processed meat is the formation of NOCs, which are known carcinogens in multiple species (53
). Exposure to NOCs occurs from endogenous formation, which is directly related to red meat intake, as well as exogenous exposure from nitrite-preserved meats (28
). Heme iron is thought to be the component of red meat that leads to increased endogenous formation of NOCs (27
). Human exposure to NOCs and subsequent cancer risk has not been studied extensively. In this report, we present an indirect measure of NOC intake by estimating exposure to various factors (i.e., red and processed meat, heme iron, and nitrate/nitrite) known to increase production of NOCs.
Meat doneness is a surrogate measure of many compounds that are formed during the cooking process (46
). We did not find an association between meat doneness levels and prostate cancer in this study. In contrast, in 2 other cohort studies, investigators did observe positive associations with meat doneness. In the Agricultural Health Study, Koutros et al. (11
) found an increased risk of prostate cancer associated with intake of well-done/very well-done meat, and in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, Cross et al. (10
) reported a 1.7-fold increased risk of incident disease for consuming more than 10 g/day of very well-done meat.
Heterocyclic amines are formed from the reaction between creatine or creatinine (found in muscle meats), amino acids, and sugars (55
). Over 20 individual heterocyclic amines have been identified; heterocyclic amines most abundant in the human diet are PhIP, MeIQx, and DiMeIQx (56
). Most heterocyclic amines are potent bacterial mutagens, and at least 10 have been found to induce multisite tumors in laboratory animals (24
). PhIP, specifically, has been associated with an increased risk of prostate tumors in rats (24
). In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (10
), men in the highest quintile of PhIP had a 1.3-fold increased risk of incident disease. However, we did not observe an association between PhIP intake and prostate cancer in this study. Our results for PhIP intake are consistent with the null associations observed in a case-control study (n
= 317 cases) in New Zealand (61
) and the Agricultural Health Study (11
). Other cohort studies collecting detailed data on meat-cooking are ongoing.
We observed an increased risk of prostate cancer with intake of grilled/barbecued meat and B[a
]P. PAHs are mutagenic compounds formed in foods prepared by smoking or grilling/barbecuing (16
). Cooking meat over a flame results in fat/meat juices’ dripping onto the hot fire, which yields flames containing a number of PAHs that coat the surface of the food. B[a
]P is one of the most potent PAHs in animal studies and can induce leukemia as well as gastric, pulmonary, fore-stomach, esophageal, and tongue tumors in rodents (62
). Grilled and well-done steak, hamburgers, and chicken contain the highest levels of B[a
]P—up to 4 ng per gram of cooked meat (16
). Depending on individual factors, total PAH intake may vary between 25 μg/day and 300 μg/day. However, there is little evidence for an association of dietary PAHs with prostate cancer in published studies. The positive association we observed in this study needs to be investigated further in other cohort studies.
For fatal prostate cancer, we observed a suggestive increased risk with red meat intake, similar to our results for total and advanced prostate cancer. Even though the risk magnitudes were similar, we had fewer cases of fatal cancer, with limited power to reach statistical significance. For the other types of meat and meat-related compounds, our results for advanced prostate cancer more resembled those for total prostate cancer; this implies that they may influence the initiation and early progression of the disease rather than terminal progression. It could also be the case that a sizable number of the fatal prostate cancer cases were diagnosed at an earlier stage; this could have attenuated the association.
The principal strength of this study was the prospective design, the large size of the cohort, and the wide range of intakes. The questionnaire included details on meat-cooking practices, which allowed us to investigate various mechanisms by which meat may exert its effect in the etiology of prostate cancer. However, we were not able to disentangle the effects of each of the measurable meat-related compounds, since they were highly correlated. Our study also collected information on nondietary variables, such as PSA screening and prostate tumor characteristics, which enabled us to evaluate relations by tumor aggressiveness. Specifically, we evaluated associations with advanced prostate cancer—an endpoint that is considered more relevant for disease progression, since the majority of prostate tumors do not progress, and is less likely to be influenced by medical screening practices. Detection bias due to more frequent PSA screening among men with low meat intakes would tend to produce underestimation of a true positive association between red meat intake and total or early-stage prostate cancer. Although studying fatal prostate cancer cases clearly reflects the tumors that do progress, our study had a limited number of fatal cases and therefore lower statistical power for this endpoint.
The issues of measurement error in this study are similar to those of any nutritional epidemiology study in which estimates are based on memory and participants’ ability to recall their usual intake over a given period. We adjusted our models for reported energy intake to try and decrease the degree of measurement error somewhat. Estimated intakes of compounds related to the various mechanisms by which meat may exert its deleterious effect were based on the best databases available to date. However, these databases are small and need further refining. The problem of residual confounding is always an issue; even after careful adjustment with known confounders, it may still be important and could explain the relatively small associations found. For example, other combinations of dietary factors or certain dietary patterns could be related to both a higher consumption of red and processed meat and prostate cancer risk, thereby confounding the associations we observed. However, adjustment for a range of potential dietary confounders (e.g., alcohol, calcium, tomatoes, α-linolenic acid, vitamin E, zinc, selenium) did not meaningfully change the associations.
In conclusion, we found that consumption of red and processed meat was associated with increased risks of total and advanced prostate cancer. Further study of heme iron, nitrite/nitrate, grilled/barbecued meat, and B[a]P may provide insights into possible mechanisms underlying these associations. These novel findings should be investigated in other studies with detailed questionnaires, databases, and biomarkers.