In this large, prospective investigation of red and processed meat intake in relation to cancer risk, we found elevated risks for colorectal and lung cancer with both meat types. Red, but not processed, meat intake was also associated with increased risk for cancer of the esophagus and liver. We observed borderline statistically significant elevated risks for advanced prostate cancer with both red and processed meat intake, for laryngeal cancer with red meat, and for bladder cancer and myeloma and with processed meat intake.
The cancer site most consistently associated with meat intake has been the colorectum. A recent meta-analysis of 15 prospective studies published through March, 2006, included approximately 7,500 cases, and reported elevated risks in the highest category of consumption of 28% for red meat and 20% for processed meat [9
]. Our study included over 5,000 colorectal cancer cases, and it lends strong support to implicate red and processed meat as risk factors for this malignancy. Consistent with previous studies [9
], we observed a stronger positive association for rectal than colon cancer.
The positive associations for both red and processed meat that we report for lung cancer were of similar magnitude to the findings for colorectal cancer. To date, our study includes the largest prospective analysis of meat intake and lung cancer risk. Previous case-control studies have reported elevated risks for lung cancer for those in the highest categories of red meat [17
], fried red meat [8
], well-done red meat [17
], and processed meat intake [20
]. Despite conducting analyses to show that very fine control of smoking history, using a 31-level variable, did not attenuate the lung cancer associations, there remains a potential issue of residual confounding by smoking, because it is such a strong risk factor for this disease.
We found a positive association between red meat intake specifically and cancers of the esophagus and liver, and a borderline significant positive association for laryngeal cancer. The first prospective study of meat intake and esophageal cancer was published recently; that study had only 65 cases and found a positive association for processed meat, but not red meat, with esophageal adenocarcinoma [21
]. Our study suggests a threshold effect for red meat intake on esophageal cancer risk, beginning at a low level of intake, with no further increase in risk with higher intakes, as reflected in the p
= 0.13), although it is possible that the referent group had a smaller-than-expected cancer incidence by chance. Data on meat intake and cancers of the liver and larynx are limited, and our study is the first prospective investigation to report on these associations. Two case-control studies reported elevated risks for laryngeal cancer for those in the highest intake categories of red meat intake [22
] and fried beef/veal [24
In our study, those in the highest quintile of processed meat intake had borderline statistically significant elevated risks for myeloma, a malignancy that has not been well-studied for dietary associations, and bladder cancer. A study of two prospective cohorts combined [25
], and one case-control study [26
], both found elevated risks of bladder cancer for those in the highest categories of processed meat consumption, but another cohort study found no association [27
Unexpectedly, we found an inverse association between red meat intake and endometrial cancer; this association was not attenuated by adjustment for known risk factors, such as body mass index or menopausal hormone therapy, or by fine control for smoking, which has been inversely associated with this malignancy [28
]. Previous studies have reported null [29
] or positive relations [31
] between red meat and endometrial cancer. We also observed inverse associations between processed meat intake and leukemia and melanoma. In contrast to our findings, childhood leukemia has been positively associated with intake of processed meats in a case-control study [32
Both red and processed meat intake were positively associated with pancreatic cancer in men, but not women. Red meat has been associated with pancreatic cancer in some [33
], but not all [35
] previous cohort studies, as has processed meat in one cohort [34
] and several case-control studies [40
]; although a sex-specific association has not been reported before. Although the association between pancreatic cancer and red or processed meat intake in men was unchanged by fine control for smoking, residual confounding by smoking is still possible.
Our study did not reveal an association between red or processed meat intake and gastric, prostate, or breast cancer, or non-Hodgkin lymphoma. In contrast to the positive relation between both red and processed meat intakes and noncardia gastric cancer in a large cohort in Europe [21
], we found no differences in risk according to gastric anatomic subsite. The evidence for a positive association between meat intake and gastric cancer has been more consistent for processed meat than red meat, with elevated risks for processed meat in several case-control [45
] and cohort studies [53
], whereas red meat has been positively associated in some [45
], but not all studies [47
Previous studies of meat intake and prostate cancer are conflicting. Some studies have reported null findings [5
], and others suggest positive associations [67
]. Despite finding no association between red or processed meat intake and overall prostate cancer risk, we observed a suggestion of an elevated risk for advanced prostate cancer with both meat types. If the relation of meat intake to prostate cancer is confined to advanced disease, this could explain some of the inconsistencies in the literature as most previous studies have not specifically addressed advanced prostate cancer.
With regard to breast cancer, a pooled analysis of eight cohort studies found no association with red meat intake [75
]; however, the two most recent prospective studies found positive associations for both red and processed meat [76
], specifically for estrogen and progesterone receptor–positive breast cancers in premenopausal women [77
]. Although breast cancer risk related to meat intake did not appear to differ by menopausal status in our study, we had very few premenopausal cases (n
= 94) and lacked information on hormone receptor status for a large number of cases.
In agreement with our findings, the majority of studies of red meat and non-Hodgkin lymphoma have been null [78
], although elevated risks were reported in some studies [86
]; similarly, of nine studies investigating processed meat and non-Hodgkin lymphoma [79
], only two found a positive association [81
]. In contrast to our null findings, some case-control studies have reported positive associations for red or processed meat intake and cancer of the oral cavity, pharynx [90
], kidney [92
], ovaries [83
], thyroid [83
], and brain [93
], although data for these cancer sites are limited.
Both red meat, regardless of processing procedure, and processed meat can be linked to carcinogenesis by different mechanisms; for example, they are both sources of saturated fat and iron, which have independently been associated with carcinogenesis. Associations between saturated fat and cancer are likely to be related to energy balance in general, whereas iron is thought to contribute to carcinogenesis specifically by generating free radicals and inducing oxidative stress [94
]. Most recently, dietary fat was positively associated with breast cancer [95
], and iron intake was positively associated with liver [96
] and colorectal cancers [97
Meat is also a source of several known mutagens, including N
-nitroso compounds (NOCs), heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs). Exposure to NOCs occurs from endogenous formation, which is directly related to red meat intake [98
], and from exogenous exposure from nitrite-preserved meats, for example [1
]. Red meat is a large source of readily available heme iron, which has been associated with increased endogenous NOC formation [99
]. Human exposure to NOCs and subsequent cancer risk has not been studied extensively; although a Finnish cohort reported an increased risk of colorectal cancer with exogenous exposure to N
-nitrosodimethylamine (from smoked and salted meats) [6
]. In addition, NOC intake and excretion were significantly greater in an area within China considered as high-risk for esophageal cancer [100
]. HCAs and PAHs, which are formed during high-temperature cooking of meat [101
], dose-dependently generate DNA adducts [3
] and tumors in rodents [2
] in a wide variety of tissues and organs, with similarities between experimental animals and humans [103
]. Epidemiologic studies with the capacity to estimate HCA and PAH intake from meat cooking information have found elevated risks of colorectal neoplasia [104
], squamous cell esophageal cancer [107
], as well as cancers of the lung [8
], pancreas [4
], and prostate [5
With regard to the stronger relation of red and processed meat to rectal cancer than to colon cancer, there is variation in several characteristics along the large intestine; for example, the average crypt length [108
], apoptotic index [109
], and propensity to form 06
] (pro-carcinogenic and a marker of NOC exposure) is greater toward the rectum than in the proximal colon. Furthermore, there is variation throughout the colorectum in bacterial enzymes [111
], in the fermentation of short chain fatty acids [112
], in the expression of metabolic enzymes [113
], and in the concentration of fecal matter, in which potential carcinogens are concentrated toward the rectum.
Despite abundant biologic pathways linking meat intake to carcinogenesis at numerous anatomic sites, this is the first comprehensive and prospective analysis of meat intake in relation to a full range of malignancies. A particular strength of this study includes the large size of the cohort, which enabled us to investigate low-incidence cancers that have not previously been prospectively explored. Our findings are strictly generalizable to US whites over 50 y old, but may readily extend to other populations, because it is unlikely that the mechanisms relating meat to carcinogenesis differ quantitatively between our study population and those to whom our results do not strictly apply. An additional strength was that our study encompassed a wide range of reported meat intake, providing adequate statistical power to detect associations. Furthermore, recall bias and reverse causation were minimized by the assessment of diet prior to cancer diagnoses.
Potential limitations of this study include some degree of measurement error associated with the assessment of dietary and lifestyle variables. The FFQ used in this study was compared with two 24-h recall diaries in a subgroup of individuals from this cohort. The energy-adjusted correlation coefficients for protein and saturated fat, the two most relevant macronutrients for meat, were 0.43 and 0.50 for men and women, respectively, for protein, and 0.76 and 0.69 for men and women, respectively, for saturated fat [114
]. These correlations compared very favorably to other commonly used FFQs that have correlations ranging from 0.29 to 0.61 in men and from 0.16 to 0.67 in women for protein intake and from 0.64 to 0.76 in men and from 0.59 to 0.76 in women for saturated fat intake [114
]. Furthermore, the correlations for red meat assessed from the FFQ compared with two 24-h recall dairies were 0.62 for men and 0.70 for women [12
]. Although some measurement error remains, the error associated with FFQs tends to result in attenuated risks [115
], and we attempted to minimize this error by energy adjustment of the models [116
]. With regard to nondietary covariates, reviews and meta-analyses have concluded that self-reported smoking behavior is accurate in most studies as assessed by plasma cotinine levels [117
], and the correlations for physical activity assessment in questionnaires similar to that used in our study produce reasonable correlations [118
]. Furthermore, self-reported height and weight is a reliable method of estimating BMI.
Some of the observed associations between meat intake and cancer risk in our study may be explained by exposure to HCAs and PAHs from meats cooked well-done by high-temperature cooking techniques; however, we lacked data on detailed cooking preferences from baseline. In addition, because we analyzed cancer incidence at multiple sites, some of our findings may have occurred by chance.
In conclusion, a diet high in red or processed meat was associated with an elevated risk of both colorectal and lung cancer; in addition, red meat was associated with an elevated risk of esophageal and liver cancer. A decrease in the consumption of red and processed meat could reduce the incidence of cancer at multiple sites.