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A number of studies have reported that intake of red meat or meat cooked at high temperatures is associated with increased risk of breast cancer, but other studies have shown no association. We assessed the association between meat, meat-cooking methods, and meat-mutagen intake and postmenopausal breast cancer in the NIH-AARP Diet and Health Study cohort of 120,755 postmenopausal women who completed a food frequency questionnaire at baseline (1995–1996) as well as a detailed meat-cooking module within 6 months following baseline. During 8 years of follow-up, 3,818 cases of invasive breast cancer were identified in this cohort. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). After adjusting for covariates, intake of total meat, red meat, meat cooked at high temperatures, and meat mutagens showed no association with breast cancer risk. This large prospective study with detailed information on meat preparation methods provides no support for a role of meat mutagens in the development of postmenopausal breast cancer. © 2008 Wiley-Liss, Inc.
High temperature cooking of meat such as grilling/barbecuing and pan-frying especially to a high degree of doneness produces high concentrations of heterocyclic amines (HCAs), such as 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), compared to stewing or microwaving of meats.1, 2 The amounts of these compounds that are produced vary depending on the cooking method, temperature, duration of cooking and type of meat.1, 3
Both HCAs and PAHs can induce mammary tumors in laboratory animals.4, 5 However, epidemiologic studies examining both meat preparation methods and estimated intake of HCAs in relation to breast cancer risk have yielded inconsistent results, with some showing a positive association with degree of doneness or estimated intake of mutagens/carcinogens6–10 and others showing no evidence of an association.11–13 Some of these studies had limited information on methods of cooking different types of meat, degree of doneness and estimation of mutagenic compounds.6, 11, 12 Additionally, case-control studies may be subject to recall and selection bias.6, 9–11, 13
In view of the inconsistent results of previous studies, we used detailed data on meat intake, meat preparation methods and estimated intake of meat-mutagens as measured in the NIH-AARP Diet and Health Study to determine whether these factors influenced the risk of breast cancer in postmenopausal women.
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Mean body mass index, use of oral contraceptives, mean energy intake and saturated fat intake increased with increasing red meat intake (Table I). In contrast, the proportions of women with higher education, who were African-American, nulliparous, over age 30 at first birth, never smokers, current users of menopausal hormone therapy, who engaged in physical activity 5+ times per week, and who were 50 or older at onset of menopause decreased with increasing meat intake.
In the age-adjusted models for intake of total meat, red meat and meat cooked at high temperatures, there were slight elevations in the HR, some of which reached statistical significance; however, there was no trend with increasing intake (Table II). In the multivariable models, intake of total meat, red meat, white meat, processed meat and meat cooked at high temperatures were not associated with breast cancer risk. Deciles of these meat variables also showed no elevation in the hazard ratios, which were all close to 1.0 (data not shown). Furthermore, omitting saturated fat as a covariate did not alter the risk estimates (data not shown). When cases diagnosed during the first 3 years of follow-up were excluded, the results were unchanged (data not shown).
Table II. Hazard Ratios (HR) and 95% Confidence Intervals (95% CI) for Meat Intake and Postmenopausal Breast Cancer (n = 3,818 Cases) in the NIH-AARP Diet and Health Study1
|Type of meat||Quintiles of daily meat intake, g/1,000 kcal||p for trend2|
|Total Meat||≤38.2||>38.2 and ≤53.7||>53.7 and ≤68.9||>68.9 and ≤89.1||>89.1|| |
| Cases/person-years||728/172,445||800/172,025||791/172,163||765/169,741||734/163,452|| |
| Age-adjusted HR (95% CI)3||1.00 (ref.)||1.10 (1.00–1.22)||1.10 (0.99–1.21)||1.08 (0.98–1.20)||1.09 (0.98–1.21)||0.21|
| Multivariable-adjusted HR (95% CI)4||1.00 (ref.)||1.07 (0.96–1.18)||1.04 (0.94–1.15)||1.02 (0.92–1.13)||1.03 (0.93–1.15)||0.91|
|Red Meat||≤13.0||>13.0 and ≤21.9||>21.9 and ≤31.1||>31.1 and ≤43.7||>43.7|| |
| Cases/person-years||718/175,830||791/172,628||818/170,852||768/167,837||723/162,679|| |
| Age-adjusted HR (95% CI)||1.00 (ref)||1.12 (1.02–1.24)||1.18 (1.06–1.30)||1.13 (1.02–1.26)||1.11 (1.00–1.23)||0.07|
| Multivariable adjusted HR (95% CI)||1.00 (ref)||1.09 (0.98–1.21)||1.13 (1.02–1.26)||1.07 (0.97–1.20)||1.05 (0.93–1.18)||0.66|
|White Meat||≤14.9||>14.9 and ≤24.1||>24.1 and ≤ 35.0||>35.0 and ≤52.2||>52.2|| |
| Cases/person-years||771/168,214||757/169,927||769/171,786||787/171,507||734/168,394|| |
| Age-adjusted HR (95% CI)||1.00 (ref)||0.96 (0.87–1.06)||0.96 (0.87–1.07)||0.99 (0.90–1.10)||0.96 (0.87–1.06)||0.68|
| Multivariable adjusted HR (95% CI)||1.00 (ref)||0.94 (0.85–1.04)||0.94 (0.85–1.04)||0.96 (0.87–1.06)||0.93 (0.84–1.04)||0.36|
|Processed Meat||≤2.2||>2.2 and ≤4.4||>4.4 and ≤7.3||>7.3 and ≤12.5||>12.5|| |
| Cases/person-years||752/173,867||790/173,015||722/170,070||817/167,420||737/165,454|| |
| Age-adjusted HR (95% CI)||1.00 (ref)||1.06 (0.95–1.17)||0.98 (0.88–1.09)||1.13 (1.02–1.25)||1.03 (0.92–1.14)||0.32|
| Multivariable adjusted HR (95% CI)||1.00 (ref)||1.02 (0.92–1.13)||0.95 (0.86–1.06)||1.09 (0.98–1.21)||1.00 (0.90–1.12)||0.55|
|Meat cooked at high temperatures||≤3.5||>3.5 and ≤7.0||>7.0 and ≤11.2||>11.2 and ≤18.0||>18.0|| |
| Cases/person-years||738/174,952||765/172,608||805/171,225||773/167,160||737/163,882|| |
| Age-adjusted HR (95% CI)||1.00 (ref)||1.05 (0.95–1.16)||1.12 (1.01–1.24)||1.11 (1.00–1.24)||1.10 (0.98–1.22)||0.07|
| Multivariable adjusted HR (95% CI)||1.00 (ref)||1.00 (0.90–1.12)||1.02 (0.91–1.14)||1.02 (0.91–1.15)||0.98 (0.86–1.11)||0.80|
Breast cancer risk was not associated with high-temperature cooking methods or level of doneness (Table III). The age-adjusted HR for intake of rare-/medium-done meat was statistically elevated, but there was no association in the fully-adjusted model.
Table III. Hazard Ratios (HR) and 95% Confidence Intervals (95% CI) for Meat Cooking Methods, Doneness Levels and Postmenopausal Breast Cancer (n = 3,818 Cases) in the NIH-AARP Diet and Health Study1
|Variable||Level of meat intake, g/1,000 kcal||p trend2|
|Meat cooking method:|
|Grilled or barbecued meat|
| ||<0.05||>0.05 and ≤5.3||> 5.3 and ≤14.3||>14.3|| |
| Cases/person-years||763/170,555||987/226,243||1,021/226, 679||1,047/226,349|| |
| Age-adjusted HR (95% CI)3||1.00 (referent)||0.98 (0.89–1.08)||1.02 (0.93–1.12)||1.07 (0.97–1.17)||0.08|
| Multivariable HR (95% CI)4||1.00 (referent)||0.96 (0.87–1.05)||0.98 (0.89–1.08)||0.99 (0.90–1.10)||0.91|
| ||0||>0 and ≤0.4||>0.4–≤2.8||>2.8|| |
| Cases/person-years||1,517/340,815||774/170,582||788/169,687||739/168,738|| |
| Age-adjusted HR (95% CI)||1.00 (referent)||1.05 (0.97–1.14)||1.08 (1.00–1.17)||1.01 (0.93–1.10)||0.33|
| Multivariable HR (95% CI)||1.00 (referent)||1.01 (0.93–1.10)||1.03 (0.94–1.12)||0.96 (0.88–1.05)||0.65|
| ||0||>0 and ≤3.8||>3.8–≤10.9||>10.9|| |
| Cases/person-years||2,413/539,286||484/103,713||462/103,492||459/103,332|| |
| Age-adjusted HR (95% CI)||1.00 (referent)||1.05 (0.95–1.15)||1.00 (0.91–1.11)||1.00 (0.91–1.11)||0.85|
| Multivariable HR (95% CI)||1.00 (referent)||1.05 (0.95–1.15)||0.99 (0.89–1.09)||0.98 (0.89–1.08)||0.87|
|Sauteed, baked, or microwaved meat|
| ||0||>0 and ≤2.3||>2.3–≤8.1||>8.1|| |
| Cases/person-years||1,198/285,684||870/187,983||867/188,003||883/188,152|| |
| Age-adjusted HR (95% CI)||1.00 (referent)||1.10 (1.01–1.19)||1.09 (1.00–1.18)||1.11 (1.02–1.21)||0.03|
| Multivariable HR (95% CI)||1.00 (referent)||1.06 (0.97–1.15)||1.04 (0.95–1.14)||1.06 (0.97–1.16)||0.20|
|Meat doneness level:|
|Rare/medium done cooked meat|
| ||0||>0 and ≤5.9||>5.9–≤16.4||>16.4|| |
| Cases/person-years||999/240,970||904/203,412||980/203,216||935/202,223|| |
| Age-adjusted HR (95% CI)||1.00 (referent)||1.07 (0.99–1.16)||1.17 (1.08–1.27)||1.14 (1.05–1.23)||0.0009|
| Multivariable HR (95% CI)||1.00 (referent)||1.01 (0.92–1.11)||1.06 (0.97–1.16)||1.00 (0.91–1.10)||0.71|
|Well/very well-done cooked meat|
| ||0||>0 and ≤4.9||>4.9–≤14.4||>14.4|| |
| Cases/person-years||300/65,378||1,186/261,152||1,180/261,762||1,152/261,530|| |
| Age-adjusted HR (95% CI)||1.00 (referent)||1.06 (0.98–1.16)||1.05 (0.96–1.15)||1.04 (0.95–1.13)||0.61|
| Multivariable HR (95% CI)||1.00 (referent)||0.98 (0.89–1.07)||0.97 (0.89–1.07)||0.98 (0.89–1.07)||0.64|
Neither the age-adjusted nor the fully-adjusted models showed any suggestion of an association between any of the 5 indicators of mutagenic activity (overall mutagenic activity, DiMeIQx, MeIQx, PhIP, or B[a]P) and breast cancer risk (Table IV). Deciles of these indicators also showed no association.
Table IV. Hazard Ratios (HR) and 95% Confidence Intervals (95% CI) for Intake of Meat Mutagens, Mutagenic Activity Index and Postmenopausal Breast Cancer (n = 3,818 Cases) in the NIH-AARP Diet and Health Study1
| ||Quintiles of daily meat mutagen intake||p for trend2|
|Overall mutagenic activity, revertant colonies/1,000 kcal|
| ||≤254||>254 and ≤640||>640 and ≤1,232||>1,232 and ≤2,414||>2,414|| |
| Cases/person-years||754/170,077||791/169,541||797/169,583||772/169,995||704/170,666|| |
| Age-adjusted HR (95% CI)3||1.00 (ref.)||1.04 (0.95–1.15)||1.07 (0.97–1.19)||1.03 (0.94–1.14)||0.95 (0.86–1.05)||0.34|
| Multivariable-adjusted HR4 (95% CI)||1.00 (ref.)||1.02 (0.92–1.13)||1.04 (0.94–1.16)||1.02 (0.92–1.13)||0.94 (0.84–1.04)||0.27|
|2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), ng/1,000 kcal|
| ||0||>0 and ≤0.05||>0.05 and ≤0.30||>0.30 and ≤0.83||>0.83|| |
| Cases/person-years||1,442/316,166||98/23,862||784/169,459||783/170,089||711/170,245|| |
| Age-adjusted HR (95% CI)||1.00 (ref)||0.94 (0.77–1.16)||1.00 (0.92–1.09)||1.01 (0.93–1.11)||0.92 (0.84–1.01)||0.25|
| Multivariable adjusted HR (95% CI)||1.00 (ref)||0.97 (0.79–1.20)||1.02 (0.93–1.11)||1.04 (0.95–1.13)||0.95 (0.86–1.04)||0.60|
|2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), ng/1,000 kcal|
| ||≤1.1||>1.1 and ≤3.0||>3.0 and ≤ 6.2||>6.2 and ≤12.7||>12.7|| |
| Cases/person-years||742/170,214||789/170,117||761/169,778||776/169,594||750/170,119|| |
| Age-adjusted HR (95% CI)||1.00 (ref)||1.07 (0.96–1.18)||1.04 (0.94–1.15)||1.09 (0.99–1.21)||1.00 (0.91–1.11)||0.79|
| Multivariable adjusted HR (95% CI)||1.00 (ref)||1.04 (0.94–1.15)||1.03 (0.93–1.14)||1.07 (0.96–1.18)||1.00 (0.89–1.11)||0.87|
|2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), ng/1,000 kcal|
| ||≤3.6||>3.6 and ≤11.4||>11.4 and ≤26.0||>26.0 and ≤60.9||>60.9|| |
| Cases/person-years||761/181,617||731/157,877||851/169,686||740/169,678||735/170,964|| |
| Age-adjusted HR (95% CI)||1.00 (ref)||1.10 (1.00–1.22)||1.15 (1.04–1.27)||1.07 (0.98–1.19)||1.01 (0.91–1.12)||0.95|
| Multivariable adjusted HR (95% CI)||1.00 (ref)||1.06 (0.96–1.18)||1.11 (1.00–1.23)||1.04 (0.93–1.15)||0.98 (0.88–1.09)||0.57|
|Benzo(a)pyrene [B(a)P], ng/1,000 kcal|
| ||≤0.4||>0.4 and ≤2.1||>2.1 and ≤6.8||>6.8 and ≤18.6||>18.6|| |
| Cases/person-years||766/169,516||764/169,283||751/170,240||758/170,234||795/170,548|| |
| Age-adjusted HR (95% CI)||1.00 (ref)||1.00 (0.90–1.10)||0.98 (0.89–1.09)||1.00 (0.90–1.10)||1.06 (0.96–1.18)||0.27|
| Multivariable adjusted HR (95% CI)||1.00 (ref)||0.96 (0.88–1.05)||0.99 (0.91–1.08)||0.98 (0.90–1.08)||0.96 (0.88–1.06)||0.68|
No significant associations were seen by hormone receptor status (ER positive, ER negative, PR positive, PR negative) for intake of total meat, red meat, meat cooked at high temperatures, or 5 indicators of mutagenic activity (data not shown).
None of the meat or meat mutagen variables was associated with breast cancer within strata of age, body mass index, parity, alcohol consumption, smoking, menopausal hormone therapy or intake of fruits and vegetables (data not shown), and there were no significant interactions between the meat variables (intake of total meat, red meat, high-temperature meat, and well-done meat) and these factors.
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This large prospective cohort of AARP members provides no support for the hypothesis that intake of meat, meat cooked at high temperatures, well-done meat, or estimated intake of mutagens/carcinogens from meat are associated with increased risk of postmenopausal breast cancer. Furthermore, our results do not indicate that consumption of meat or meat cooked at high temperatures affected breast cancer risk in subgroups, such as obese or nulliparous women, consumers of alcohol, smokers, users of menopausal hormone therapy or women with low physical activity or with a low intake of fruits or vegetables.
A recent analysis from the NIH-AARP study reported on the association of intake of red and processed meat in relation to the risk of 21 cancers. Positive associations were seen with several cancers, including those of the colorectum and lung, but not with breast cancer.25 This article extends the findings of Cross et al. with regard to breast cancer by presenting more detailed results relating to meat preparation and intake of meat mutagens for the subcohort with complete meat module data.
In a previous publication from the NIH-AARP study,26 saturated fat intake showed a significant positive association with postmenopausal breast cancer risk; hence, it is included here as a covariate. However, in models omitting saturated fat intake, meat intake and use of high temperature preparation methods were not associated with breast cancer risk.
Previous epidemiologic studies that have examined the association of meat intake with breast cancer have yielded conflicting results. A meta-analysis of 31 studies with information on meat intake27 obtained a summary relative risk for the highest compared to the lowest level of total meat intake of 1.17 (95% CI 1.06-1.29). However, a pooled analysis of 8 cohort studies (3 of which were included in the meta-analysis) found no association with intake of total meat, red meat, or white meat.28 In contrast to the meta-analysis, the pooled analysis included only cohort studies with at least 200 cases and which had used a validated food-frequency questionnaire and involved reanalysis of the raw data from each of the studies using a common approach. Our results are in agreement with those of the pooled analysis.
Of a smaller number of studies (both case-control and cohort) that examined meat preparation methods and/or degree of doneness of consumed meat and estimated intake of meat mutagens with breast cancer risk, several reported positive associations,6–10 whereas others found no association.11–13 Among those studies reporting positive associations, two found a strong association with HCA exposure or degree of doneness of meat,6, 7 whereas others observed a more modest association.9, 10 One study10 observed a modest association for intake of grilled or barbecued and smoked meats over the life course in postmenopausal (but not premenopausal) women but no associations with FFQ-derived measures of PAHs or HCAs based on type of meat, cooking methods, and doneness. Several studies examined possible interactions between intake of meat or well-doneness and polymorphisms in genes involved in the metabolism of HCAs and PAHs.11–13, 29–32 The results of these studies are inconsistent and several had very small numbers in the key subgroups to assess interactions.31, 32
Strengths of this study include the use of a detailed questionnaire to assess intake of different types of meat, meat preparation, and doneness preferences as well as a linked database to estimate exposure to meat mutagens. In addition, this study had a wide range of variation in dietary intake. For example, among women in our study, median intake of red meat in the highest quintile was 7 times that in the lowest quintile. Other strengths include the prospective nature of the study, completeness of follow-up, the large number of postmenopausal breast cancer cases, and the ability to adjust for a large number of potential confounding variables. The large sample size and the wide range of food consumption habits of the cohort enhanced the ability to detect an association and to examine possible interactions.
Limitations include the fact that we were not able to assess the association of meat-related variables with premenopausal breast cancer because of the small number of such cancers in the cohort. Dietary intake based on FFQs is affected by measurement error,33, 34 which, if nondifferential, could reduce an association. In this study, as in most previous studies, diet was assessed in midlife. Therefore, it is possible that meat intake and exposure to meat mutagens at a younger age, and particularly during adolescence when the breasts are developing, may affect the risk of breast cancer. We were also unable to examine the effect of genes involved in the metabolism of HCAs and PAHs, such as N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2), cytochrome P450 1A2 (CYP 1A2), and glutathione transferases (GSTs).
In conclusion, results of this large prospective cohort of postmenopausal women do not support the hypothesis that a high intake of meat, red meat, processed meat, meat cooked at high temperatures, or meat mutagens is associated with increased risk of breast cancer.