Conceived and designed the experiments: SP JH IC EK JW. Performed the experiments: SP JH IC EK JW. Analyzed the data: SP JH JW. Contributed reagents/materials/analysis tools: JH EK JW. Wrote the paper: SP JH IC EK JW.
The authors have declared that no competing interests exist.
The association between meat consumption and prostate cancer remains unclear, perhaps reflecting heterogeneity in the types of tumors studied and the method of meat preparation—which can impact the production of carcinogens.
We address both issues in this case-control study focused on aggressive prostate cancer (470 cases and 512 controls), where men reported not only their meat intake but also their meat preparation and doneness level on a semi-quantitative food-frequency questionnaire. Associations between overall and grilled meat consumption, doneness level, ensuing carcinogens and aggressive prostate cancer were assessed using multivariate logistic regression.
Higher consumption of any ground beef or processed meats were positively associated with aggressive prostate cancer, with ground beef showing the strongest association (OR = 2.30, 95% CI:1.39–3.81; P-trend = 0.002). This association primarily reflected intake of grilled or barbequed meat, with more well-done meat conferring a higher risk of aggressive prostate cancer. Comparing high and low consumptions of well/very well cooked ground beef to no consumption gave OR's of 2.04 (95% CI:1.41–2.96) and 1.51 (95% CI:1.06–2.14), respectively. In contrast, consumption of rare/medium cooked ground beef was not associated with aggressive prostate cancer. Looking at meat mutagens produced by cooking at high temperatures, we detected an increased risk with 2-amino-3,8-Dimethylimidazo-[4,5-f]Quinolaxine (MelQx) and 2-amino-3,4,8-trimethylimidazo(4,5-f)qunioxaline (DiMelQx), when comparing the highest to lowest quartiles of intake: OR = 1.69 (95% CI:1.08–2.64;P-trend = 0.02) and OR = 1.53 (95% CI:1.00–2.35; P-trend = 0.005), respectively.
Higher intake of well-done grilled or barbequed red meat and ensuing carcinogens could increase the risk of aggressive prostate cancer.
Prostate cancer is the most common non-skin cancer and second most common cause of cancer related death in men in the United States
Numerous epidemiological studies have assessed the impact of dietary factors on prostate cancer, and those investigating meat consumption have given mixed results
One possible explanation for these equivocal results is that any potential meat association might be restricted to more advanced or aggressive disease. Prostate cancer is extremely heterogeneous: some tumors remain latent while others are more aggressive and rapidly progress. Studies focused on the more aggressive subtypes of prostate tumors have detected associations with meat intake
Another possible explanation for these equivocal results is that the key exposure is not just meat intake, but also how it is prepared. Recent studies looking at the doneness level or charred index of meat preparation have suggested an increased risk of prostate cancer from meats cooked at high temperatures, such as pan-frying or grilling
Here we further investigate the possibility that meat associations depend on prostate cancer aggressiveness and cooking methods. In particular, we studied the consumption of overall versus grilled meat, how well-done the latter was prepared, and the ensuing production of heterocyclic amines in a case-control study of men with aggressive prostate cancer. Given the public heath impact of prostate cancer, any dietary and chemo-preventive strategies to reduce the economic, emotional, and physical burden of prostate cancer would be critically important.
Between 2001 and 2004, aggressive incident prostate cancer cases and frequency- matched controls were recruited from the major medical institutions in Cleveland, Ohio (The Cleveland Clinic, University Hospitals of Cleveland, and their affiliates). Physicians at these institutions see a large majority of men diagnosed with prostate cancer in the Greater Cleveland area. Hence, while the sample was not formally population-based, the cases were fairly representative of men diagnosed with prostate cancer in the Cleveland region.
The cases were newly diagnosed with histologically confirmed disease, with any one of the following: Gleason score ≥7; tumor stage ≥T2c; or a prostate-specific antigen level greater than 10 ng/ml at diagnosis. Cases were contacted as quickly as possible following diagnosis with prostate cancer (median time between diagnosis and recruitment, 4.7 months). Studying more aggressive cases allowed us to focus on men with the most clinically relevant disease. Case diagnoses were verified from medical record review and Gleason scores were based on pathology reports from radical prostatectomy specimens when available and otherwise from biopsy specimens. A total of 501 cases were fully recruited into the study (e.g., provided biospecimens for other research); 470 completed the Food Frequency Questionnaire (FFQ) and 466 completed the meat preparation questionnaire and are included here.
To ensure the controls were representative of the source population of cases, controls were men who underwent annual medical exams at the collaborating medical institutions. Controls had no diagnosis of prostate cancer or any other non-skin cancer. At the study entry all controls underwent prostate cancer screening with serum PSA testing and follow-up if their PSA was inflated. If a value of 4.0 ng/ml or greater was attained then a formal evaluation for prostate cancer by a urologist was undertaken. Depending on the evaluation, a biopsy of the prostate for histological diagnosis was preformed. Follow up of 50 control patients with a PSA greater than 4.0 ng/ml led to the diagnosis of two new prostate cancer cases. Both cases met the criteria for aggressive prostate cancer and were subsequently included as cases in this study. Controls were frequency matched to cases with respect to age (within five years), ethnicity, and medical institution. Data was collected on demographic, clinical, and histological measures during an in-person computer aided interview. A total of 538 controls were recruited into the study. 512 of these completed the FFQ and 511 completed the meat preparation questionnaire and are included here.
Ethics approval for this study was obtained from the Institutional Review Board at the University of California, San Francisco committee on human research as well at all institutions/hospitals where participants were recruited and human experimentation was conducted (University Hospitals of Cleveland, and their affiliates - Cleveland Clinic Foundation, Case Western Reserve University, and the Henry Ford Health Systems). All patients in this study provided written informed consent.
Information regarding diet was collected using a validated semi-quantitative food frequency questionnaire (FFQ) developed by the Nutrition Assessment Shared Resource of the Fred Hutchinson Cancer Research Center with a particular focus on prostate cancer (
HCA and polycyclic aromatic hydrocarbon consumption levels were estimated for red meats by multiplying the grams of intake prepared in a particular manner by the appropriate mutagen content provided by the National Cancer Institute's CHARRED database (
For these analyses, we excluded 21 subjects because of implausible values for total calorie intake (<500 or >5,000 kcal/d), leaving 470 cases and 512 controls for the total meats analysis. In addition 5 subjects did not complete the grilled meat and food doneness table, and so are excluded from those analyses.
We examined the association between total and grilled meat intake, red meat doneness, and HCAs and aggressive prostate cancer using logistic regression models. We evaluated the main effects of individual meats and red meats combined. Meats were combined based on the way they were grouped on the food frequency questionnaire. Meat intake was categorized into three or four categories of increasing consumption based on the distribution of servings per week among control patients. HCAs were categorized into approximate quartiles based on their distribution among controls. Odds ratios and 95% confidence intervals comparing increasing weekly servings of meat to no meat consumption were reported. We also examined the joint effect of red meat consumption and doneness level. P-trend values were calculated with the exposures modeled continuously across all categories (i.e., assigning values of 1, 2, 3, and 4 for individuals within each of the four quartiles, respectively).
All logistic regression models were adjusted for the matching variables (age, ethnicity, and medical institution) as well as for total energy intake, incorporating calories as a continuous variable. Furthermore, to evaluate potential confounding due to other factors that might impact consuming more meats and prostate cancer screening, we examined the impact of the following covariates: family history of prostate cancer in first degree relatives (prostate cancer in brother and/or father), smoking (never, former, or current), body mass index (kilograms per meter squared (kg/m2)), prior history of PSA testing for prostate cancer (never/once/twice or more), education level (4 categories of levels of schooling), and omega 3 fatty acid intake. None of these covariates materially influenced the associations between meat, doneness, or HCA and prostate cancer (always resulting in a <10% change in the corresponding regression coefficients) and are thus excluded from our final models. All analyses were undertaken with SAS software (version 9.1; SAS Institute).
The demographic and clinical characteristics of the study subjects are presented in
Characteristic |
Cases (n = 470) | Controls (n = 512) | P-value |
||
Age (years), mean (SD |
65.8 | (8.3) | 65.9 | (8.5) | 0.86 |
Ethnicity, n (%) | 0.63 | ||||
African-American | 78 | (16.6) | 91 | (17.8) | |
Caucasian | 392 | (83.4) | 421 | (82.2) | |
Education, n (%) | <0.001 | ||||
<12 years | 43 | (9.1) | 45 | (8.8) | |
12 years or high school | 105 | (22.3) | 68 | (13.3) | |
Some college | 98 | (20.9) | 91 | (17.8) | |
≥College graduate | 223 | (47.4) | 306 | (59.8) | |
Family history of prostate cancer |
<0.0001 | ||||
Negative | 359 | (76.4) | 452 | (88.3) | |
Positive | 110 | (23.4) | 55 | (10.7) | |
Smoking, n (%) | 0.35 | ||||
Never | 192 | (40.9) | 208 | (40.6) | |
Former | 224 | (47.7) | 255 | (49.8) | |
Current | 53 | (11.3) | 45 | (8.8) | |
Body mass index (kg/m2) mean (SD) | 26.2 | (3.7) | 26.4 | (3.7) | 0.55 |
Prior history of PSA test, n (%) | 0.02 | ||||
Never | 100 | (21.3) | 113 | (22.1) | |
Once | 53 | (11.3) | 68 | (13.3) | |
Twice or more | 296 | (63.0) | 286 | (55.9) | |
Serum PSA value (ng/ml), mean (SD) | 14.1 | (24.8) | 1.7 | (1.7) | <0.0001 |
Clinical stage, n (%) | |||||
T1 | 294 | (62.6) | |||
T2 | 119 | (25.3) | |||
T3 & T4 | 39 | (8.3) | |||
Histologic tumor grade: Gleason score n (%) | |||||
≤6 | 69 | (14.7) | |||
7 | 298 | (63.4) | |||
≥8 | 103 | (21.9) |
Some totals do not add to 100 percent due to missing data.
From T-test comparing means, or chi-square tests comparing counts.
SD, standard deviation.
Positive family history of prostate cancer was defined as prostate cancer in a first degree relative.
Energy, Meat, and Mutagens | Cases | Controls | P-value |
||
Mean | SD |
Mean | SD | ||
|
2,278 | (879) | 2,080 | (787) | <0.001 |
|
|||||
Beef, pork, ham, and lamb | 2.2 | (1.9) | 1.9 | (1.9) | 0.02 |
Ground meat: hamburgers and meatloaf | 1.3 | (1.2) | 1.0 | (1.0) | <0.001 |
Chicken and turkey | 1.2 | (1.2) | 1.3 | (1.2) | 0.06 |
Regular hotdogs and sausage | 0.4 | (0.4) | 0.7 | (0.6) | 0.35 |
Bacon and breakfast sausage | 1.1 | (1.8) | 0.9 | (1.3) | 0.03 |
Lunch meats: ham, turkey and lowfat bologna | 1.4 | (1.8) | 1.3 | (1.7) | 0.57 |
Other lunch meat: bologna, salami and Spam | 0.6 | (0.5) | 1.2 | (1.1) | 0.02 |
Low or reduced fat hot dogs and sausage | 0.2 | (0.6) | 0.2 | (0.5) | 0.69 |
Liver, chicken liver and organ meats | 0.2 | (0.6) | 0.1 | (0.3) | 0.008 |
|
|||||
Beef | 1.0 | (1.4) | 0.8 | (1.1) | 0.007 |
Hamburger | 1.4 | (1.9) | 1.0 | (1.5) | <0.001 |
Pork | 0.6 | (0.8) | 0.5 | (0.8) | 0.31 |
Hot Dogs | 0.2 | (0.4) | 0.2 | (0.5) | 0.81 |
Chicken | 1.4 | (1.8) | 1.2 | (1.6) | 0.02 |
|
|||||
MelQx | 46 | (53) | 38 | (53) | 0.05 |
DiMeIQx | 1.8 | (3.0) | 1.3 | (2.7) | 0.02 |
PhIP | 203 | (273) | 185 | (291) | 0.40 |
BaP | 89 | (110) | 89.2 | (103) | 0.12 |
SD, standard deviation.
From T-test comparing means.
Means given in servings per week or ng/week for mutagens.
N = 469 cases and 508 controls due to missing values.
MelQx: 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline;
DiMelQx: 2-amino-3,4,8-trimethylimidazo(4,5-f)quinoxaline;
PhIP: 2-amino-1-methyl-6-pheylimidazol(4,5-b)pyridine;
BaP: benzo(a)pyrene.
The associations between overall meat intake and aggressive prostate cancer are given in
Meat | Servings per Week |
||||
None | Low | Medium | High | ||
|
|||||
Case/Control Median |
0/0 | 0.58/0.58 | 2.00/2.00 | 3.46/3.46 | |
Cases/Controls (N) | 34/47 | 105/125 | 170/200 | 161/140 | |
Odds Ratios |
1.00 | 1.13 (0.67,1.89) | 1.03 (0.63, 1.70) | 1.25 (0.74, 2.11) | 0.43 |
|
|||||
Case/Control Median |
0/0 | 0.58/0.58 | 1.00/1.00 | 2.00/2.00 | |
Cases/Controls (N) | 35/70 | 162/199 | 123/130 | 150/112 | |
Odds Ratios |
1.00 | 1.59 (1.00, 2.52) | 1.78 (1.09, 2.89) | 2.30 (1.39, 3.81) | 0.002 |
|
|||||
Case/Control Median |
0.25/0.25 | 0.58/0.58 | 1.00/1.00 | 2.00/2.00 | |
Cases/Controls (N) | 92/101 | 135/120 | 107/103 | 135/188 | |
Odds Ratios |
1.00 | 1.23 (0.84, 1.79) | 1.08 (0.73, 1.61) | 0.70 (0.49, 1.02) | 0.22 |
|
|||||
Case/Control Median |
0/0 | 0.25/0.25 | 0.58/0.58 | 1.00/1.00 | |
Cases/Controls (N) | 167/221 | 123/111 | 115/110 | 64/70 | |
Odds Ratios |
1.00 | 1.35 (0.97, 1.88) | 1.24 (0.88, 1.74) | 0.97 (0.63, 1.48) | 0.70 |
|
|||||
Case/Control Median |
0/0 | 0.25/0.25 | 0.58/0.58 | 2.00/2.00 | |
Cases/Controls (N) | 116/143 | 69/86 | 95/92 | 190/191 | |
Odds Ratios |
1.00 | 0.93 (0.62, 1.40) | 1.18 (0.80, 1.74) | 1.11 (0.80, 1.54) | 0.41 |
|
|||||
Case/Control Median |
0/0 | 0.58/0.58 | 2.00/2.00 | 3.46/3.46 | |
Cases/Controls (N) | 115/131 | 144/159 | 125/129 | 85/93 | |
Odds Ratios |
1.00 | 1.01 (0.72, 1.42) | 1.01 (0.71, 1.45) | 0.89 (0.60, 1.33) | 0.63 |
|
|||||
Case/Control Median |
0/0 | 0.25/0.25 | 2.00/2.00 | ||
Cases/Controls (N) | 241/332 | 126/97 | 102/82 | ||
Odds Ratios |
1.00 | 1.74 (1.27, 2.39) | 1.57 (1.11, 2.21) | <0.001 | |
|
|||||
Case/Control Median |
0/0 | 0.25/0.25 | 0.58/0.58 | ||
Cases/Controls (N) | 347/376 | 48/54 | 74/82 | ||
Odds Ratios |
1.00 | 0.97 (0.64, 1.48) | 0.92 (0.64, 1.31) | 0.63 | |
|
|||||
Case/Control Median |
0/0 | 0.25/0.25 | 1.00/0.58 | ||
Cases/Controls (N) | 386/437 | 41/52 | 43/23 | ||
Odds Ratios |
1.00 | 0.90 (0.58, 1.39) | 2.24 (1.29, 3.88) | 0.02 |
Groupings defined so sufficient numbers are in each group given categorical nature of questionnaire.
Median of category, servings per week for cases and controls.
Odds ratios adjusted for age, race, institution, and energy intake.
P-trend values from continuous model across categories.
Grilled Meat | Servings per Week |
||||
None | Low | Medium | High | ||
|
|||||
Case/Control Median |
0/0 | 0.25/0.25 | 0.88/0.88 | 2.00/1.63 | |
Cases/Controls (N) | 131/200 | 85/87 | 124/108 | 129/113 | |
Odds Ratios (95% CI) |
1.00 | 1.50 (1.03, 2.19) | 1.69 (1.19, 2.38) | 1.61 (1.13, 2.28) | 0.004 |
|
|||||
Case/Control Median |
0/0 | 0.63/0.50 | 1.25/1.25 | 3.00/2.63 | |
Cases/Controls (N) | 117/180 | 106/117 | 126/121 | 120/90 | |
Odds Ratios (95% CI) |
1.00 | 1.41 (0.99, 2.01) | 1.58 (1.11, 2.24) | 1.86 (1.28, 2.71) | 0.001 |
|
|||||
Case/Control Median |
0/0 | 0.25/0.25 | 0.76/0.88 | 1.63/1.63 | |
Cases/Controls (N) | 195/255 | 95/88 | 96/84 | 83/81 | |
Odds Ratios (95% CI) |
1.00 | 1.39 (0.98, 1.97) | 1.44 (1.01, 2.04) | 1.21 (0.83, 1.75) | 0.07 |
|
|||||
Case/Control Median |
0/0 | 0.63/0.63 | 1.26/1.26 | 3.00/3.00 | |
Cases/Controls (N) | 128/170 | 107/130 | 103/96 | 131/112 | |
Odds Ratios (95% CI) |
1.00 | 1.14 (0.80, 1.61) | 1.43 (0.99, 2.06) | 1.48 (1.04, 2.11) | 0.006 |
|
|||||
Case/Control Median |
0/0 | 0.25/0.25 | 0.63/0.63 | 1.00/1.00 | |
Cases/Controls (N) | 289/336 | 67/75 | 83/54 | 30/43 | |
Odds Ratios (95% CI) |
1.00 | 1.04 (0.72, 1.50) | 1.67 (1.13, 2.45) | 0.71 (0.43, 1.18) | 0.55 |
Groupings defined so sufficient numbers are in each group given categorical nature of questionnaire.
Median of category, servings per week for cases and controls.
Odds ratios adjusted for age, race, institution, and energy intake.
P-trend values from continuous model across categories.
Focusing on the grilled or barbecued beef and hamburger, we then investigated the effect of both consumption levels and doneness on aggressive prostate cancer (
Rare/Medium Done |
Well & Very-Well Done | |||||
Grilled Meat | None | Low Intake | High Intake | Low Intake | High Intake | |
|
||||||
Case/Control Median |
0/0 | 0.50/0.63 | 1.63/1.63 | 0.63/0.50 | 1.26/1.26 | |
Cases/Controls (N) | 131/200 | 93/99 | 92/99 | 81/65 | 69/43 | |
Odds Ratios (95% CI) |
1.00 | 1.35 (0.94, 1.95) | 1.29 (0.89, 1.88) | 1.92 (1.29, 2.86) | 2.16 (1.37, 3.38) | <0.001 |
|
||||||
Case/Control Median |
0/0 | 0.63/0.63 | 2.00/2.00 | 0.63/0.63 | 2.25/2.00 | |
Cases/Controls (N) | 117/180 | 60/65 | 47/59 | 113/114 | 128/87 | |
Odds Ratios (95% CI) |
1.00 | 1.35 (0.88, 2.07) | 1.12 (0.71, 1.79) | 1.51 (1.06, 2.14) | 2.04 (1.41, 2.95) | <0.001 |
Groupings defined so sufficient numbers are in each group given categorical nature of questionnaire.
Median of category, servings per week for cases and controls.
Odds ratios adjusted for age, race, institution, and energy intake.
P-trend values from continuous model across categories.
With respect to meat mutagens produced by cooking at high temperatures, MelQX and DiMelQx were positively associated with increased risk of aggressive prostate cancer (
Mutagen |
Quartiles | ||||
1 | 2 | 3 | 4 | ||
|
|||||
Case/Control Median |
4.0/4.0 | 15.8/15.5 | 34.7/33.6 | 89.6/88.5 | |
Cases/Controls (N) | 75/93 | 89/96 | 90/84 | 106/71 | |
Odds Ratios (95% CI) |
1.00 | 1.16 (0.76, 1.78) | 1.31 (0.85, 2.03) | 1.69 (1.08, 2.64) | 0.02 |
|
|||||
Case/Control Median |
0/0 | 0.7/0.5 | 4.6/1.6 | 5.5/4.4 | |
Cases/Controls (N) | 163/195 | 44/45 | 82/54 | 71/50 | |
Odds Ratios (95% CI)e | 1.00 | 1.21(0.76, 1.95) | 1.84 (1.22, 2.77) | 1.53 (1.00, 2.35) | 0.005 |
|
|||||
Case/Control Median |
21.2/18.8 | 73.6/66.3 | 154.5/151.0 | 404.5/432.1 | |
Cases/Controls (N) | 86/91 | 80/95 | 93/85 | 101/73 | |
Odds Ratios (95% CI)e | 1.00 | 0.88 (0.57, 1.34) | 1.10 (0.72, 1.69) | 1.32 (0.86, 2.05) | 0.13 |
Benzo[ |
|||||
Case/Control Median |
3.3/3.3 | 24.1/20.0 | 82.4/76.0 | 186.6/173.5 | |
Cases/Controls (N) | 81/97 | 89/86 | 93/83 | 97/78 | |
Odds Ratios (95% CI)e | 1.00 | 1.22 (0.80, 1.87) | 1.32 (0.87, 2.02) | 1.34 (0.87, 2.07) | 0.17 |
Mutagens are:
MelQx: 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline;
DiMelQx: 2-amino-3,4,8-trimethylimidazo(4,5-f)quinoxaline (analyzed using 4 categories);
PhIP: 2-amino-1-methyl-6-pheylimidazol(4,5-b)pyridine;
P-trend values across quartiles.
Medians given in ng per week for cases and controls.
Odds Ratios adjusted for age, sex, race, institution, and energy intake.
The key finding here was that higher consumption of red meat was positively associated with risk of aggressive prostate cancer. This result appeared primarily driven by red meat that was grilled or barbequed—especially when cooked well-done. Furthermore, eating more meat mutagens MelQX and DiMelQx, which are produced by cooking over high heat, was associated with disease. In addition, we observed that increased consumption of higher fat lunch meats and liver, along with other meats grilled or barbequed, were associated with aggressive prostate cancer.
Our findings are supported by some previous studies
Our finding of an association between increased consumption of well or very well done red meat and aggressive prostate cancer is also in agreement with other studies. The Agricultural Health Study identified 668 incident cases of prostate cancer (140 advanced) with 197,017 person years of follow up
The mechanism through which the consumption of well-done meat may increase prostate cancer risk is via the release of mutagenic compounds during cooking
Animal studies have shown that the HCA PhIP can induce the development of tumors in rat prostates
The current study has several strengths including its ability to look at various meat types, preparation methods, doneness, and meat mutagens. Furthermore, all cases were men with aggressive prostate cancer, reflecting a disease phenotype that is more likely to progress and require treatment. The study had several limitations. There is a potential for measurement error due to recall bias in the assessment of meat consumption by study participants. The cases were asked to recall their food consumption over the year prior to their diagnosis of prostate cancer, while the controls were asked to recall their food consumption during the previous year. However, since incident cases and controls were recruited into the study at roughly the same time, the period over which recall of dietary intake occurred should be similar between the two groups. Secondly, the food frequency questionnaire had a limited ability to comprehensively assess all the potential food, vitamin and minerals that may effect or confound the associations seen between meat consumption and prostate cancer risk. Futhermore, HCA consumption was deduced using nutrient databases and is therefore subject to the inherent limitations of these databases. Finally, although controls were screened for prostate cancer and evaluated for it if they were thought to be at higher risk of prostate cancer we cannot exclude the potential that controls patients may have prostate cancer that was missed on initial screening and evaluation. However, we would expect the same misclassification of case or control to exist between those with high or low levels of meat consumption. As a result, this misclassification bias would be non-differential and would only attenuate the results. Therefore, the true association between meat consumption and aggressive prostate cancer may be greater if this bias truly exists.
In summary, this study found that high consumption of meats, especially those prepared by grilling, was positively associated with an increased risk of aggressive prostate cancer. Furthermore, increasing intake of well or very well done red meat was positively associated with disease. Although certain mutagenic compounds, such as MelQx and DiMelQx, may play a role in this process, other molecules may also be involved and further studies are required to better characterize the potential role of these compounds in prostate carcinogenesis and to see whether these compounds may be targeted for chemoprevention of prostate cancer.
The food frequency questionnaire.
(PDF)