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n-3 polyunsaturated fatty acids is associated with increased risk of prostate cancer
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Nutrition Research 31 (2011) 1 – 8 www.nrjournal.com
A high ratio of dietary n-6/n-3 polyunsaturated fatty acids is associated with increased risk of prostate cancer Christina D. Williams a,b,c,f,⁎, Brian M. Whitley c,f , Cathrine Hoyo d , Delores J. Grant e , Jared D. Iraggi c,f , Kathryn A. Newman c,f , Leah Gerber c,f , Loretta A. Taylor c,f , Madeline G. McKeever c,f , Stephen J. Freedland c,f,g a
Division of General Internal Medicine, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA b Center for Health Services Research in Primary Care, Durham VA Medical Center, Durham, NC 27705, USA c Duke Prostate Center, Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA d Department of Community and Family Medicine and the Duke Comprehensive Cancer Center, Durham, NC 27710, USA e Cancer Research Program, JLC-Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA f Department of Surgery, Durham VA Medical Center, Durham, NC 27705, USA g Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA Received 17 August 2010; revised 28 December 2010; accepted 4 January 2011
Abstract Experimental studies suggest omega-3 (n-3) polyunsaturated fatty acids (PUFA) suppress and n-6 PUFA promote prostate tumor carcinogenesis. Epidemiologic evidence remains inconclusive. The objectives of this study were to examine the association between n-3 and n-6 PUFA and prostate cancer risk and determine if these associations differ by race or disease aggressiveness. We hypothesize that high intakes of n-3 and n-6 PUFA will be associated with lower and higher prostate cancer risk, respectively. A case-control study comprising 79 prostate cancer cases and 187 controls was conducted at the Durham VA Medical Center. Diet was assessed using a food frequency questionnaire. Logistic regression analyses were used to obtain odds ratios (ORs) and 95% confidence intervals (95% CI) for the associations between n-3 and n-6 PUFA intakes, the dietary ratio of n-6/n-3 fatty acids, and prostate cancer risk. Our results showed no significant associations between specific n-3 or n-6 PUFA intakes and prostate cancer risk. The highest dietary ratio of n-6/ n-3 was significantly associated with elevated risk of high-grade (OR, 3.55; 95% CI, 1.18-10.69; Ptrend = 0.03), but not low-grade prostate cancer (OR, 0.95; 95% CI, 0.43-2.17). In race-specific analyses, an increasing dietary ratio of n-6/n-3 fatty acids correlated with higher prostate cancer risk among white men (Ptrend = 0.05), but not black men. In conclusion, our findings suggest that a high dietary ratio of n-6/n-3 fatty acids may increase the risk of overall prostate cancer among white men and possibly increase the risk of high-grade prostate cancer among all men. © 2011 Elsevier Inc. All rights reserved. Keywords: Abbreviations:
Dietary fatty acids; Prostate cancer; Veterans; Race; Case control AA, arachidonic acid; ALA, α-linolenic acid; BMI, body mass index; BPH, benign prostate hyperplasia; CI, confidence interval; EPA, eicosapentaenoic acid; DHA, docosahexanoic acid; FFQ, food frequency questionnaire; LA, linoleic acid; OR, odds ratio; PSA, prostate-specific antigen; PUFA, polyunsaturated fatty acid.
⁎ Corresponding author. Durham VAMC HSR&D, 508 Fulton St (152), Durham, NC 27705, USA. Tel.: +1 919 286 0411x5397; fax: +1 919 416 8025. E-mail address: [email protected] (C.D. Williams). 0271-5317/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.nutres.2011.01.002
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1. Introduction Prostate cancer is the most commonly diagnosed cancer among men in the United States [1], and dietary factors are thought to play a role in prostate cancer development [2]. There is limited evidence that total fat is a risk factor for prostate cancer [3], and evidence for an association between specific fatty acids and prostate cancer development or progression is conflicting [4-10]. The 2 classes of essential fatty acids are omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs). Polyunsaturated fatty acids are substrates for eicosanoid synthesis, with n-6 fatty acids being converted into proinflammatory eicosanoids and n-3 PUFA being converted to anti-inflammatory eicosanoids [4,11]. Animal and in vitro studies suggest that n-3 and n-6 PUFA have opposite effects on cancer development: n-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), suppress tumor carcinogenesis, whereas n-6 PUFA promote development [12]. However, results from epidemiologic studies, in general, have not confirmed these findings, with many finding no association between prostate cancer risk and intake of n-3 or n-6 PUFA [4-8]. One explanation for inconsistent findings among studies is that the balance of n-3 to n-6 PUFA may be more relevant for prostate cancer risk than absolute intakes of these fatty acids [13,14]. The recommended dietary ratio of n-6/n-3 fatty acids for health benefits is 1:1-2:1 [15], yet the typical Western diet often contains 10 or more times the amount of n-6 relative to n-3 PUFA [16]. Alternatively, the relationship between diet and prostate cancer may differ according to race and ethnicity. Prostate cancer incidence and mortality rates are highest among black men [1], yet few studies have focused on race-specific associations between diet and prostate cancer risk. Dietary factors may also have stronger associations for more aggressive prostate cancers [9,17], and this finding would be missed when all prostate cancers are combined. The objectives of this study were to examine the relationship between prostate cancer risk and n-3 and n-6 PUFA intake, and the dietary ratio of n-6/n-3 fatty acids using a case-control study in veterans and to determine whether these associations vary by disease aggressiveness and race. Based on experimental evidence, we hypothesized that high intake of n-3 PUFA will be associated with lower risk of prostate cancer, whereas increased intake of n-6 PUFA will correlate with elevated prostate cancer risk.
2. Methods and materials 2.1. Study design and participants Data collection methods have been described elsewhere [18]. Briefly, men who had been screened for prostate cancer in the last 12 months were recruited to participate in an ongoing case-control study at the Durham Veterans Affairs Medical Center (DVAMC) in Durham, NC, from January 2007 to November 2009. Cases were men 18 years or older
with no history of prostate cancer who were scheduled for a prostate needle biopsy at the urology clinic. Of the 485 eligible cases, 450 consented to participate; therefore, the response rate was 91%. Among those who had the biopsy done (n = 420), 166 were biopsy positive. Controls were identified through the urology and internal medicine clinics at the DVAMC and shared the same eligibility criteria as cases, with the exception of not being recommended for a prostate needle biopsy. Of the 421 eligible controls, 307 provided written consent to participate, yielding a 73% response rate. Analyses were restricted to participants with complete questionnaires, and as a result, the analytic sample consisted of 79 biopsy-positive cases and 187 controls. Cases were men with biopsy-positive prostate cancer, and healthy controls were men with no biopsy indication. This study was approved by the Duke University and DVAMC Institutional Review Boards. 2.2. Data collection Anthropometric measurements (weight and height) were taken by trained personnel. Weight was measured using a digital scale, and a stadiometer was used to measure height [19]. These measurements were used to calculate body mass index (BMI), defined as weight (in kilograms) divided by the square of height (in meters squared). All questionnaires were self-administered and typically filled out the day of the scheduled clinic visit or returned shortly thereafter by mail prior to the patient knowing the outcome of their biopsy. Risk factor questionnaires queried information on sociodemographic characteristics, lifestyle factors such as smoking and alcohol use, medication use, and family history of prostate cancer. Dietary information was obtained using the Harvard food frequency questionnaire (FFQ), developed and tested for validity by Willett et al [20] and Holmes et al [21]. This 61item food frequency questionnaire assessed the frequency of consumption as well as the portion size for each food and beverage item. Subjects reported their intake in the past 12 months, and this time period was selected to account for seasonal variation in consumption. Daily food, nutrient, and total energy intakes were determined using the reported frequency of consumption and portion sizes. The nutrients of interest for this study were n-3 PUFA (α-linolenic acid [ALA], EPA, DHA) and n-6 PUFA (arachidonic acid [AA], linoleic acid [LA]). α-Linolenic acid, the predominant n-3 fatty acid in the Western diet, is found in green leafy vegetables, nuts, animal meats, and some vegetable oils, whereas EPA and DHA are abundant in fatty fish and fish oils [22]. Arachidonic acid is found in animal sources, and LA is in most vegetable oils and animal meats [22]. 2.3. Statistical analyses Descriptive statistics (means ± SD), medians (interquartile range), and percentages for cases and controls were
C.D. Williams et al. / Nutrition Research 31 (2011) 1–8
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compared using a χ test for categorical variables and Wilcoxon rank sum test for continuous variables. All PUFA data were represented as the percent of total energy intake. Correlations between n-3 PUFA and n-6 PUFA were determined using Pearson correlation coefficients. Each PUFA was categorized into tertiles, which were based on the overall distribution of each PUFA among all controls. Unconditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) of prostate cancer risk across tertile categories of PUFA intake relative to the lowest (first) tertile. Odds ratios were adjusted for factors potentially associated with prostate cancer risk: age (continuous), BMI (b25, 25-29.9, ≥30 kg/m2), family history of prostate cancer (yes/no), smoking status (never, former, current), total energy (continuous), and, where appropriate, race (black, white, other). We conducted a linear trend test by incorporating the median tertile values among controls into a logistic regression model as a continuous predictor. To test for interaction, a cross-product term for race and each PUFA variable was entered into separate logistic regression models. We then stratified the models by race to obtain race-specific risk estimates. To determine the relationship between PUFA intake and disease aggressiveness, we used multinomial logistic regression to model the following outcomes: no cancer, low-grade prostate cancer (Gleason sum b7), and high-grade prostate cancer (Gleason sum ≥7). Because of our relatively small sample size, we were unable to perform race-specific analyses according to disease aggressiveness. All analyses were done using SAS version 9.2 (SAS Institute, Inc, Cary, NC), and a P b .05 was considered statistically significant.
Table 1 Participant characteristics by case-control status
3. Results
Values are expresses are mean ± SD. IQR indicates interquartile range. a Based on Wilcoxon rank sum test for continuous variables and χ2 test for categorical variables.
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Compared with controls, prostate cancer cases were more likely to have a lower BMI (P =.03), and a higher proportion of cases had a family history of prostate cancer (P =.06; Table 1). The median prostate-specific antigen (PSA) level was also higher in cases than controls (P b.0001). There were no differences in age, education, or smoking status between cases and controls. There was also no difference between cases and controls for daily mean intakes of total energy and PUFA, and the average dietary ratio of n-6/n-3 fatty acids in cases (9.1) and controls (8.6) was also similar. Table 2 shows that among n-3 PUFAs, EPA and DHA were nearly perfectly correlated in cases (r = 0.97) and controls (r = 0.92). Interestingly, we also observed strong correlations between n-3 ALA and n-6 LA (r = 0.78 in cases; r = 0.65 in controls). Overall, we observed no statistically significant associations between self-reported intakes of total or specific n-3 or n-6 PUFA and prostate cancer risk among all men combined (Table 3). Risk estimates for high intakes of the n-3 PUFA ALA and DHA were similar in combined analyses, yet neither reached statistical significance. Although n-3 PUFA EPA and DHA were highly correlated, we did not observe
Cases, n (%) n Mean (SD) age (y) Race (%) Black White Other Education (%) ≤High school Vocational/technical training Some College College graduate/ Advanced degree BMI (%) b25 kg/m2 25-29.9 kg/m2 ≥30 kg/m2 Mean (SD; kg/m2) Smoking status (%) Current smoker Former smoker Never smoker Family history of prostate cancer (%) Yes Median (IQR) PSA (ng/L) Mean (SD) daily intakes Total energy (kJ) (% of total energy) Total n-3 PUFA ALA EPA DHA Total n-6 PUFA AA LA n-6/n-3 ratio
Controls, n (%)
79 63 (6)
187 62 (7)
40 (51) 38 (48) 1 (1)
69 (37) 112 (60) 4 (2)
P
a
.34 .24
.34 27 7 18 24
(35) (9) (24) (32)
47 26 58 52
(26) (14) (32) (28)
14 34 29 29
(18) (44) (38) (5)
22 (12) 56 (31) 100 (56) 31 (6)
24 (30) 54 (68) 1 (1)
43 (23) 134 (72) 10 (5)
19 (24) 5.8 (4.6-7.5)
27 (14) 0.80 (0.5-1.4)
.03
.07 .17
.06 b.0001
8342 (4930)
7706 (3545)
.74
0.80 (0.51) 0.59 (0.28) 0.09 (0.18) 0.11 (0.13) 6.2 (1.8) 0.09 (0.04) 6.1 (1.9) 9.1 (3.1)
0.76 (0.36) 0.57 (0.24) 0.08 (0.12) 0.10 (0.10) 5.9 (1.6) 0.09 (0.04) 5.8 (1.6) 8.6 (2.9)
.50 .77 .89 .54 .12 .19 .27 .20
any statistically significant results when simultaneously adjusting for EPA and DHA (data not shown). Intake of total, n-3, and n-6 PUFA remained unrelated to prostate cancer risk when we examined the associations by race, and there was no evidence of multiplicative interaction between race and PUFA intake. The dietary ratio of n-6/n-3 fatty acids in all men combined was not associated with risk of prostate cancer. An increasing dietary ratio of n-6/n-3 among white men appeared to correlate with higher prostate cancer risk (Ptrend = 0.05), yet no linear trend was observed in black men. In Table 4, we present risk estimates among all men for low-grade (Gleason sum b7, n = 43) and high-grade (Gleason sum ≥7, n = 36) prostate cancer as compared with controls. We found no evidence of an association or trend between intake of PUFA and low-grade prostate cancer. There was, however, a statistically significant elevated risk of high-grade prostate cancer for men in the highest ratio category of dietary n-6/n-3 PUFA (OR, 3.55; 95% CI, 1.18-10.69), as well as a positive linear trend (Ptrend = 0.03).
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C.D. Williams et al. / Nutrition Research 31 (2011) 1–8
Table 2 Pearson correlation coefficients of n-3 and n-6 PUFAs Cases
n-3 PUFA ALA EPA DHA n-6 PUFA AA LA
Controls
ALA
EPA
DHA
AA
LA
ALA
EPA
DHA
AA
LA
1.00
0.38 ⁎ 1.00
0.38 ⁎ 0.97 ⁎ 1.00
-0.04 0.31 ⁎ 0.40 ⁎
0.78 ⁎ 0.21 0.25 ⁎
1.00
0.22 ⁎ 1.00
0.17 0.92 ⁎ 1.00
-0.01 0.29 ⁎ 0.52 ⁎
0.65 ⁎ 0.04 0.02
1.00
0.05 1.00
1.00
0.04 1.00
⁎ P b.05. Table 3 ORs and 95% CIs for the association between tertiles of PUFA intake and prostate cancer risk a
Total PUFA, tertile Tertile 1: b5.7 2: 5.7-7.0 3: 7.1-14.5 Ptrend Total n-3 PUFA 1: b0.57 2: 0.57-0.81 3: 0.81-2.6 Ptrend ALA 1: b0.45 2: 0.45-0.58 3: 0.58-1.87 Ptrend EPA 1: b0.019 2: 0.019-0.078 3: 0.079-0.83 Ptrend DHA 1: b0.054 2: 0.054-0.10 3: 0.10-0.64 Ptrend Total n-6 PUFA 1: b5.0 2: 5.0-6.2 3: 6.3-12.5 Ptrend AA 1: b0.07 2: 0.07-0.10 3: 0.10-0.26 Ptrend LA 1: b4.9 2: 4.9-6.2 3: 6.2-12.5 Ptrend n-6/n-3 ratio 1: b7.6 2: 7.6-9.5 3: 9.5-19.0 Ptrend a
Combined (n = 266)
Black (n = 109)
White (n = 150)
Cases
OR (95% CI)
Cases
OR (95% CI)
Cases
OR (95% CI)
30 15 34
1.00 0.46 (0.22-0.99) 1.29 (0.67-2.50) .38
17 6 17
1.00 0.25 (0.08-0.82) 1.53 (0.53-4.39) .39
13 9 16
1.00 0.85 (0.29-2.44) 1.34 (0.53-3.42) .52
33 21 25
1.00 0.62 (0.31-1.23) 0.83 (0.42-1.63) .73
17 11 12
1.00 0.66 (0.24-1.84) 0.93 (0.32-2.68) 1.00
16 9 13
1.00 0.53 (0.20-1.47) 0.85 (0.33-2.17) .87
30 25 24
1.00 0.75 (0.38-1.48) 0.82 (0.41-1.65) .64
16 15 9
1.00 0.61 (0.22-1.69) 0.46 (0.14-1.49) .21
14 10 14
1.00 0.81 (0.30-2.22) 1.29 (0.50-3.29) .55
27 25 27
1.00 1.04 (0.53-2.06) 1.13 (0.56-2.24) .73
12 13 15
1.00 1.27 (0.44-3.64) 1.46 (0.51-4.13) .52
14 12 12
1.00 0.98 (0.38-2.53) 0.91 (0.34-2.46) .85
29 26 24
1.00 0.91 (0.47-1.76) 0.82 (0.40-1.68) .60
14 9 17
1.00 0.55 (0.18-1.68) 0.87 (0.32-2.40) .99
14 17 7
1.00 1.41 (0.59-3.38) 0.58 (0.18-1.91) .43
25 18 36
1.00 0.82 (0.39-1.71) 1.62 (0.82-3.17) .15
15 8 17
1.00 0.42 (0.14-1.29) 1.65 (0.58-4.73) .32
10 10 18
1.00 1.72 (0.59-5.03) 1.98 (0.73-5.36) .18
37 23 19
1.00 0.71 (0.37-1.39) 0.52 (0.25-1.08) .08
15 13 12
1.00 0.64 (0.22-1.83) 0.42 (0.14-1.20) .11
22 9 7
1.00 0.57 (0.22-1.50) 0.64 (0.21-1.95) .37
24 20 35
1.00 0.93 (0.45-1.91) 1.60 (0.82-3.15) .16
14 10 16
1.00 0.70 (0.24-2.05) 1.62 (0.56-4.67) .37
10 9 19
1.00 1.22 (0.41-3.59) 2.37 (0.88-6.41) .08
21 23 35
1.00 1.10 (0.53-2.27) 1.57 (0.79-3.11) .17
12 13 15
1.00 0.98 (0.35-2.79) 0.91 (0.32-2.56) .85
9 10 19
1.00 1.17 (0.39-3.50) 2.52 (0.93-6.79) .05
Pinteraction
.34
.84
.01
.16
.40
.29
.40
.85
.06
Adjusted for age, BMI, family history of prostate cancer, smoking status, total energy, and, in combined analyses, race.
C.D. Williams et al. / Nutrition Research 31 (2011) 1–8 Table 4 ORs and 95% CIs for the association between PUFA intake and low-grade and high-grade prostate cancer risk a Low-grade prostate High-grade prostate cancer (Gleason sum, cancer (Gleason sum, b7; n = 43), OR (95% CI) ≥7; n = 36), OR (95% CI) Total PUFA Tertile 1 2 3 Ptrend Total n-3 PUFA 1 2 3 Ptrend ALA 1 2 3 Ptrend EPA 1 2 3 Ptrend DHA 1 2 3 Ptrend Total n-6 PUFA 1 2 3 Ptrend AA 1 2 3 Ptrend LA 1 2 3 Ptrend n-6/n-3 ratio 1 2 3 Ptrend
1.00 0.39 (0.15-1.03) 1.15 (0.52-2.54) .65
1.00 0.54 (0.19-1.54) 1.43 (0.58-3.57) .40
1.00 0.69 (0.30-1.59) 0.93 (0.41-2.10) .98
1.00 0.56 (0.21-1.47) 0.76 (0.30-1.91) .65
1.00 0.81 (0.36-1.85) 0.86 (0.37-2.00) .77
1.00 0.74 (0.29-1.90) 0.87 (0.34-2.24) .82
1.00 1.43 (0.62-3.31) 1.40 (0.59-3.31) .56
1.00 0.72 (0.28-1.88) 0.87 (0.34-2.20) .89
1.00 1.01 (0.44-2.32) 1.15 (0.49-2.70) .73
1.00 0.77 (0.32-1.90) 0.49 (0.17-1.38) .18
1.00 0.76 (0.31-1.87) 1.48 (0.66-3.35) .32
1.00 0.87 (0.30-2.47) 1.88 (0.74-4.77) .17
1.00 0.89 (0.40-1.96) 0.55 (0.23-1.36) .19
1.00 0.50 (0.20-1.30) 0.46 (0.17-1.27) .15
1.00 1.06 (0.44-2.58) 1.70 (0.74-3.91) .20
1.00 0.77 (0.28-2.13) 1.51 (0.61-3.79) .37
1.00 0.68 (0.29-1.60) 0.95 (0.43-2.17) .96
1.00 2.51 (0.78-8.03) 3.55 (1.18-10.69) .03
a Adjusted for age, BMI, family history of prostate cancer, smoking status, total energy, and race.
4. Discussion In this case-control study, intakes of total, n-3, and n-6 PUFA were not associated with prostate cancer risk. In whites, a high dietary ratio of n-6/n-3 fatty acids was suggestive of higher prostate cancer risk, yet there was a practically null association between the dietary ratio of n-6/ n-3 fatty acids and prostate cancer risk in blacks. Among all men, there was evidence of a strong positive association and
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significant trend between the dietary ratio of n-6/n-3 fatty acids and high-grade prostate cancer, whereas this ratio was unrelated to low-grade prostate cancer. These results do not confirm the hypothesis that specific dietary n-3 and n-6 PUFA are associated with prostate cancer risk; however, our findings suggest that the dietary ratio of n-6/n-3 fatty acids is positively associated with the risk of overall prostate cancer among white men and high-grade prostate cancer among all men. In vitro and animal studies provide evidence that n-3 PUFAs, particularly EPA and DHA, suppress prostate tumor growth, whereas n-6 PUFA stimulate tumor growth [13,14,23,24]. The most likely mechanism by which these fatty acids may affect prostate cancer risk is through the conversion of n-3 PUFA to anti-inflammatory and n-6 PUFA to proinflammatory eicosanoids [11]. The n-6 PUFA (AA and LA) are metabolized into inflammatory eicosanoids, such as prostaglandin E2, through the cyclooxygenase pathway [25]. The n-3 PUFA EPA and DHA can inhibit this metabolic pathway and thereby exert their anti-inflammatory properties. Other possible mechanisms by which n-3 PUFA exhibit antineoplastic activity include regulating gene expression and transcription factor activity, altering the production of free radicals and modulating insulin sensitivity [11]. α-Linolenic acid, the parent fatty acid of all n-3 PUFA, represents approximately 85% to 94% of total n-3 intake [26]. Along with n-6 LA, it is 1 of the 2 most frequently investigated fatty acids potentially associated with prostate cancer [2]. Our finding regarding the null association between intake of n-3 ALA and prostate cancer risk is in agreement with numerous epidemiologic studies showing no association between ALA and prostate cancer [17,27-30]. A meta-analysis by Simon et al [7] reported an increased risk of prostate cancer for high blood and tissue concentrations of ALA, yet no association between prostate cancer and dietary ALA was observed. On the contrary, a recent meta-analysis of 5 prospective studies suggested a small risk reduction for dietary ALA intakes greater than 1.5 g/d [31]. There is evidence for antiproliferative effects of the n-3 PUFA EPA and DHA [32,33]. In support of these observations, some epidemiologic studies have observed inverse associations between EPA and DHA and prostate cancer risk [9,17,28], whereas others have reported positive associations [29,34]. The results of our study did not confirm the hypothesis for a protective effect of these fatty acids. High intakes of both EPA and DHA were unrelated to prostate cancer in our study, as was the case in other studies [10,27,30], one of which was another case-control study in North Carolina that assessed biomarkers of fatty acid consumption [10]. Findings for n-6 PUFA have also been inconsistent, because several studies including ours have found no evidence for associations between n-6 PUFA and risk of prostate cancer [8,30,34]. Linoleic acid, the predominant n-6 fatty acid, has been positively correlated with elevated prostate cancer risk in some studies [10,35], although one study reported significant inverse associations
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C.D. Williams et al. / Nutrition Research 31 (2011) 1–8
between LA and the risk of overall, localized, and aggressive prostate cancer [9]. Omega-3 (n-3) and n-6 PUFA have competing roles in inflammatory pathways where a high n-3 intake can reduce the production of proinflammatory eicosanoids derived from n-6 PUFA, partially because n-3 fatty acids are the preferential substrates for enzymes involved in eicosanoid metabolism [11,16]. For this reason, the balance of n-6 and n-3 PUFA in the diet may have stronger effects on prostate cancer risk than individual PUFA. Experimental data suggest that the balance between n-6 and n-3 PUFA can alter the behavior of prostate tumors [14,23,24,36]. For example, animal models have shown a growth inhibitory effect on prostate cancer by lowering the ratio of n-6/n-3 in the diet [14,36,37]. A recent low-fat dietary intervention trial among men with prostate cancer reported that lower serum n-6 and/ or higher serum n-3 levels were associated with decreased proliferation of LNCaP (lymph node cancer of the prostate) cells when the patient's serum was added to the cancer cells in vitro [38]. An observational study by Fradet et al [17] found that a high ratio of long-chain n-3 PUFA (ie, EPA, DHA, and docosapentaenoic acid) to n-6 PUFA was associated with a significant lower risk for aggressive prostate cancer (defined as Gleason sum, ≥7; TNM stage, NT2; and PSA, ≥10). A high dietary ratio of n-6/n-3 fatty acids in our study was only suggestive of an elevated risk of overall prostate cancer; however, there was a significant positive association with high-grade (ie, aggressive) prostate cancer. This finding not only supports the idea that the ratio of n-6 to n-3 fatty acids may be more relevant to prostate cancer than individual n-6 and n-3 fatty acids but may also reflect the fact that not all prostate cancers are the same. In general, studies reporting lower prostate cancer risk with intakes of n-3 PUFA or fish, the major source of n-3 PUFA, have observed stronger associations for advanced, aggressive, or metastatic disease and prostate cancer death [9,39-44]. Furthermore, our findings suggest that the association between the dietary ratio of these 2 classes of PUFA may differ between whites and blacks. A positive trend was seen in white men, whereas no association was observed among black men. Although we cannot exclude the possibility of a chance finding, diet-gene interaction is a possible explanation for this difference. Racial differences in genetic variants of cyclooxygenase 2, a key enzyme in fatty acid metabolism may exist and therefore modify the associations between PUFA and prostate cancer in racial subgroups [45]. Unfortunately, we were unable to assess this interaction in our study. Other studies have reported different diet and prostate cancer associations for blacks and whites [43,46]. For example, Hayes et al [43] observed an increased risk of prostate cancer among whites but not blacks for high intakes of dairy foods and sweets, whereas high animal fat intake correlated with increased risk in black s but not whites. Together, these findings stress the importance of examining diet and prostate cancer associations separately for different race/ethnic groups. To our knowledge, our study is the first
to investigate the relationship between PUFA and prostate cancer risk in a racially diverse sample of US veterans. The veteran population is ideal for assessing factors that may contribute to racial disparities due to this system of equal access to health care. There are several limitations to our study. Case-control study designs are often subject to selection bias and recall bias. Although it is possible that selection bias was introduced in our results, recall bias is less likely because cases in our study were interviewed before their biopsy; thus, they were unaware of their prostate cancer status at the time of interview which helps to minimize differential recall between cases and controls. Most findings in this study were null, and it is not clear whether this stems from a true lack of association or limited statistical power due to our relatively small sample size, particularly for stratified analyses. Measurement error from using a FFQ is possible because the questionnaire may not have included enough foods to accurately assess intake of PUFA. In addition, there may have been insufficient variability in intake in our population to detect associations with more extreme dietary intakes. For example, the mean ratio of dietary n-6 to n-3 fatty acids among controls in our study was 8.6, with a range of 2.719.0. Although this is similar to the average dietary ratio of n-6/n-3, which is 9.8 in the United States [26], the range in our study simply represents variations of a Western diet. It has been suggested that optimal ratios for overall health are closer to 1:1 or 2:1 [15]; thus, it is possible that not enough men in the current study had low enough values to show a substantially lower risk of prostate cancer, though this, of course, requires further testing. Because our findings were derived from veterans who had been screened for prostate cancer, studies in different populations are needed to validate these findings. This study focused exclusively on prostate cancer. However, other prostate-related diseases such as benign prostate hyperplasia (BPH) are also clinically important as BPH can significantly affect quality of life. Moreover, BPH has been suggested to be related to diet and specifically dietary fat intake [47]. We were unable to address this because our study was developed as a casecontrol series of men with prostate cancer, though we hope to explore this in future studies. Finally, we cannot exclude the possibility of chance findings due to multiple comparisons and a lack of strong linear associations with risk. In summary, we found specific n-3 and n-6 PUFAs intake to be unrelated to overall prostate cancer risk in this casecontrol study among US veterans. There was evidence for an association between a high dietary ratio of n-6/n-3 PUFA and increased risk of high-grade prostate cancer, whereas no specific PUFA or the ratio of PUFA was associated with low-grade prostate cancer. Our data also suggest that prostate cancer risk may increase with higher dietary ratios of n-6/n-3 fatty acid intake in white men but not in black men. Therefore, our findings emphasize the importance of examining the ratio of n-6 and n-3 PUFA when assessing the relationship between PUFA intake and prostate cancer
C.D. Williams et al. / Nutrition Research 31 (2011) 1–8
risk and the need to examine these associations in subgroups of tumor grade and race/ethnicity. Acknowledgment This work was supported by the Agency for Healthcare Research and Quality (T32 HS00079), National Institutes of Health NCMHC (P20 MD000175), Department of Defense (PC060233), Department of Veterans Affairs, and the American Urological Association Foundation/Astellas Rising Star in Urology. References [1] American Cancer Society. Cancer Facts & Figures 2009. Atlanta (GA): American Cancer Society; 2009. [2] Sonn GA, Aronson W, Litwin MS. Impact of diet on prostate cancer: a review. Prostate Cancer Prostatic Dis 2005;8:304-10. [3] American Institute for Cancer Research/World Cancer Research Fund. Food, nutrition, physical activity and the prevention of cancer: a global perspective. Washington, DC: AICR; 2007. [4] Terry PD, Rohan TE, Wolk A. Intakes of fish and marine fatty acids and the risks of cancers of the breast and prostate and of other hormone-related cancers: a review of the epidemiologic evidence. Am J Clin Nutr 2003;77:532-43. [5] Astorg P. Dietary N-6 and N-3 polyunsaturated fatty acids and prostate cancer risk: a review of epidemiological and experimental evidence. Cancer Causes Control 2004;15:367-86. [6] Brouwer IA. Omega-3 PUFA: good or bad for prostate cancer? Prostaglandins Leukot Essent Fatty Acids 2008;79:97-9. [7] Simon JA, Chen YH, Bent S. The relation of alpha-linolenic acid to the risk of prostate cancer: a systematic review and meta-analysis. Am J Clin Nutr 2009;89:1558S-64S. [8] Park SY, Wilkens LR, Henning SM, Le Marchand L, Gao K, Goodman MT, et al. Circulating fatty acids and prostate cancer risk in a nested case-control study: the Multiethnic Cohort. Cancer Causes Control 2009;20:211-23. [9] Chavarro JE, Stampfer MJ, Li H, Campos H, Kurth T, Ma J. A prospective study of polyunsaturated fatty acid levels in blood and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2007;16: 1364-70. [10] Godley PA, Campbell MK, Gallagher P, Martinson FE, Mohler JL, Sandler RS. Biomarkers of essential fatty acid consumption and risk of prostatic carcinoma. Cancer Epidemiol Biomarkers Prev 1996;5:889-95. [11] Larsson SC, Kumlin M, Ingelman-Sundberg M, Wolk A. Dietary longchain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. Am J Clin Nutr 2004;79:935-45. [12] Rose DP. Dietary fatty acids and prevention of hormone-responsive cancer. Proc Soc Exp Biol Med 1997;216:224-33. [13] Kelavkar UP, Hutzley J, McHugh K, Allen KG, Parwani A. Prostate tumor growth can be modulated by dietarily targeting the 15lipoxygenase-1 and cyclooxygenase-2 enzymes. Neoplasia 2009;11: 692-9. [14] Kobayashi N, Barnard RJ, Henning SM, Elashoff D, Reddy ST, Cohen P, et al. Effect of altering dietary omega-6/omega-3 fatty acid ratios on prostate cancer membrane composition, cyclooxygenase-2, and prostaglandin E2. Clin Cancer Res 2006;12:4662-70. [15] Simopoulos AP. Evolutionary aspects of the dietary omega-6:omega-3 fatty acid ratio: medical implications. World Rev Nutr Diet 2009;100: 1-21. [16] Daniel CR, McCullough ML, Patel RC, Jacobs EJ, Flanders WD, Thun MJ, et al. Dietary intake of omega-6 and omega-3 fatty acids and risk of colorectal cancer in a prospective cohort of U.S. men and women. Cancer Epidemiol Biomarkers Prev 2009;18:516-25.
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[17] Fradet V, Cheng I, Casey G, Witte JS. Dietary omega-3 fatty acids, cyclooxygenase-2 genetic variation, and aggressive prostate cancer risk. Clin Cancer Res 2009;15:2559-66. [18] Antonelli JA, Jones LW, Banez LL, Thomas JA, Anderson K, Taylor LA, et al. Exercise and prostate cancer risk in a cohort of veterans undergoing prostate needle biopsy. J Urol 2009;182:2226-31. [19] Roebuck JA. Anthropometric methods: designing to fit the human body. Santa Monica (CA): Human Factors and Ergonomics Society; 1995. [20] Willett WC, Sampson L, Stampfer MJ, Rosner B, Bain C, Witschi J, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985;122:51-65. [21] Holmes MD, Powell IJ, Campos H, Stampfer MJ, Giovannucci EL, Willett WC. Validation of a food frequency questionnaire measurement of selected nutrients using biological markers in AfricanAmerican men. Eur J Clin Nutr 2007;61:1328-36. [22] Meyer BJ, Mann NJ, Lewis JL, Milligan GC, Sinclair AJ, Howe PR. Dietary intakes and food sources of omega-6 and omega-3 polyunsaturated fatty acids. Lipids 2003;38:391-8. [23] Rose DP, Connolly JM. Effects of fatty acids and eicosanoid synthesis inhibitors on the growth of two human prostate cancer cell lines. Prostate 1991;18:243-54. [24] Pandalai PK, Pilat MJ, Yamazaki K, Naik H, Pienta KJ. The effects of omega-3 and omega-6 fatty acids on in vitro prostate cancer growth. Anticancer Res 1996;16:815-20. [25] Reese AC, Fradet V, Witte JS. Omega-3 fatty acids, genetic variants in COX-2 and prostate cancer. J Nutrigenet Nutrigenomics 2009;2: 149-58. [26] Kris-Etherton PM, Taylor DS, Yu-Poth S, Huth P, Moriarty K, Fishell V, et al. Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr 2000;71:179S-88S. [27] Park SY, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Fat and meat intake and prostate cancer risk: the multiethnic cohort study. Int J Cancer 2007;121:1339-45. [28] Koralek DO, Peters U, Andriole G, Reding D, Kirsh V, Subar A, et al. A prospective study of dietary alpha-linolenic acid and the risk of prostate cancer (United States). Cancer Causes Control 2006;17:783-91. [29] Wallstrom P, Bjartell A, Gullberg B, Olsson H, Wirfalt EA. Prospective study on dietary fat and incidence of prostate cancer (Malmo, Sweden). Cancer Causes Control 2007;18:1107-21. [30] Hodge AM, English DR, McCredie MR, Severi G, Boyle P, Hopper JL, et al. Foods, nutrients and prostate cancer. Cancer Causes Control 2004;15:11-20. [31] Carayol M, Grosclaude P, Delpierre C. Prospective studies of dietary alpha-linolenic acid intake and prostate cancer risk: a meta-analysis. Cancer Causes Control 2010;21:347-55. [32] Rose DP. Effects of dietary fatty acids on breast and prostate cancers: evidence from in vitro experiments and animal studies. Am J Clin Nutr 1997;66:1513S-22S. [33] Connolly JM, Coleman M, Rose DP. Effects of dietary fatty acids on DU145 human prostate cancer cell growth in athymic nude mice. Nutr Cancer 1997;29:114-9. [34] Crowe FL, Allen NE, Appleby PN, Overvad K, Aardestrup IV, Johnsen NF, et al. Fatty acid composition of plasma phospholipids and risk of prostate cancer in a case-control analysis nested within the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr 2008;88:1353-63. [35] Hedelin M, Chang ET, Wiklund F, Bellocco R, Klint A, Adolfsson J, et al. Association of frequent consumption of fatty fish with prostate cancer risk is modified by COX-2 polymorphism. Int J Cancer 2007; 120:398-405. [36] Kelavkar UP, Hutzley J, Dhir R, Kim P, Allen KG, McHugh K. Prostate tumor growth and recurrence can be modulated by the omega6:omega-3 ratio in diet: athymic mouse xenograft model simulating radical prostatectomy. Neoplasia 2006;8:112-24. [37] Lloyd JC, Masko EM, Antonelli JA, Phillips TE, Thomas JA, Poulton SH, Aronson WJ, Freedland SJ, editors. Does type of dietary fat
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Nutrition Research 31 (2011) 1 – 8 www.nrjournal.com
A high ratio of dietary n-6/n-3 polyunsaturated fatty acids is associated with increased risk of prostate cancer Christina D. Williams a,b,c,f,⁎, Brian M. Whitley c,f , Cathrine Hoyo d , Delores J. Grant e , Jared D. Iraggi c,f , Kathryn A. Newman c,f , Leah Gerber c,f , Loretta A. Taylor c,f , Madeline G. McKeever c,f , Stephen J. Freedland c,f,g a
Division of General Internal Medicine, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA b Center for Health Services Research in Primary Care, Durham VA Medical Center, Durham, NC 27705, USA c Duke Prostate Center, Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA d Department of Community and Family Medicine and the Duke Comprehensive Cancer Center, Durham, NC 27710, USA e Cancer Research Program, JLC-Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA f Department of Surgery, Durham VA Medical Center, Durham, NC 27705, USA g Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA Received 17 August 2010; revised 28 December 2010; accepted 4 January 2011
Abstract Experimental studies suggest omega-3 (n-3) polyunsaturated fatty acids (PUFA) suppress and n-6 PUFA promote prostate tumor carcinogenesis. Epidemiologic evidence remains inconclusive. The objectives of this study were to examine the association between n-3 and n-6 PUFA and prostate cancer risk and determine if these associations differ by race or disease aggressiveness. We hypothesize that high intakes of n-3 and n-6 PUFA will be associated with lower and higher prostate cancer risk, respectively. A case-control study comprising 79 prostate cancer cases and 187 controls was conducted at the Durham VA Medical Center. Diet was assessed using a food frequency questionnaire. Logistic regression analyses were used to obtain odds ratios (ORs) and 95% confidence intervals (95% CI) for the associations between n-3 and n-6 PUFA intakes, the dietary ratio of n-6/n-3 fatty acids, and prostate cancer risk. Our results showed no significant associations between specific n-3 or n-6 PUFA intakes and prostate cancer risk. The highest dietary ratio of n-6/ n-3 was significantly associated with elevated risk of high-grade (OR, 3.55; 95% CI, 1.18-10.69; Ptrend = 0.03), but not low-grade prostate cancer (OR, 0.95; 95% CI, 0.43-2.17). In race-specific analyses, an increasing dietary ratio of n-6/n-3 fatty acids correlated with higher prostate cancer risk among white men (Ptrend = 0.05), but not black men. In conclusion, our findings suggest that a high dietary ratio of n-6/n-3 fatty acids may increase the risk of overall prostate cancer among white men and possibly increase the risk of high-grade prostate cancer among all men. © 2011 Elsevier Inc. All rights reserved. Keywords: Abbreviations:
Dietary fatty acids; Prostate cancer; Veterans; Race; Case control AA, arachidonic acid; ALA, α-linolenic acid; BMI, body mass index; BPH, benign prostate hyperplasia; CI, confidence interval; EPA, eicosapentaenoic acid; DHA, docosahexanoic acid; FFQ, food frequency questionnaire; LA, linoleic acid; OR, odds ratio; PSA, prostate-specific antigen; PUFA, polyunsaturated fatty acid.
⁎ Corresponding author. Durham VAMC HSR&D, 508 Fulton St (152), Durham, NC 27705, USA. Tel.: +1 919 286 0411x5397; fax: +1 919 416 8025. E-mail address: [email protected] (C.D. Williams). 0271-5317/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.nutres.2011.01.002
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C.D. Williams et al. / Nutrition Research 31 (2011) 1–8
1. Introduction Prostate cancer is the most commonly diagnosed cancer among men in the United States [1], and dietary factors are thought to play a role in prostate cancer development [2]. There is limited evidence that total fat is a risk factor for prostate cancer [3], and evidence for an association between specific fatty acids and prostate cancer development or progression is conflicting [4-10]. The 2 classes of essential fatty acids are omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs). Polyunsaturated fatty acids are substrates for eicosanoid synthesis, with n-6 fatty acids being converted into proinflammatory eicosanoids and n-3 PUFA being converted to anti-inflammatory eicosanoids [4,11]. Animal and in vitro studies suggest that n-3 and n-6 PUFA have opposite effects on cancer development: n-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), suppress tumor carcinogenesis, whereas n-6 PUFA promote development [12]. However, results from epidemiologic studies, in general, have not confirmed these findings, with many finding no association between prostate cancer risk and intake of n-3 or n-6 PUFA [4-8]. One explanation for inconsistent findings among studies is that the balance of n-3 to n-6 PUFA may be more relevant for prostate cancer risk than absolute intakes of these fatty acids [13,14]. The recommended dietary ratio of n-6/n-3 fatty acids for health benefits is 1:1-2:1 [15], yet the typical Western diet often contains 10 or more times the amount of n-6 relative to n-3 PUFA [16]. Alternatively, the relationship between diet and prostate cancer may differ according to race and ethnicity. Prostate cancer incidence and mortality rates are highest among black men [1], yet few studies have focused on race-specific associations between diet and prostate cancer risk. Dietary factors may also have stronger associations for more aggressive prostate cancers [9,17], and this finding would be missed when all prostate cancers are combined. The objectives of this study were to examine the relationship between prostate cancer risk and n-3 and n-6 PUFA intake, and the dietary ratio of n-6/n-3 fatty acids using a case-control study in veterans and to determine whether these associations vary by disease aggressiveness and race. Based on experimental evidence, we hypothesized that high intake of n-3 PUFA will be associated with lower risk of prostate cancer, whereas increased intake of n-6 PUFA will correlate with elevated prostate cancer risk.
2. Methods and materials 2.1. Study design and participants Data collection methods have been described elsewhere [18]. Briefly, men who had been screened for prostate cancer in the last 12 months were recruited to participate in an ongoing case-control study at the Durham Veterans Affairs Medical Center (DVAMC) in Durham, NC, from January 2007 to November 2009. Cases were men 18 years or older
with no history of prostate cancer who were scheduled for a prostate needle biopsy at the urology clinic. Of the 485 eligible cases, 450 consented to participate; therefore, the response rate was 91%. Among those who had the biopsy done (n = 420), 166 were biopsy positive. Controls were identified through the urology and internal medicine clinics at the DVAMC and shared the same eligibility criteria as cases, with the exception of not being recommended for a prostate needle biopsy. Of the 421 eligible controls, 307 provided written consent to participate, yielding a 73% response rate. Analyses were restricted to participants with complete questionnaires, and as a result, the analytic sample consisted of 79 biopsy-positive cases and 187 controls. Cases were men with biopsy-positive prostate cancer, and healthy controls were men with no biopsy indication. This study was approved by the Duke University and DVAMC Institutional Review Boards. 2.2. Data collection Anthropometric measurements (weight and height) were taken by trained personnel. Weight was measured using a digital scale, and a stadiometer was used to measure height [19]. These measurements were used to calculate body mass index (BMI), defined as weight (in kilograms) divided by the square of height (in meters squared). All questionnaires were self-administered and typically filled out the day of the scheduled clinic visit or returned shortly thereafter by mail prior to the patient knowing the outcome of their biopsy. Risk factor questionnaires queried information on sociodemographic characteristics, lifestyle factors such as smoking and alcohol use, medication use, and family history of prostate cancer. Dietary information was obtained using the Harvard food frequency questionnaire (FFQ), developed and tested for validity by Willett et al [20] and Holmes et al [21]. This 61item food frequency questionnaire assessed the frequency of consumption as well as the portion size for each food and beverage item. Subjects reported their intake in the past 12 months, and this time period was selected to account for seasonal variation in consumption. Daily food, nutrient, and total energy intakes were determined using the reported frequency of consumption and portion sizes. The nutrients of interest for this study were n-3 PUFA (α-linolenic acid [ALA], EPA, DHA) and n-6 PUFA (arachidonic acid [AA], linoleic acid [LA]). α-Linolenic acid, the predominant n-3 fatty acid in the Western diet, is found in green leafy vegetables, nuts, animal meats, and some vegetable oils, whereas EPA and DHA are abundant in fatty fish and fish oils [22]. Arachidonic acid is found in animal sources, and LA is in most vegetable oils and animal meats [22]. 2.3. Statistical analyses Descriptive statistics (means ± SD), medians (interquartile range), and percentages for cases and controls were
C.D. Williams et al. / Nutrition Research 31 (2011) 1–8
3
compared using a χ test for categorical variables and Wilcoxon rank sum test for continuous variables. All PUFA data were represented as the percent of total energy intake. Correlations between n-3 PUFA and n-6 PUFA were determined using Pearson correlation coefficients. Each PUFA was categorized into tertiles, which were based on the overall distribution of each PUFA among all controls. Unconditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) of prostate cancer risk across tertile categories of PUFA intake relative to the lowest (first) tertile. Odds ratios were adjusted for factors potentially associated with prostate cancer risk: age (continuous), BMI (b25, 25-29.9, ≥30 kg/m2), family history of prostate cancer (yes/no), smoking status (never, former, current), total energy (continuous), and, where appropriate, race (black, white, other). We conducted a linear trend test by incorporating the median tertile values among controls into a logistic regression model as a continuous predictor. To test for interaction, a cross-product term for race and each PUFA variable was entered into separate logistic regression models. We then stratified the models by race to obtain race-specific risk estimates. To determine the relationship between PUFA intake and disease aggressiveness, we used multinomial logistic regression to model the following outcomes: no cancer, low-grade prostate cancer (Gleason sum b7), and high-grade prostate cancer (Gleason sum ≥7). Because of our relatively small sample size, we were unable to perform race-specific analyses according to disease aggressiveness. All analyses were done using SAS version 9.2 (SAS Institute, Inc, Cary, NC), and a P b .05 was considered statistically significant.
Table 1 Participant characteristics by case-control status
3. Results
Values are expresses are mean ± SD. IQR indicates interquartile range. a Based on Wilcoxon rank sum test for continuous variables and χ2 test for categorical variables.
2
Compared with controls, prostate cancer cases were more likely to have a lower BMI (P =.03), and a higher proportion of cases had a family history of prostate cancer (P =.06; Table 1). The median prostate-specific antigen (PSA) level was also higher in cases than controls (P b.0001). There were no differences in age, education, or smoking status between cases and controls. There was also no difference between cases and controls for daily mean intakes of total energy and PUFA, and the average dietary ratio of n-6/n-3 fatty acids in cases (9.1) and controls (8.6) was also similar. Table 2 shows that among n-3 PUFAs, EPA and DHA were nearly perfectly correlated in cases (r = 0.97) and controls (r = 0.92). Interestingly, we also observed strong correlations between n-3 ALA and n-6 LA (r = 0.78 in cases; r = 0.65 in controls). Overall, we observed no statistically significant associations between self-reported intakes of total or specific n-3 or n-6 PUFA and prostate cancer risk among all men combined (Table 3). Risk estimates for high intakes of the n-3 PUFA ALA and DHA were similar in combined analyses, yet neither reached statistical significance. Although n-3 PUFA EPA and DHA were highly correlated, we did not observe
Cases, n (%) n Mean (SD) age (y) Race (%) Black White Other Education (%) ≤High school Vocational/technical training Some College College graduate/ Advanced degree BMI (%) b25 kg/m2 25-29.9 kg/m2 ≥30 kg/m2 Mean (SD; kg/m2) Smoking status (%) Current smoker Former smoker Never smoker Family history of prostate cancer (%) Yes Median (IQR) PSA (ng/L) Mean (SD) daily intakes Total energy (kJ) (% of total energy) Total n-3 PUFA ALA EPA DHA Total n-6 PUFA AA LA n-6/n-3 ratio
Controls, n (%)
79 63 (6)
187 62 (7)
40 (51) 38 (48) 1 (1)
69 (37) 112 (60) 4 (2)
P
a
.34 .24
.34 27 7 18 24
(35) (9) (24) (32)
47 26 58 52
(26) (14) (32) (28)
14 34 29 29
(18) (44) (38) (5)
22 (12) 56 (31) 100 (56) 31 (6)
24 (30) 54 (68) 1 (1)
43 (23) 134 (72) 10 (5)
19 (24) 5.8 (4.6-7.5)
27 (14) 0.80 (0.5-1.4)
.03
.07 .17
.06 b.0001
8342 (4930)
7706 (3545)
.74
0.80 (0.51) 0.59 (0.28) 0.09 (0.18) 0.11 (0.13) 6.2 (1.8) 0.09 (0.04) 6.1 (1.9) 9.1 (3.1)
0.76 (0.36) 0.57 (0.24) 0.08 (0.12) 0.10 (0.10) 5.9 (1.6) 0.09 (0.04) 5.8 (1.6) 8.6 (2.9)
.50 .77 .89 .54 .12 .19 .27 .20
any statistically significant results when simultaneously adjusting for EPA and DHA (data not shown). Intake of total, n-3, and n-6 PUFA remained unrelated to prostate cancer risk when we examined the associations by race, and there was no evidence of multiplicative interaction between race and PUFA intake. The dietary ratio of n-6/n-3 fatty acids in all men combined was not associated with risk of prostate cancer. An increasing dietary ratio of n-6/n-3 among white men appeared to correlate with higher prostate cancer risk (Ptrend = 0.05), yet no linear trend was observed in black men. In Table 4, we present risk estimates among all men for low-grade (Gleason sum b7, n = 43) and high-grade (Gleason sum ≥7, n = 36) prostate cancer as compared with controls. We found no evidence of an association or trend between intake of PUFA and low-grade prostate cancer. There was, however, a statistically significant elevated risk of high-grade prostate cancer for men in the highest ratio category of dietary n-6/n-3 PUFA (OR, 3.55; 95% CI, 1.18-10.69), as well as a positive linear trend (Ptrend = 0.03).
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C.D. Williams et al. / Nutrition Research 31 (2011) 1–8
Table 2 Pearson correlation coefficients of n-3 and n-6 PUFAs Cases
n-3 PUFA ALA EPA DHA n-6 PUFA AA LA
Controls
ALA
EPA
DHA
AA
LA
ALA
EPA
DHA
AA
LA
1.00
0.38 ⁎ 1.00
0.38 ⁎ 0.97 ⁎ 1.00
-0.04 0.31 ⁎ 0.40 ⁎
0.78 ⁎ 0.21 0.25 ⁎
1.00
0.22 ⁎ 1.00
0.17 0.92 ⁎ 1.00
-0.01 0.29 ⁎ 0.52 ⁎
0.65 ⁎ 0.04 0.02
1.00
0.05 1.00
1.00
0.04 1.00
⁎ P b.05. Table 3 ORs and 95% CIs for the association between tertiles of PUFA intake and prostate cancer risk a
Total PUFA, tertile Tertile 1: b5.7 2: 5.7-7.0 3: 7.1-14.5 Ptrend Total n-3 PUFA 1: b0.57 2: 0.57-0.81 3: 0.81-2.6 Ptrend ALA 1: b0.45 2: 0.45-0.58 3: 0.58-1.87 Ptrend EPA 1: b0.019 2: 0.019-0.078 3: 0.079-0.83 Ptrend DHA 1: b0.054 2: 0.054-0.10 3: 0.10-0.64 Ptrend Total n-6 PUFA 1: b5.0 2: 5.0-6.2 3: 6.3-12.5 Ptrend AA 1: b0.07 2: 0.07-0.10 3: 0.10-0.26 Ptrend LA 1: b4.9 2: 4.9-6.2 3: 6.2-12.5 Ptrend n-6/n-3 ratio 1: b7.6 2: 7.6-9.5 3: 9.5-19.0 Ptrend a
Combined (n = 266)
Black (n = 109)
White (n = 150)
Cases
OR (95% CI)
Cases
OR (95% CI)
Cases
OR (95% CI)
30 15 34
1.00 0.46 (0.22-0.99) 1.29 (0.67-2.50) .38
17 6 17
1.00 0.25 (0.08-0.82) 1.53 (0.53-4.39) .39
13 9 16
1.00 0.85 (0.29-2.44) 1.34 (0.53-3.42) .52
33 21 25
1.00 0.62 (0.31-1.23) 0.83 (0.42-1.63) .73
17 11 12
1.00 0.66 (0.24-1.84) 0.93 (0.32-2.68) 1.00
16 9 13
1.00 0.53 (0.20-1.47) 0.85 (0.33-2.17) .87
30 25 24
1.00 0.75 (0.38-1.48) 0.82 (0.41-1.65) .64
16 15 9
1.00 0.61 (0.22-1.69) 0.46 (0.14-1.49) .21
14 10 14
1.00 0.81 (0.30-2.22) 1.29 (0.50-3.29) .55
27 25 27
1.00 1.04 (0.53-2.06) 1.13 (0.56-2.24) .73
12 13 15
1.00 1.27 (0.44-3.64) 1.46 (0.51-4.13) .52
14 12 12
1.00 0.98 (0.38-2.53) 0.91 (0.34-2.46) .85
29 26 24
1.00 0.91 (0.47-1.76) 0.82 (0.40-1.68) .60
14 9 17
1.00 0.55 (0.18-1.68) 0.87 (0.32-2.40) .99
14 17 7
1.00 1.41 (0.59-3.38) 0.58 (0.18-1.91) .43
25 18 36
1.00 0.82 (0.39-1.71) 1.62 (0.82-3.17) .15
15 8 17
1.00 0.42 (0.14-1.29) 1.65 (0.58-4.73) .32
10 10 18
1.00 1.72 (0.59-5.03) 1.98 (0.73-5.36) .18
37 23 19
1.00 0.71 (0.37-1.39) 0.52 (0.25-1.08) .08
15 13 12
1.00 0.64 (0.22-1.83) 0.42 (0.14-1.20) .11
22 9 7
1.00 0.57 (0.22-1.50) 0.64 (0.21-1.95) .37
24 20 35
1.00 0.93 (0.45-1.91) 1.60 (0.82-3.15) .16
14 10 16
1.00 0.70 (0.24-2.05) 1.62 (0.56-4.67) .37
10 9 19
1.00 1.22 (0.41-3.59) 2.37 (0.88-6.41) .08
21 23 35
1.00 1.10 (0.53-2.27) 1.57 (0.79-3.11) .17
12 13 15
1.00 0.98 (0.35-2.79) 0.91 (0.32-2.56) .85
9 10 19
1.00 1.17 (0.39-3.50) 2.52 (0.93-6.79) .05
Pinteraction
.34
.84
.01
.16
.40
.29
.40
.85
.06
Adjusted for age, BMI, family history of prostate cancer, smoking status, total energy, and, in combined analyses, race.
C.D. Williams et al. / Nutrition Research 31 (2011) 1–8 Table 4 ORs and 95% CIs for the association between PUFA intake and low-grade and high-grade prostate cancer risk a Low-grade prostate High-grade prostate cancer (Gleason sum, cancer (Gleason sum, b7; n = 43), OR (95% CI) ≥7; n = 36), OR (95% CI) Total PUFA Tertile 1 2 3 Ptrend Total n-3 PUFA 1 2 3 Ptrend ALA 1 2 3 Ptrend EPA 1 2 3 Ptrend DHA 1 2 3 Ptrend Total n-6 PUFA 1 2 3 Ptrend AA 1 2 3 Ptrend LA 1 2 3 Ptrend n-6/n-3 ratio 1 2 3 Ptrend
1.00 0.39 (0.15-1.03) 1.15 (0.52-2.54) .65
1.00 0.54 (0.19-1.54) 1.43 (0.58-3.57) .40
1.00 0.69 (0.30-1.59) 0.93 (0.41-2.10) .98
1.00 0.56 (0.21-1.47) 0.76 (0.30-1.91) .65
1.00 0.81 (0.36-1.85) 0.86 (0.37-2.00) .77
1.00 0.74 (0.29-1.90) 0.87 (0.34-2.24) .82
1.00 1.43 (0.62-3.31) 1.40 (0.59-3.31) .56
1.00 0.72 (0.28-1.88) 0.87 (0.34-2.20) .89
1.00 1.01 (0.44-2.32) 1.15 (0.49-2.70) .73
1.00 0.77 (0.32-1.90) 0.49 (0.17-1.38) .18
1.00 0.76 (0.31-1.87) 1.48 (0.66-3.35) .32
1.00 0.87 (0.30-2.47) 1.88 (0.74-4.77) .17
1.00 0.89 (0.40-1.96) 0.55 (0.23-1.36) .19
1.00 0.50 (0.20-1.30) 0.46 (0.17-1.27) .15
1.00 1.06 (0.44-2.58) 1.70 (0.74-3.91) .20
1.00 0.77 (0.28-2.13) 1.51 (0.61-3.79) .37
1.00 0.68 (0.29-1.60) 0.95 (0.43-2.17) .96
1.00 2.51 (0.78-8.03) 3.55 (1.18-10.69) .03
a Adjusted for age, BMI, family history of prostate cancer, smoking status, total energy, and race.
4. Discussion In this case-control study, intakes of total, n-3, and n-6 PUFA were not associated with prostate cancer risk. In whites, a high dietary ratio of n-6/n-3 fatty acids was suggestive of higher prostate cancer risk, yet there was a practically null association between the dietary ratio of n-6/ n-3 fatty acids and prostate cancer risk in blacks. Among all men, there was evidence of a strong positive association and
5
significant trend between the dietary ratio of n-6/n-3 fatty acids and high-grade prostate cancer, whereas this ratio was unrelated to low-grade prostate cancer. These results do not confirm the hypothesis that specific dietary n-3 and n-6 PUFA are associated with prostate cancer risk; however, our findings suggest that the dietary ratio of n-6/n-3 fatty acids is positively associated with the risk of overall prostate cancer among white men and high-grade prostate cancer among all men. In vitro and animal studies provide evidence that n-3 PUFAs, particularly EPA and DHA, suppress prostate tumor growth, whereas n-6 PUFA stimulate tumor growth [13,14,23,24]. The most likely mechanism by which these fatty acids may affect prostate cancer risk is through the conversion of n-3 PUFA to anti-inflammatory and n-6 PUFA to proinflammatory eicosanoids [11]. The n-6 PUFA (AA and LA) are metabolized into inflammatory eicosanoids, such as prostaglandin E2, through the cyclooxygenase pathway [25]. The n-3 PUFA EPA and DHA can inhibit this metabolic pathway and thereby exert their anti-inflammatory properties. Other possible mechanisms by which n-3 PUFA exhibit antineoplastic activity include regulating gene expression and transcription factor activity, altering the production of free radicals and modulating insulin sensitivity [11]. α-Linolenic acid, the parent fatty acid of all n-3 PUFA, represents approximately 85% to 94% of total n-3 intake [26]. Along with n-6 LA, it is 1 of the 2 most frequently investigated fatty acids potentially associated with prostate cancer [2]. Our finding regarding the null association between intake of n-3 ALA and prostate cancer risk is in agreement with numerous epidemiologic studies showing no association between ALA and prostate cancer [17,27-30]. A meta-analysis by Simon et al [7] reported an increased risk of prostate cancer for high blood and tissue concentrations of ALA, yet no association between prostate cancer and dietary ALA was observed. On the contrary, a recent meta-analysis of 5 prospective studies suggested a small risk reduction for dietary ALA intakes greater than 1.5 g/d [31]. There is evidence for antiproliferative effects of the n-3 PUFA EPA and DHA [32,33]. In support of these observations, some epidemiologic studies have observed inverse associations between EPA and DHA and prostate cancer risk [9,17,28], whereas others have reported positive associations [29,34]. The results of our study did not confirm the hypothesis for a protective effect of these fatty acids. High intakes of both EPA and DHA were unrelated to prostate cancer in our study, as was the case in other studies [10,27,30], one of which was another case-control study in North Carolina that assessed biomarkers of fatty acid consumption [10]. Findings for n-6 PUFA have also been inconsistent, because several studies including ours have found no evidence for associations between n-6 PUFA and risk of prostate cancer [8,30,34]. Linoleic acid, the predominant n-6 fatty acid, has been positively correlated with elevated prostate cancer risk in some studies [10,35], although one study reported significant inverse associations
6
C.D. Williams et al. / Nutrition Research 31 (2011) 1–8
between LA and the risk of overall, localized, and aggressive prostate cancer [9]. Omega-3 (n-3) and n-6 PUFA have competing roles in inflammatory pathways where a high n-3 intake can reduce the production of proinflammatory eicosanoids derived from n-6 PUFA, partially because n-3 fatty acids are the preferential substrates for enzymes involved in eicosanoid metabolism [11,16]. For this reason, the balance of n-6 and n-3 PUFA in the diet may have stronger effects on prostate cancer risk than individual PUFA. Experimental data suggest that the balance between n-6 and n-3 PUFA can alter the behavior of prostate tumors [14,23,24,36]. For example, animal models have shown a growth inhibitory effect on prostate cancer by lowering the ratio of n-6/n-3 in the diet [14,36,37]. A recent low-fat dietary intervention trial among men with prostate cancer reported that lower serum n-6 and/ or higher serum n-3 levels were associated with decreased proliferation of LNCaP (lymph node cancer of the prostate) cells when the patient's serum was added to the cancer cells in vitro [38]. An observational study by Fradet et al [17] found that a high ratio of long-chain n-3 PUFA (ie, EPA, DHA, and docosapentaenoic acid) to n-6 PUFA was associated with a significant lower risk for aggressive prostate cancer (defined as Gleason sum, ≥7; TNM stage, NT2; and PSA, ≥10). A high dietary ratio of n-6/n-3 fatty acids in our study was only suggestive of an elevated risk of overall prostate cancer; however, there was a significant positive association with high-grade (ie, aggressive) prostate cancer. This finding not only supports the idea that the ratio of n-6 to n-3 fatty acids may be more relevant to prostate cancer than individual n-6 and n-3 fatty acids but may also reflect the fact that not all prostate cancers are the same. In general, studies reporting lower prostate cancer risk with intakes of n-3 PUFA or fish, the major source of n-3 PUFA, have observed stronger associations for advanced, aggressive, or metastatic disease and prostate cancer death [9,39-44]. Furthermore, our findings suggest that the association between the dietary ratio of these 2 classes of PUFA may differ between whites and blacks. A positive trend was seen in white men, whereas no association was observed among black men. Although we cannot exclude the possibility of a chance finding, diet-gene interaction is a possible explanation for this difference. Racial differences in genetic variants of cyclooxygenase 2, a key enzyme in fatty acid metabolism may exist and therefore modify the associations between PUFA and prostate cancer in racial subgroups [45]. Unfortunately, we were unable to assess this interaction in our study. Other studies have reported different diet and prostate cancer associations for blacks and whites [43,46]. For example, Hayes et al [43] observed an increased risk of prostate cancer among whites but not blacks for high intakes of dairy foods and sweets, whereas high animal fat intake correlated with increased risk in black s but not whites. Together, these findings stress the importance of examining diet and prostate cancer associations separately for different race/ethnic groups. To our knowledge, our study is the first
to investigate the relationship between PUFA and prostate cancer risk in a racially diverse sample of US veterans. The veteran population is ideal for assessing factors that may contribute to racial disparities due to this system of equal access to health care. There are several limitations to our study. Case-control study designs are often subject to selection bias and recall bias. Although it is possible that selection bias was introduced in our results, recall bias is less likely because cases in our study were interviewed before their biopsy; thus, they were unaware of their prostate cancer status at the time of interview which helps to minimize differential recall between cases and controls. Most findings in this study were null, and it is not clear whether this stems from a true lack of association or limited statistical power due to our relatively small sample size, particularly for stratified analyses. Measurement error from using a FFQ is possible because the questionnaire may not have included enough foods to accurately assess intake of PUFA. In addition, there may have been insufficient variability in intake in our population to detect associations with more extreme dietary intakes. For example, the mean ratio of dietary n-6 to n-3 fatty acids among controls in our study was 8.6, with a range of 2.719.0. Although this is similar to the average dietary ratio of n-6/n-3, which is 9.8 in the United States [26], the range in our study simply represents variations of a Western diet. It has been suggested that optimal ratios for overall health are closer to 1:1 or 2:1 [15]; thus, it is possible that not enough men in the current study had low enough values to show a substantially lower risk of prostate cancer, though this, of course, requires further testing. Because our findings were derived from veterans who had been screened for prostate cancer, studies in different populations are needed to validate these findings. This study focused exclusively on prostate cancer. However, other prostate-related diseases such as benign prostate hyperplasia (BPH) are also clinically important as BPH can significantly affect quality of life. Moreover, BPH has been suggested to be related to diet and specifically dietary fat intake [47]. We were unable to address this because our study was developed as a casecontrol series of men with prostate cancer, though we hope to explore this in future studies. Finally, we cannot exclude the possibility of chance findings due to multiple comparisons and a lack of strong linear associations with risk. In summary, we found specific n-3 and n-6 PUFAs intake to be unrelated to overall prostate cancer risk in this casecontrol study among US veterans. There was evidence for an association between a high dietary ratio of n-6/n-3 PUFA and increased risk of high-grade prostate cancer, whereas no specific PUFA or the ratio of PUFA was associated with low-grade prostate cancer. Our data also suggest that prostate cancer risk may increase with higher dietary ratios of n-6/n-3 fatty acid intake in white men but not in black men. Therefore, our findings emphasize the importance of examining the ratio of n-6 and n-3 PUFA when assessing the relationship between PUFA intake and prostate cancer
C.D. Williams et al. / Nutrition Research 31 (2011) 1–8
risk and the need to examine these associations in subgroups of tumor grade and race/ethnicity. Acknowledgment This work was supported by the Agency for Healthcare Research and Quality (T32 HS00079), National Institutes of Health NCMHC (P20 MD000175), Department of Defense (PC060233), Department of Veterans Affairs, and the American Urological Association Foundation/Astellas Rising Star in Urology. References [1] American Cancer Society. Cancer Facts & Figures 2009. Atlanta (GA): American Cancer Society; 2009. [2] Sonn GA, Aronson W, Litwin MS. Impact of diet on prostate cancer: a review. Prostate Cancer Prostatic Dis 2005;8:304-10. [3] American Institute for Cancer Research/World Cancer Research Fund. Food, nutrition, physical activity and the prevention of cancer: a global perspective. Washington, DC: AICR; 2007. [4] Terry PD, Rohan TE, Wolk A. Intakes of fish and marine fatty acids and the risks of cancers of the breast and prostate and of other hormone-related cancers: a review of the epidemiologic evidence. Am J Clin Nutr 2003;77:532-43. [5] Astorg P. Dietary N-6 and N-3 polyunsaturated fatty acids and prostate cancer risk: a review of epidemiological and experimental evidence. Cancer Causes Control 2004;15:367-86. [6] Brouwer IA. Omega-3 PUFA: good or bad for prostate cancer? Prostaglandins Leukot Essent Fatty Acids 2008;79:97-9. [7] Simon JA, Chen YH, Bent S. The relation of alpha-linolenic acid to the risk of prostate cancer: a systematic review and meta-analysis. Am J Clin Nutr 2009;89:1558S-64S. [8] Park SY, Wilkens LR, Henning SM, Le Marchand L, Gao K, Goodman MT, et al. Circulating fatty acids and prostate cancer risk in a nested case-control study: the Multiethnic Cohort. Cancer Causes Control 2009;20:211-23. [9] Chavarro JE, Stampfer MJ, Li H, Campos H, Kurth T, Ma J. A prospective study of polyunsaturated fatty acid levels in blood and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2007;16: 1364-70. [10] Godley PA, Campbell MK, Gallagher P, Martinson FE, Mohler JL, Sandler RS. Biomarkers of essential fatty acid consumption and risk of prostatic carcinoma. Cancer Epidemiol Biomarkers Prev 1996;5:889-95. [11] Larsson SC, Kumlin M, Ingelman-Sundberg M, Wolk A. Dietary longchain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. Am J Clin Nutr 2004;79:935-45. [12] Rose DP. Dietary fatty acids and prevention of hormone-responsive cancer. Proc Soc Exp Biol Med 1997;216:224-33. [13] Kelavkar UP, Hutzley J, McHugh K, Allen KG, Parwani A. Prostate tumor growth can be modulated by dietarily targeting the 15lipoxygenase-1 and cyclooxygenase-2 enzymes. Neoplasia 2009;11: 692-9. [14] Kobayashi N, Barnard RJ, Henning SM, Elashoff D, Reddy ST, Cohen P, et al. Effect of altering dietary omega-6/omega-3 fatty acid ratios on prostate cancer membrane composition, cyclooxygenase-2, and prostaglandin E2. Clin Cancer Res 2006;12:4662-70. [15] Simopoulos AP. Evolutionary aspects of the dietary omega-6:omega-3 fatty acid ratio: medical implications. World Rev Nutr Diet 2009;100: 1-21. [16] Daniel CR, McCullough ML, Patel RC, Jacobs EJ, Flanders WD, Thun MJ, et al. Dietary intake of omega-6 and omega-3 fatty acids and risk of colorectal cancer in a prospective cohort of U.S. men and women. Cancer Epidemiol Biomarkers Prev 2009;18:516-25.
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