Epidemiological and laboratory evidence supports a role for cholesterol in prostate cancer (PC). Dietary saturated fat content impacts serum cholesterol levels. However, epidemiological associations between saturated fat and PC aggressiveness are inconsistent. We hypothesized that high saturated fat intake would be associated with increased PC aggressiveness, and that statin use would modify this association.
Of 1854 PC cases in the North Carolina-Louisiana PC Project, 321 (17%) were classified as high aggressive (Gleason sum ⩾ 8, PSA420 ng ml− 1, or Gleason sum ⩾7 and clinical stage T3-4) or low/intermediate aggressive (all other cases). Using low/ intermediate aggressive cases as the referent group, we examined the association between tertiles of total fat-adjusted saturated fat intake and high aggressive PC using logistic regression, overall and stratified by race and statin use. We examined total fat-adjusted polyunsaturated and monounsaturated fatty acids (PUFA and MUFA, respectively), trans fat and cholesterol intake in secondary analysis.
High total fat-adjusted saturated fat intake was associated with an elevated odds ratio (OR) for aggressive PC (ORT3vsT1 1.51; 95% CI 1.10–2.06; P-trend = 0.009), with an attenuated association in statin users (ORT3vsT1 1.16; 95% CI 0.67–2.01; P-trend = 0.661) compared with non-users (ORT3vsT1 1.71; 95% CI 1.16–2.51; P-trend = 0.053). High total fat-adjusted cholesterol intake was associated with aggressive PC in European Americans (ORT3vsT1 1.62; 95% CI 1.02–2.58; P-trend = 0.056), but not African Americans (ORT3vsT1 0.92; 95% CI 0.60–1.42; P-trend = 0.750). High total fat-adjusted PUFA was inversely associated with PC aggressiveness (ORT3vsT1 0.75; 95% CI 0.55–1.03), although this was not significant. No associations were found between total fat-adjusted MUFA or trans fat and PC aggressiveness.
High total fat-adjusted saturated fat intake was associated with increased PC aggressiveness, with a suggestion of a stronger effect in men not using statins. The association between total fat-adjusted cholesterol intake and PC aggressiveness was most pronounced in European Americans.
Prostate Cancer and Prostatic Diseases (2017) 20, 48–54; doi:10.1038/pcan.2016.39; published online 6 September 2016
Prostate cancer (PC) incidence rates vary more than 25-fold worldwide, and are highest in western countries.1 International variation in incidence rates is due in part to differences in screening practices between countries, but dietary factors may also play a role. Dietary fat intake, unlike other macronutrients, varies more than fivefold worldwide, and western populations are among the highest consumers of saturated and trans fats, and cholesterol.2
High-fat dietary interventions in mouse models of PC drive tumor growth,3,4 but several large prospective cohort studies found no association between different types of dietary fat and PC risk.5–7 However, other cohort studies support an association between elevated intake of saturated fat and increased PC aggressiveness8,9 and mortality.8,10,11 Many prior studies were limited by incomplete assessment of potential confounders, including PC screening.7 In addition, prior studies were primarily carried out in white populations, and so the impact of race on these associations remains poorly understood.
Using the North Carolina-Louisiana PC Project (PCaP), a case only study of incident PC in European Americans (EAs) and African Americans (AAs), we examined associations between dietary saturated fat intake and PC aggressiveness, overall and stratified by race. Dietary saturated fat intake impacts serum cholesterol levels,12 and epidemiological evidence supports a role for serum cholesterol and cholesterol-lowering statins in PC.13,14 Indeed, we previously reported an inverse association between statin use and PC aggressiveness in PCaP.15 As such, we explored the hypothesis that the association between saturated fat and PC aggressiveness would be weaker in men using statins to control serum cholesterol levels. In secondary analysis, we examined associations between total fat, polyunsaturated fatty acid (PUFA), monounsaturated fatty acid (MUFA), trans fat, cholesterol intake and PC aggressiveness.
MATERIALS AND METHODS
Study population: PCaP enrolled men 40–79 years of age diagnosed with PC on or after 1 July 2004, as previously described.16 Research subjects self-identified as either AA/black or Caucasian/white (EA) in response to the open-ended question 'What is your race?' Recruitment ended October 2007 in North Carolina (NC) and July 2009 in Louisiana (LA). Informed consent was obtained from all research subjects. Research protocols were approved by the institutional review boards at the University of North Carolina, Louisiana State University Health Services Center, and Department of Defense PC Research Program.
Exposure assessment and explanatory variables
PCaP research nurses administered questionnaires during an in-home visit approximately 3 months after diagnosis.16 PC screening frequency was classified as a three-level variable (never screened, ⩽1 PSA and/or digital rectal exam per year, 41 PSA and/or digital rectal exam per year), as previously described.15 The dietary assessment instrument was a modified National Cancer Institute (NCI) Diet History Questionnaire17,18 to which southern US foods were added. Research subjects reported dietary intake during the 12 month period prior to PC diagnosis. Dietary intake of fatty acids and cholesterol was calculated using Diet*Calc analysis software (version 1.4.3, NCI, Applied Research Program, November 2005). No gold standard exists for validating calories from dietary fats and cholesterol. However, a comparative validation study indicated that energy-adjusted correlations between multiple 24 h recalls and Diet History Questionnaire estimates were 0.68 for saturated fat, 0.61 for PUFA, 0.60 for MUFA, 0.66 for total fat and 0.64 for cholesterol.17 Research subjects gathered all prescription medications used in the 2-week period prior to interview and presented them to the research nurse at the time of interview for documentation of current statin use. We previously reported an inverse association between statin use and PC aggressiveness, with no differences in this association by statin type or dose.15 Therefore, we did not consider statin type or dose in the present analysis. Duration of statin use was not available.
Clinical stage, biopsy Gleason sum and serum PSA at diagnosis were abstracted from medical records. High aggressive PC, our outcome of interest, was defined as Gleason sum ⩾8, or PSA 420 ng ml− 1, or Gleason sum ⩾7 and clinical stage T3-T4. Low/intermediate aggressive PC (all other cases) was used as the referent group for all analyses.16 We excluded 85 research subjects lacking sufficient clinical data to define a PC aggressiveness category. We also excluded research subjects missing body mass index (n = 21), PC screening frequency (n = 221), smoking status (n = 1) and those who reported implausibly low or high caloric intake (<800 or ⩾6000 kcal per day, respectively; n = 76). These exclusions resulted in 1854 research subjects (n = 993 EA and n = 861 AA) for the present analysis.
We examined differences in patient and tumor characteristics between low/intermediate vs high aggressive PC cases, and across tertiles of total fat-adjusted saturated fat intake, using chi-square tests for categorical variables, Student’s t-tests for continuous, normally distributed variables and rank sum tests for continuous non-normally distributed variables.
Dietary variables were log transformed to improve normality. Saturated fat intake was adjusted for total fat intake using the residual method to examine the impact of saturated fat on PC aggressiveness independent of total fat intake.19 Total fat-adjusted saturated fat intake was analyzed as a categorical variable, based on tertiles of the distribution among low/ intermediate aggressive PC cases. Logistic regression was used to estimate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between tertiles of total fat-adjusted saturated fat intake and PC aggressiveness (high vs low/intermediate) using the lowest tertile (T1) as the referent. For multivariable analysis, we selected covariates using a directed acyclic graph and performed backwards selection (using P⩾0.1 as the threshold for exclusion of variables from the model) to build our final model, which included age (continuous), race (AA, EA), site (NC, LA), marital status (married/living as married, divorced/separated/widowed, single), body mass index (continuous), statin use (yes, no), smoking status (never, former, current), PC screening frequency (never, ⩽ 1 screening test per year, 41 screening test per year), energy intake (kcal; continuous), and energy-adjusted total fat intake (calculated using the residual method; continuous). Physical activity, education, income, Charlson comorbidity index and family history of PC were dropped by backwards selection and therefore not included in the final model. Tests for trend of categorical variables were conducted by assigning each research subject the median value of their tertile of intake and modeling these values as a continuous variable. We tested for interaction between race and dietary fat intake for predicting PC aggressiveness by incorporating a cross product term into the logistic regression model, and calculating the global P-value of the interaction term using the Wald test. We explored statin use as an effect modifier of associations between total fat-adjusted saturated fat intake and PC aggressiveness using models stratified by statin use.
In secondary analysis, using the same method as described for total fat-adjusted saturated fat, we examined associations for tertiles of total fat-adjusted PUFA, MUFA, trans fat, and cholesterol intake and for tertiles of energy-adjusted total fat intake. We also explored race-specific tertiles of total fat-adjusted saturated fat, PUFA, MUFA, trans fat, and cholesterol intake and race-specific tertiles of energy-adjusted total fat intake. In sensitivity analysis, we explored associations between saturated fat intake and PC aggressiveness in men reporting a history of PC screening, and in men who were never screened. Finally, we explored associations between tertiles of energy-adjusted saturated fat and PC aggressiveness but, given that this approach produced largely similar findings to the total fat-adjusted saturated fat results, these data are not presented.
Statistical analyses were performed using Stata 13.1 (Stata, College Station, TX, USA). We did not make adjustments for multiple comparisons. Statistical significance was two-sided with P<0.05.
Demographic characteristics by PC aggressiveness Research subjects with high aggressive PC tended to be older at diagnosis, and were more likely to be AA than EA (Table 1). High aggressive PC cases were less likely to be married/living as married, less likely to report a history of PC screening, and had lower education and income levels than low/intermediate cases. Alcohol intake and level of physical activity did not differ by PC aggressiveness (data not shown), but research subjects with high aggressive disease were more likely to be current smokers and obese, and less likely to be statin users.
Saturated fat made up a larger percentage of total fat intake and PUFA made up a smaller percentage of total fat intake in research subjects with high vs low/intermediate aggressive PC, but there were no differences in percent MUFA or trans fat intake by PC aggressiveness (Table 1). Relative to research subjects with low/intermediate aggressive PC, those with high aggressive PC consumed a greater percentage of calories from total fat, and had higher cholesterol intake and higher daily energy intake. Dietary fat, cholesterol and energy intake by race are presented in Supplementary Table S1.
Demographic and tumor characteristics by tertiles of total fatadjusted saturated fat intake
Age at diagnosis did not differ by saturated fat intake, but AAs consumed less saturated fat than EAs (Table 2). Research subjects who consumed greater amounts of saturated fat were more likely to have high aggressive PC, less likely to be married/living as married and less likely to report a history of PC screening. Level of education, income, smoking and obesity status did not differ across tertiles of total fat-adjusted saturated fat intake. Prevalence of statin use differed across tertiles of total fat-adjusted saturated fat intake, but there was no clear pattern of association (Table 2).
Total dietary fat intake and PC aggressiveness
Among 1854 PC cases, 321 (n = 175 AA and n = 146 EA) had high aggressive disease. Relative to the lowest tertile, research subjects in the upper tertile of energy-adjusted total fat intake had an elevated OR for high aggressive PC following adjustment for potential confounders (ORT3vsT1 1.48; 95% CI 1.08–2.02; P-trend = 0.016; Table 3). Race-stratified analyses suggested that this effect was more pronounced in EAs (ORT3vsT1 1.84; 95% CI 1.13–2.98; P-trend = 0.010) than AAs (ORT3vsT1 1.19; 95% CI 0.77–1.83; P-trend = 0.408), but there was no significant interaction by race (P-interaction = 0.322). Race-specific tertiles of total dietary fat intake produced similar findings (Supplementary Table S2).
Dietary fat composition and PC aggressiveness
We explored the effects of dietary fat type on PC aggressiveness by adjusting each type of dietary fat for total fat intake using the residual method. Total fat-adjusted saturated fat intake was associated with increased PC aggressiveness (ORT3vsT1 1.51; 95% CI 1.10–2.06; P-trend = 0.009; Table 3), with a more pronounced effect in EAs (ORT3vsT1 1.96; 95% CI 1.23–3.12; P-trend = 0.003) than AAs (ORT3vsT1 1.25; 95% CI 0.81–1.93; P-trend = 0.321). However, there was no significant interaction by race (P-interaction = 0.452). We observed an inverse association between high total fat-adjusted PUFA intake and PC aggressiveness among all research subjects (ORT3vsT1 0.75; 95% CI 0.55–1.03; P-trend = 0.075), with a similar magnitude of inverse association in both EAs and AAs although neither overall nor race-stratified findings were statistically significant (Table 3). There were no significant associations between total fat-adjusted MUFA or trans fat intake and PC aggressiveness, overall or in race-stratified analyses. High total fat-adjusted cholesterol intake was associated with increased PC aggressiveness in EAs (ORT3vsT1 1.62; 95% CI 1.02–2.58; P-trend = 0.056) but not AAs (ORT3vsT1 0.92; 95% CI 0.60–1.42; P-trend = 0.750), although the interaction by race was not statistically significant (P-interaction = 0.244).
The use of race-specific tertiles of dietary fat intake did not substantially impact our findings (Supplementary Table S2). Positive associations between saturated fat and PC aggressiveness were observed in screened and unscreened men, although the magnitude of the association was attenuated and no longer statistically significant in never-screened men (Supplementary Table S3).
Statin use as an effect modifier of the saturated fat–PC aggressiveness association
Analyses stratified by statin use showed that research subjects in the upper tertile of total fat-adjusted saturated fat intake had an elevated OR for high aggressive PC regardless of statin use status. However, there was a weaker association in statin users (ORT3vsT1 1.16; 95% CI 0.67–2.01; P-trend = 0.661) compared with non-users (ORT3vsT1 1.71; 95% CI 1.16–2.51; P-trend = 0.053; Table 4), although there was no significant interaction by statin use (Pinteraction = 0.430).
Using data from the population-based, case-only PCaP, we report that total dietary fat content and dietary fat composition impacted PC aggressiveness. Research subjects with higher total fat intake, and with saturated fat making up a greater proportion of total fat intake, had more aggressive disease at diagnosis. Although there was no strong evidence for racial differences in these associations, effect estimates for total fat and saturated fat intake were larger in EAs relative to AAs, and high dietary cholesterol was associated with higher PC aggressiveness only in EAs. These findings support a role for dietary fat content and composition in PC aggressiveness in both EA and AA men, although future studies are required to test the suggestion that these associations may be stronger in EAs.
Relatively few studies to date have examined associations between dietary fat and PC by race. The prospective Multiethnic Cohort (MEC) study reported no associations between any type of dietary fat or cholesterol intake and either total or aggressive PC risk in any of five racial/ethnic groups examined.5 A case–control study of four different racial/ethnic groups in North America reported a positive association between saturated fat intake and PC risk in both EAs and AAs.20 Two studies indirectly assessed saturated fat intake by measuring red meat and animal fat consumption; one multi-center case–control study in the USA showed a positive association between animal fat intake and aggressive disease in both EAs and AAs,21 while the prospective Cancer Prevention Study II reported stronger associations between red meat consumption and PC risk in AAs.22 Collectively, the findings of these prior studies and those of the present analysis do not provide strong evidence for racial differences in associations between dietary fat and cholesterol intake and PC aggressiveness and if a racial difference exists, the difference appears small.
A number of biologic mechanisms may contribute to associations between dietary fat and PC aggressiveness. High-fat diets can modulate androgen signaling,23 up-regulate the insulin-like growth factor pathway and increase prostate inflammation, thereby promoting PC growth.24,25 Moreover, saturated fat intake is an important dietary determinant of serum cholesterol levels.12,26 Epidemiological data support a positive association between high serum cholesterol and PC aggressiveness27 and an inverse association between statin use and PC aggressiveness.15,28 If saturated fat intake promotes PC aggressiveness by raising serum cholesterol levels, the association between saturated fat and PC aggressiveness should be attenuated in individuals using statins to control serum cholesterol levels. We observed a weaker magnitude of effect in statin users, but found no strong evidence to support statin use as an effect modifier of the saturated fat–PC aggressiveness association. These findings may reflect the complex relationship between saturated fat and PC aggressiveness, given multiple determinants (both dietary and genetic) of serum cholesterol levels, in addition to the aforementioned cholesterol-independent mechanisms by which saturated fat may impact PC aggressiveness.
PC screening bias is important to consider when screening history is associated with the exposure of interest. In order to investigate whether higher saturated fat intake among never-screened men could explain the positive association between saturated fat intake and PC aggressiveness, we conducted a sensitivity analysis stratified by PC screening history. We observed a partially attenuated association between saturated fat intake and PC aggressiveness in never-screened men, relative to those reporting a history of PC screening. One caveat is that the number of never-screened men was relatively low, potentially limiting our ability to detect a significant association in this group. However, these findings suggest that lower screening rates in men with high saturated fat intake may contribute to, but do not entirely explain, the association between higher total and saturated fat intake and PC aggressiveness. However, studies conducted in the US prior to introduction of widespread PSA screening9 and in European populations with much lower screening rates10 have reported positive associations between saturated fat intake and PC aggressiveness, supporting our findings from PCaP that the association between saturated fat and PC aggressiveness is not wholly attributable to PC screening biases.
Epidemiological evidence supporting an association between PUFA intake and PC aggressiveness is sparse and inconsistent. Individual studies have reported positive,6 inverse29 and null associations,8 and a recent meta-analysis reported a null association between PUFA intake and risk of both total and aggressive PC.7 Furthermore, a recent systematic review found no consistent role for fish oil, an important source of omega-3 PUFAs, in reducing PC incidence, aggressiveness or mortality.30 In the present study, although the direction of association between PUFA intake and PC aggressiveness was inverse, these findings were not statistically significant either overall or in race-stratified analysis.
Several limitations of this study should be considered. First, dietary data were collected after diagnosis and knowledge of disease status may have biased responses by research subjects. However, all of our research subjects were incident PC cases, thereby reducing this potential source of bias. Furthermore, the use of rapid case ascertainment limited the time between diagnosis and enrollment in PCaP, thus reducing the likelihood of bias from time or treatment. Second, serum levels of fatty acids and cholesterol were not measured in PCaP as measurements at the time of diagnosis may be impacted by presence of PC, raising concerns about reverse causality.31 Measurement of dietary fat intake using a validated Food Frequency Questionnaire may be less subject to this potential source of bias. Finally, given that duration of statin use was not available in PCaP, we were unable to distinguish long-term users from users who began statins only near the time of PC diagnosis. This may have resulted in misclassification of pre-diagnosis statin exposure, although the direction of bias would likely be towards the null. As such, this may have limited our ability to observe effect modification of the association between saturated fat intake and PC aggressiveness by statin use. These limitations are balanced by several important strengths. All types of dietary fat and cholesterol were adjusted for total fat intake using the residual method, and models were adjusted for energy-adjusted total fat intake and energy intake. This approach separated the effects of each fat type from total fat on PC aggressiveness while controlling for energy intake. In contrast to many studies examining risk of developing PC, PCaP was designed to accurately capture information on PC aggressiveness at diagnosis in an ethnically and geographically diverse population. Furthermore, the use of less aggressive cases as the reference group allowed for the identification of factors associated with aggressive PC at diagnosis rather than risk of developing the disease. Finally, an important strength of this study is the inclusion of both EAs and AAs in similar proportions, in addition to our comprehensive assessment of clinical and demographic characteristics and adjustment for these potential confounders in our analysis.
In summary, we found that both the total amount and the composition of dietary fat impacted PC aggressiveness. Although we observed no statistically significant racial differences in these associations, high total fat intake and a dietary fat composition higher in saturated fat were suggestively more strongly associated with PC aggressiveness in EAs than AAs, and cholesterol was associated with higher PC aggressiveness only in EAs. Established PC risk factors, including older age, AA race and family history of PC, are not modifiable. If confirmed, these findings may be relevant for aggressive PC prevention efforts, given that dietary fat content and composition are modifiable risk factors.
Read More: Commentary from the Editor of PCAN
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EH Allott1,2, L Arab3, LJ Su4, L Farnan2, ETH Fontham5, JL Mohler2,6,7, JT Bensen1,2 and SE Steck8
1. Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
3 David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
4 Winthrop P Rockefeller Cancer Institute and College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
5 School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
6 Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA
7 Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA and
8 Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC, USA. Correspondence: Dr EH Allott, Department of Nutrition, CB 7461, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, NC 27599, USA.