Abstract
Although dietary fat has been associated with prostate cancer risk, the association between specific fatty acids and prostate cancer survival remains unclear. Dietary intake of 14 fatty acids was analyzed in a population-based cohort of 525 Swedish men with prostate cancer in Örebro County (1989–1994). Multivariable hazard ratios and 95% confidence intervals for time to prostate cancer death by quartile and per standard deviation increase in intake were estimated by Cox proportional hazards regression. Additional models examined the association by stage at diagnosis (localized: T0-T2/M0; advanced: T0-T4/M1, T3-T4/M0). Among all men, those with the highest omega-3 docosahexaenoic acid and total marine fatty acid intakes were 40% less likely to die from prostate cancer (Ptrend = 0.05 and 0.04, respectively). Among men with localized prostate cancer, hazard ratios of 2.07 (95% confidence interval: 0.93, 4.59; Ptrend = 0.03) for elevated total fat, 2.39 (95% confidence interval: 1.06, 5.38) for saturated myristic acid, and 2.88 (95% confidence interval: 1.24, 6.67) for shorter chain (C4-C10) fatty acid intakes demonstrated increased risk for disease-specific mortality for the highest quartile compared with the lowest quartile. This study suggests that high intake of total fat and certain saturated fatty acids may worsen prostate cancer survival, particularly among men with localized disease. In contrast, high marine omega-3 fatty acid intake may improve disease-specific survival for all men.
Keywords: fatty acids, prostatic neoplasms, survival analysis
The association between dietary fat and prostate cancer incidence has been studied extensively following early ecologic evidence linking per capita fat consumption to prostate cancer mortality (1, 2). The fatty acid composition of the diet has also been investigated in relation to prostate cancer incidence, with reports of a decreased risk of developing prostate cancer with high dietary and blood levels of marine omega-3 (n-3) polyunsaturated fatty acids (3–5) and a positive association between alpha-linolenic acid and advanced (6) and fatal (7, 8) prostate cancer, although the findings are not always convergent (9, 10).
Fewer studies have focused on prostate cancer progression after diagnosis, an important outcome in light of the considerable biologic heterogeneity of the disease. High saturated fat consumption was associated with a 3-fold increased risk of death from prostate cancer in a Canadian population (11). Additionally, fish intake, a source of n-3 fatty acids, has been associated with decreased disease-specific mortality (12); however, there is a need for more evidence linking dietary fat to survival. Furthermore, the role of individual fatty acids and prostate cancer survival has yet to be elucidated. We examined the association between dietary intake of 14 individual fatty acids and overall and prostate cancer-specific survival in a population-based cohort of Swedish men with confirmed prostate cancer completely followed for up to 20 years after diagnosis. We also explored whether these associations differed by disease severity at diagnosis.
MATERIALS AND METHODS
Study population
The study population consisted of 525 men diagnosed with incident prostate cancer and originally recruited for a population-based case-control study in Örebro County, Sweden, during 2 periods: January 1989–September 1991 and May 1992–July 1994 (participation rate, 80.6%) (13–15). Eligible participants were born in Sweden, aged 80 years or less, and living in Örebro County at the time of diagnosis. All cases of prostate cancer were cytologically and/or histologically confirmed by a study pathologist. As regular prostate cancer screening did not occur in this population at the time of study, most cases were diagnosed because of prostate-related symptoms. The current study was approved by the ethics review board of Uppsala University, Sweden (16).
Exposure assessment
Participants completed a self-administered food frequency questionnaire to assess regular diet in the year prior to diagnosis, with the majority of questionnaires completed within 3 months of diagnosis. During the first study period (January 1989–September 1991), nondietary factors were assessed through in-person interviews. Cases recruited during the second study period (May 1992–July 1994) completed mailed questionnaires extended to include questions on nondietary factors; questionnaires were completed by phone when necessary (14). Body mass index was calculated by using clinical measurements. Information on primary treatment for prostate cancer was obtained through medical records reviewed by trained study staff.
The food frequency questionnaire included 68 food items selected to represent the common Swedish diet during the study period. Frequencies of consumption were multiplied by age-specific standard portion sizes based on the 1988 Swedish National Food Administration handbook and by the nutrient composition of foods specific to Sweden to determine daily energy and nutrient intakes (17). A validation study was conducted among 87 control subjects enrolled in the original case-control study who completed four 1-week dietary records, given 4 times over the course of 1 year. Pearson's correlation coefficients between energy-adjusted nutrients assessed from the questionnaires and dietary records ranged between 0.2 and 0.6, with r = 0.5 for energy intake, saturated fat, and polyunsaturated fat and r = 0.4 for total fat; specific fatty acids were not reported (14). Dietary intake of 14 fatty acids was calculated from questionnaire data: saturated lauric (C12:0), myristic (C14:0), palmitic (C16:0), stearic (C18:0), and arachidic (C20:0) acids; monounsaturated palmitoleic (C16:1) and oleic (C18:1) acids; n-3 polyunsaturated alpha-linolenic (C18:3), eicosapentaenoic (EPA; C20:5), docosapentaenoic (DPA; C22:5), and docosahexaenoic (DHA; C22:6) acids; n-6 polyunsaturated linoleic (C18:2) and arachidonic (C20:4) acids; and a composite variable representing shorter chain saturated fatty acids (C4-C10).
Outcome ascertainment
Tumors were graded by board-certified pathologists according to the 1980 World Health Organization criteria and staged by using the 1978 TNM classification system. We defined localized tumors as those confined to the prostate at diagnosis (stage T0-T2/M0). Tumors that had progressed through the capsule or metastasized at diagnosis were defined as advanced stage (T3-T4/M0, T0-T4/M1). The study population was routinely screened for skeletal metastases (14).
The men have been followed prospectively for mortality and cause of death through linkage to the Swedish Cause of Death Registry. In Sweden, individuals are linked to national comprehensive health registries through a personal identification number. In this manner, we achieved complete follow-up of our study population. Cause of death was confirmed through medical record review by a committee of study urologists (S. O. A., O. A., Jan-Erik Johansson).
Statistical analysis
Dietary intake of each fatty acid was calculated in grams per day (g/day), and values were log10 transformed to improve normality. We calculated age- and energy-adjusted Spearman's correlation coefficients to investigate the correlation among the 14 fatty acids. Fatty acid intake was adjusted for non-alcohol energy intake by the residual method (18) and categorized into quartiles. We also examined the association between individual fatty acid intake and prostate cancer-specific mortality, modeling a 1-standard deviation increment in fatty acid intake continuously.
Cox proportional hazards models were constructed to estimate hazard ratios and 95% confidence intervals, with the lowest quartile of intake for each fatty acid as the referent. Cox models were also utilized to estimate the hazard ratio per standard deviation increment of each individual fatty acid. Follow-up time was calculated from date of cancer diagnosis to death from prostate cancer or death from other causes, or it was censored at the end of follow-up (March 1, 2011).
Our primary analysis focused on time to death from prostate cancer associated with dietary intake of each individual fatty acid, as well as total fat intake. Subsequent analyses grouped fatty acids according to saturation level (saturated, monounsaturated, n-3 polyunsaturated, n-6 polyunsaturated). To assess potential competing risks, we examined time to death from other causes and all-cause mortality. Multivariable models were adjusted for age at diagnosis (<65, 65–69, 70–74, ≥75 years), body mass index (weight (kg)/height (m)2), smoking status (never, former, current), family history of prostate cancer (father or brother), calendar year of diagnosis (1989–1991, 1992–1994), and alcohol intake (nondrinker, <55 g/week, ≥55 g/week). Four men missing data on body mass index were assigned the mean value (25.9 kg/m2). We found no evidence of confounding by treatment, and the variable was not retained in final models. Although we have information on tumor cell differentiation (World Health Organization categories: well, moderate, poor), this may be an intermediate on the causal pathway if an association exists and, thus, was not included in final models.
We examined the ratio of n-3 to n-6 polyunsaturated fatty acids, following experimental evidence suggesting opposing effects on tumor growth, and the balance between the 2 groups may affect prostate cancer risk and tumor characteristics (19, 20). We compared quartiles of total n-3 with total n-6 fatty acid intake and also compared intake of the most common n-3 fatty acid, alpha-linolenic acid, with the most common n-6 fatty acid, linoleic acid.
We tested for linear trend across categorical models by modeling the median of each fatty acid quartile as a semicontinuous variable and including this variable in a multivariable model. All models were additionally stratified by stage at diagnosis (localized or advanced) to assess whether associations with survival varied by clinical stage. We conducted a sensitivity analysis excluding all deaths occurring within the first 2 years of follow-up to minimize the possibility that men with the most severe disease recalled fat intake differently from other men. All tests were 2 sided, and P < 0.05 was considered statistically significant. Analyses were conducted by using SAS, version 9.1, software (SAS Institute, Inc., Cary, North Carolina).
The proportional hazards assumption was tested by adding an interaction term between the median value for each fatty acid quartile and follow-up time (continuous) to the multivariable model of the fatty acid main effect (quartiles). The proportional hazards assumption was satisfied for 12 fatty acids; however, significant interaction terms in the models of palmitoleic and stearic acids suggest that the association between those fatty acids and survival may vary with time. This discrepancy should be noted when interpreting models of the 2 acids.
We explored an interaction between stage at diagnosis and total fat intake with multivariable Cox models that included an indicator variable for advanced stage and the product term of stage with fat as a continuous variable. A likelihood ratio test with 1 df assessed statistical significance, comparing the above model with one without the product term.
We further adjusted models of marine-derived fatty acids (EPA, DPA, DHA) for energy-adjusted vitamin D intake (continuous) because fish is a source of vitamin D, and vitamin D may be associated with improved prostate cancer survival (21). We also constructed a summary variable combining dietary EPA, DPA, and DHA. The new variable was assessed per standard deviation increment and per energy-adjusted quartiles to explore associations with prostate cancer-specific mortality overall and by stage at diagnosis.
Because patterns of fatty acid intake rather than specific fatty acids may be important predictors of prostate cancer outcome, we conducted a principal components analysis to identify a smaller set of variables that explained the majority of the total variance of the 14 original fatty acids. Principal components, or eigenvectors, were retained until 90% of the total variance could be explained, following the percentage of variance criterion (22). Three eigenvectors were included in a multivariable model to explore an association with prostate cancer-specific survival, overall and stratified by stage at diagnosis.
RESULTS
In the study population, 230 (44%) men were diagnosed with localized disease, and 11% had poorly differentiated tumors, with a mean age at diagnosis of 70.7 years. Men with low total fat intake were diagnosed at younger ages, on average, than men with the highest total fat intake (chi-squared P = 0.03), were less likely to smoke (P = 0.01), but had similar distributions of tumor differentiation (P = 0.84) and alcohol intake (P = 0.14) (Table 1). The mean intake of each fatty acid did not vary by stage or level of differentiation at diagnosis (data not shown). The mean body mass index (25.9 kg/m2) was representative of Swedish men during the study period (23). Distribution of crude fatty acid intake is detailed in Appendix Table 1. By March 2011, 222 men had died from prostate cancer, and 268 had died from other causes after up to 20 years of follow-up. The mean total fat consumption was 84 g/day in the study population. Spearman's correlation coefficients revealed strong correlations between most saturated fatty acids and among marine n-3 fatty acids, although they weakened after adjustment for total energy intake (Table 2).
Table 1.
Selected Characteristics of the Study Population Consisting of 525 Men With Prostate Cancer From Örebro, Sweden (1989–1994), Comparing the Highest and Lowest Quartiles of Fat Intake
| Total Fat Intake, g/day |
Saturated Fat Intake, g/day |
Marine Fatty Acida Intake, g/day |
||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Quartile 1 |
Quartile 4 |
Quartile 1 |
Quartile 4 |
Quartile 1 |
Quartile 4 |
|||||||||||||
| No. | % | Mean (SD) | No. | % | Mean (SD) | No. | % | Mean (SD) | No. | % | Mean (SD) | No. | % | Mean (SD) | No. | % | Mean (SD) | |
| Total deaths | 117 | 124 | 119 | 125 | 125 | 122 | ||||||||||||
| Prostate cancer deaths | 61 | 56 | 59 | 52 | 66 | 50 | ||||||||||||
| Person-years of follow-up | 9.5 (6) | 6.8 (6) | 8.8 (6) | 7.2 (6) | 6.7 (5) | 8.1 (6) | ||||||||||||
| Mean total fat intake, g/day | 65.5 (19) | 102.7 (38) | 65.5 (19) | 101.4 (37) | 84.2 (28) | 83.1 (35) | ||||||||||||
| Body mass indexb | 5.4 (3) | 25.8 (3) | 25.7 (3) | 26.0 (3) | 25.9 (3) | 25.8 (3) | ||||||||||||
| Mean daily intake | ||||||||||||||||||
| Nonalcohol energy, kcal | 2,069 (487) | 2,117 (660) | 2,052 (485) | 2,120 (638) | 2,175 (569) | 1,983 (599) | ||||||||||||
| Saturated fatty acids, g | 28.0 (9) | 47.2 (18) | 27.1 (8) | 48.4 (17) | 39.5 (14.4) | 35.5 (15) | ||||||||||||
| Marine fatty acids, ga | 0.4 (0.3) | 0.5 (0.3) | 0.4 (0.3) | 0.5 (0.3) | 0.2 (0.1) | 0.8 (0.4) | ||||||||||||
| Age at diagnosis | ||||||||||||||||||
| <65 | 27 | 20.6 | 18 | 13.7 | 28 | 21.4 | 17 | 13.0 | 14 | 10.7 | 28 | 21.4 | ||||||
| 65–69 | 36 | 27.5 | 22 | 16.8 | 32 | 24.4 | 20 | 15.3 | 23 | 17.6 | 35 | 26.7 | ||||||
| 70–74 | 41 | 31.3 | 50 | 38.2 | 41 | 31.3 | 49 | 37.4 | 43 | 32.8 | 32 | 24.4 | ||||||
| ≥75 | 27 | 20.6 | 41 | 31.3 | 30 | 22.9 | 45 | 34.4 | 51 | 38.9 | 36 | 27.5 | ||||||
| Year of diagnosis | ||||||||||||||||||
| 1989–1991 | 57 | 43.5 | 65 | 49.6 | 59 | 45.0 | 65 | 49.6 | 53 | 40.5 | 70 | 53.4 | ||||||
| 1992–1994 | 74 | 56.5 | 66 | 50.4 | 72 | 55.0 | 66 | 50.4 | 78 | 59.5 | 61 | 46.6 | ||||||
| Tumor differentiation (WHO classification) | ||||||||||||||||||
| Well | 74 | 56.4 | 65 | 49.6 | 75 | 57.3 | 66 | 50.4 | 72 | 55.0 | 64 | 48.9 | ||||||
| Moderate | 43 | 32.8 | 49 | 37.4 | 40 | 30.5 | 48 | 36.6 | 44 | 33.6 | 50 | 38.2 | ||||||
| Poor | 14 | 10.7 | 17 | 13.0 | 16 | 12.2 | 17 | 13.0 | 15 | 11.5 | 17 | 13.0 | ||||||
| Tumor stage | ||||||||||||||||||
| T0/T1 | 29 | 22.1 | 32 | 24.4 | 34 | 26.0 | 36 | 27.5 | 28 | 21.4 | 30 | 22.9 | ||||||
| T2 | 37 | 28.2 | 22 | 16.8 | 28 | 21.4 | 16 | 12.2 | 23 | 17.6 | 31 | 23.7 | ||||||
| T3 | 42 | 32.1 | 44 | 33.6 | 43 | 32.8 | 45 | 34.4 | 41 | 31.3 | 48 | 36.6 | ||||||
| T4/M1 | 23 | 17.6 | 33 | 25.2 | 26 | 19.9 | 34 | 26.0 | 39 | 29.8 | 22 | 16.8 | ||||||
| Treatment | ||||||||||||||||||
| Watchful waiting | 88 | 67.2 | 91 | 69.5 | 82 | 62.6 | 91 | 69.5 | 96 | 73.3 | 85 | 64.9 | ||||||
| Hormone therapy | 31 | 23.7 | 30 | 22.9 | 37 | 28.2 | 32 | 24.4 | 27 | 20.6 | 31 | 23.7 | ||||||
| Prostatectomy | 8 | 6.1 | 3 | 2.3 | 7 | 5.3 | 2 | 1.5 | 3 | 2.3 | 7 | 5.3 | ||||||
| Other treatment | 4 | 3.1 | 7 | 5.3 | 5 | 3.8 | 6 | 4.6 | 5 | 3.8 | 8 | 6.1 | ||||||
| Family history (father or brother) | ||||||||||||||||||
| Yes | 17 | 13.0 | 16 | 12.2 | 12 | 9.2 | 16 | 12.2 | 18 | 13.7 | 11 | 8.4 | ||||||
| No | 114 | 87.0 | 115 | 87.8 | 119 | 90.8 | 115 | 87.8 | 113 | 86.3 | 120 | 91.6 | ||||||
| Smoking status | ||||||||||||||||||
| Never smoker | 51 | 38.9 | 28 | 21.4 | 57 | 43.5 | 31 | 23.7 | 49 | 37.4 | 21 | 16.0 | ||||||
| Former smoker | 52 | 39.7 | 43 | 32.8 | 50 | 38.2 | 49 | 37.4 | 53 | 40.5 | 57 | 43.5 | ||||||
| Current smoker | 23 | 17.6 | 40 | 30.5 | 19 | 14.5 | 33 | 25.2 | 19 | 14.5 | 36 | 27.5 | ||||||
| Missing | 5 | 3.8 | 20 | 15.3 | 5 | 3.8 | 18 | 13.7 | 10 | 7.6 | 17 | 13.0 | ||||||
| Alcohol intake, g/week | ||||||||||||||||||
| Nondrinker | 56 | 42.8 | 55 | 42.0 | 55 | 42.0 | 60 | 45.8 | 75 | 57.3 | 51 | 38.9 | ||||||
| <55 | 41 | 31.3 | 34 | 26.0 | 40 | 30.5 | 32 | 24.4 | 35 | 26.7 | 32 | 24.4 | ||||||
| ≥55 | 34 | 26.0 | 42 | 32.1 | 36 | 27.5 | 39 | 29.8 | 21 | 16.0 | 48 | 36.6 | ||||||
Abbreviations: SD, standard deviation; WHO, World Health Organization.
a Sum of docosahexaenoic acid, docosapentaenoic acid, and eicosapentaenoic acid.
b Body mass index: weight (kg)/height (m)2.
Appendix Table 1.
Distribution of Crude Intake of 14 Fatty Acids (Grams per Day) by Survival Status of 525 Men Diagnosed With Prostate Cancer in Örebro County, Sweden (1989–1994)
| Fatty Acid | All Cases (n = 525) |
Prostate Cancer-specific Mortality (n = 222) |
Other Cause Mortality (n = 268) |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean | Median | Range | Mean % of Total Fat, %a | Mean | Median | Range | Mean % of Total Fat, % | Mean | Median | Range | Mean % of Total Fat, % | |
| Saturated fatty acids | ||||||||||||
| Lauric acid | 1.8 | 1.6 | 0.2–7.0 | 2.2 | 1.8 | 1.6 | 0.2–7.0 | 2.2 | 1.9 | 1.7 | 0.4–7.0 | 2.2 |
| Myristic acid | 4.2 | 3.8 | 0.5–12.4 | 4.9 | 4.1 | 3.7 | 0.5–11.8 | 4.9 | 4.3 | 3.9 | 1.2–12.4 | 4.9 |
| Palmitic acid | 19.5 | 18.4 | 3.0–57.3 | 23.0 | 19.1 | 18.2 | 3.0–46.0 | 22.9 | 20.0 | 18.9 | 7.2–57.3 | 23.0 |
| Stearic acid | 8.1 | 7.5 | 1.2–27.0 | 9.4 | 7.9 | 7.4 | 1.2–21.3 | 9.4 | 8.3 | 7.7 | 2.6–27.0 | 9.5 |
| Arachidic acid | 0.3 | 0.2 | 0.04–0.7 | 0.3 | 0.3 | 0.2 | 0.04–0.7 | 0.3 | 0.3 | 0.3 | 0.1–0.7 | 0.3 |
| Shorter chain fatty acidsb | 2.9 | 2.6 | 0.3–9.3 | 3.4 | 2.9 | 2.6 | 0.4–9.3 | 3.5 | 3.0 | 2.7 | 0.7–9.1 | 3.5 |
| Monounsaturated fatty acids | ||||||||||||
| Palmitoleic acid | 1.6 | 1.5 | 0.1–6.4 | 1.9 | 1.6 | 1.4 | 0.1–4.6 | 1.9 | 1.7 | 1.5 | 0.4–6.4 | 1.9 |
| Oleic acid | 27.2 | 25.4 | 4.4–88.9 | 32.1 | 26.6 | 25.1 | 4.4–68.1 | 32.0 | 28.0 | 25.8 | 9.5–88.9 | 32.2 |
| Omega-3 polyunsaturated fatty acids | ||||||||||||
| Alpha-linolenic acid | 1.5 | 1.4 | 0.3–3.8 | 1.8 | 1.5 | 1.4 | 0.3–3.8 | 1.8 | 1.5 | 1.4 | 0.4–3.8 | 1.8 |
| Eicosapentaenoic acid | 0.1 | 0.1 | 0–0.8 | 0.1 | 0.1 | 0.1 | 0–0.8 | 0.1 | 0.1 | 0.1 | 0–0.8 | 0.1 |
| Docosapentaenoic acid | 0.1 | 0.1 | 0–0.3 | 0.1 | 0.1 | 0.1 | 0–0.3 | 0.1 | 0.1 | 0.1 | 0–0.3 | 0.1 |
| Docosahexaenoic acid | 0.3 | 0.2 | 0–1.7 | 0.3 | 0.3 | 0.2 | 0.02–1.7 | 0.3 | 0.3 | 0.3 | 0–1.6 | 0.3 |
| Omega-6 polyunsaturated fatty acids | ||||||||||||
| Linoleic acid | 7.9 | 7.5 | 2.0–21.0 | 9.6 | 7.8 | 7.2 | 2.1–21.0 | 9.7 | 8.1 | 7.6 | 2.0–20.1 | 9.5 |
| Arachidonic acid | 0.2 | 1.4 | 0.01–0.8 | 0.2 | 0.2 | 0.1 | 0.01–0.6 | 0.2 | 0.2 | 0.2 | 0.02–0.8 | 0.2 |
a Values do not sum to 100% as we utilize data on 14 fatty acids, which make up approximately 90% of total fat intake.
b Shorter chain fatty acids may include butyric (C4), valeric (C5), caproic (C6), enanthic (C7), caprylic (C8), pelargonic (C9), and capric (C10) acids.
Table 2.
Spearman's Correlation Coefficients Between Total Fat and Dietary Fatty Acids, Adjusted for Age at Diagnosis and Total Energy Intake, Örebro, Sweden (1989–1994)
| Total Fat | C4-10 | C12:0 | C14:0 | C16:0 | C16:1 | C18:0 | C18:1 | C18:2 | C18:3 | C20:0 | C20:4 | C20:5 | C22:5 | C22:6 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total fat | 1.0 | 0.54 | 0.38 | 0.66 | 0.97 | 0.86 | 0.89 | 0.92 | 0.32 | 0.25 | 0.69 | 0.52 | 0.03 | 0.41 | 0.25 |
| C4-10 | 1.0 | 0.49 | 0.98 | 0.66 | 0.19 | 0.51 | 0.24 | −0.36 | −0.002 | 0.10 | −0.13 | −0.19 | −0.28 | −0.25 | |
| C12:0 | 1.0 | 0.51 | 0.40 | 0.14 | 0.11 | 0.25 | 0.03 | 0.37 | 0.46 | −0.25 | −0.15 | −0.32 | −0.26 | ||
| C14:0 | 1.0 | 0.76 | 0.33 | 0.62 | 0.37 | −0.29 | 0.01 | 0.21 | −0.02 | −0.15 | −0.17 | −0.16 | |||
| C16:0 | 1.0 | 0.80 | 0.91 | 0.83 | 0.14 | 0.11 | 0.58 | 0.46 | −0.03 | 0.32 | 0.17 | ||||
| C16:1 | 1.0 | 0.80 | 0.90 | 0.43 | 0.13 | 0.67 | 0.76 | 0.22 | 0.70 | 0.50 | |||||
| C18:0 | 1.0 | 0.80 | 0.10 | −0.10 | 0.53 | 0.60 | −0.004 | 0.47 | 0.25 | ||||||
| C18:1 | 1.0 | 0.53 | 0.35 | 0.81 | 0.63 | 0.08 | 0.57 | 0.35 | |||||||
| C18:2 | 1.0 | 0.69 | 0.56 | 0.35 | 0.13 | 0.44 | 0.30 | ||||||||
| C18:3 | 1.0 | 0.39 | −0.07 | 0.05 | 0.02 | 0.04 | |||||||||
| C20:0 | 1.0 | 0.36 | −0.04 | 0.33 | 0.15 | ||||||||||
| C20:4 | 1.0 | 0.40 | 0.89 | 0.70 | |||||||||||
| C20:5 | 1.0 | 0.58 | 0.87 | ||||||||||||
| C22:5 | 1.0 | 0.83 | |||||||||||||
| C22:6 | 1.0 |
Notations and abbreviations: C4-10, shorter chain fatty acids; C12:0, lauric acid; C14:0, myristic acid; C16:0, palmitic acid; C16:1, palmitoleic acid; C18:0, stearic acid; C18:1, oleic acid; C18:2, linoleic acid; C18:3; alpha-linolenic acid; C20:0, arachidic acid; C20:4, arachidonic acid; C20:5, eicosapentaenoic acid (EPA); C22:5, docosapentaenoic acid (DPA); C22:6, docosahexaenoic acid (DHA).
Overall, the top quartile of total fat intake (Table 3) was associated with a nonsignificant increase in disease-specific mortality (hazard ratioquartile 4 vs. quartile 1 (HRQ4 vs. Q1) = 1.29, 95% confidence interval (CI): 0.89, 1.87) when compared with the lowest quartile; the continuous model did not show a significant increase. Among men diagnosed with localized prostate cancer, those in the top quartile of total fat intake had a 2-fold increase in disease-specific mortality (HRQ4 vs. Q1 = 2.07, 95% CI: 0.93, 4.59; Ptrend = 0.03); no association was observed among men diagnosed at an advanced stage, and the interaction was not statistically significant (P = 0.35). However, among all participants, the top 3 quartiles of total fat consumption were significantly associated with an approximate 1.5-fold increased risk of death from other (non-prostate cancer) causes when compared with the lowest quartile (Ptrend = 0.02). This association appeared stronger among men with advanced stage disease, with a 3-fold increased risk of death from other causes for men in the top 3 quartiles of total fat intake, compared with the lowest quartile (Ptrend = 0.003); there was no significant association among men diagnosed at a localized stage. Analysis grouping fatty acids by level of saturation (Table 4) found no significant associations with survival, including total saturated fatty acids by quartile (HRQ4 vs. Q1 = 1.15, 95% CI: 0.78, 1.68) or per standard deviation increment (hazard ratio = 1.08, 95% CI: 0.94, 1.23); results stratified by stage were not significant.
Table 3.
Total Dietary Fat Intake (Grams per Day) and Prostate Cancer-specific Survival Among 525 Men With Prostate Cancer by Stage at Diagnosis, Örebro, Sweden (1989–1994)
| All Cases (n = 222) |
Localized Stage (n = 46)a |
Advanced Stage (n = 176)b |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Median, g/day | No. of Events | Hazard Ratioc | 95% CI | Median, g/day | No. of Events | Hazard Ratio | 95% CI | Median, g/day | No. of Events | Hazard Ratio | 95% CI | |
| Per 1-SD increased | 1.05 | 0.91, 1.20 | 1.11 | 0.82, 1.52 | 1.05 | 0.88, 1.24 | ||||||
| Total fat quartile | ||||||||||||
| Quartile 1 | 67.6 | 61 | 1.00 | Referent | 68.3 | 12 | 1.00 | Referent | 67.3 | 49 | 1.00 | Referent |
| Quartile 2 | 78.7 | 50 | 1.03 | 0.70, 1.50 | 79.3 | 8 | 0.85 | 0.34, 2.13 | 78.2 | 42 | 0.98 | 0.64, 1.50 |
| Quartile 3 | 88.4 | 55 | 1.21 | 0.83, 1.75 | 88.4 | 12 | 1.84 | 0.81, 4.20 | 88.4 | 43 | 0.97 | 0.64, 1.49 |
| Quartile 4 | 99 | 56 | 1.29 | 0.89, 1.87 | 100.4 | 14 | 2.07 | 0.93, 4.59 | 98.6 | 42 | 1.09 | 0.71, 1.69 |
| Ptrende | 0.13 | 0.03 | 0.74 | |||||||||
| Pinteractionf | 0.35 | |||||||||||
Abbreviations: CI, confidence interval; SD, standard deviation.
a Defined as stage T0-T2/M0 at diagnosis.
b Defined as stage T3-T4/M0 or T0-T4/M1 at diagnosis.
c Cox proportional hazards models adjusted for age at diagnosis (<65, 65–69, 70–74, ≥75 years), family history of prostate cancer (yes/no), smoking status (never, former, current), calendar year of treatment (1989–1991, 1992–1994), alcohol intake (nondrinker, <55 g/week, ≥55 g/week), and body mass index (kg/m2).
d Modeling the hazard ratio for a 1-standard deviation increase in total fat intake as a continuous variable; models were adjusted for the covariates listed above.
e Test for trend across quartiles; all tests were 2 sided.
f P value from likelihood ratio test for an interaction between fat (continuous) by stage at diagnosis, 1 df.
Table 4.
Association Between Prostate Cancer-specific Survival and Intake of 14 Fatty Acids (Grams per Day, Overall and Stratified by Stage at Diagnosis), Örebro, Sweden (1989–1994)
| Common Name | Notation | Continuousa | 95% CI | Hazard Ratios and 95% Confidence Intervals Per Quartile of Intakeb |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Quartile 1 |
Quartile 2 |
Quartile 3 |
Quartile 4 |
Ptrendc | ||||||||
| Hazard Ratio | 95% CI | Hazard Ratio | 95% CI | Hazard Ratio | 95% CI | Hazard Ratio | 95% CI | |||||
| Saturated fatty acids | ||||||||||||
| Total saturated fatty acids | ||||||||||||
| All cases | 1.08 | 0.94, 1.23 | 1.00 | Referent | 1.15 | 0.80, 1.67 | 1.18 | 0.80, 1.74 | 1.15 | 0.78, 1.68 | 0.47 | |
| Localizedd | 1.15 | 0.86, 1.55 | 1.00 | Referent | 1.04 | 0.42, 2.53 | 1.88 | 0.80, 4.40 | 1.87 | 0.79, 4.40 | 0.07 | |
| Advancede | 1.09 | 0.92, 1.28 | 1.00 | Referent | 1.12 | 0.74, 1.70 | 1.08 | 0.70, 1.68 | 0.95 | 0.61, 1.49 | 0.82 | |
| Lauric acid | C12:0 | |||||||||||
| All cases | 1.06 | 0.92, 1.22 | 1.00 | Referent | 1.10 | 0.75, 1.60 | 1.02 | 0.70, 1.49 | 1.25 | 0.86, 1.83 | 0.27 | |
| Localized | 1.24 | 0.95, 2.63 | 1.00 | Referent | 0.56 | 0.21, 1.47 | 0.93 | 0.41, 2.08 | 1.66 | 0.78, 3.55 | 0.07 | |
| Advanced | 0.98 | 0.82, 1.17 | 1.00 | Referent | 1.15 | 0.75, 1.75 | 1.05 | 0.67, 1.64 | 1.08 | 0.69, 1.71 | 0.89 | |
| Myristic acid | C14:0 | |||||||||||
| All cases | 1.12 | 0.97, 1.28 | 1.00 | Referent | 0.93 | 0.64, 1.35 | 0.97 | 0.66, 1.42 | 1.27 | 0.88, 1.83 | 0.15 | |
| Localized | 1.24 | 0.92, 1.65 | 1.00 | Referent | 1.28 | 0.55, 3.00 | 0.91 | 0.35, 2.34 | 2.39 | 1.06, 5.38 | 0.04 | |
| Advanced | 1.12 | 0.95, 1.32 | 1.00 | Referent | 0.83 | 0.54, 1.30 | 1.01 | 0.65, 1.57 | 1.06 | 0.68, 1.66 | 0.52 | |
| Palmitic acid | C16:0 | |||||||||||
| All cases | 1.06 | 0.93, 1.21 | 1.00 | Referent | 1.01 | 0.69, 1.46 | 1.28 | 0.88, 1.86 | 1.13 | 0.77, 1.65 | 0.30 | |
| Localized | 1.10 | 0.81, 1.48 | 1.00 | Referent | 0.96 | 0.39, 2.36 | 2.27 | 0.99, 5.20 | 1.73 | 0.72, 4.15 | 0.06 | |
| Advanced | 1.07 | 0.91, 1.26 | 1.00 | Referent | 0.97 | 0.64, 1.48 | 1.09 | 0.70, 1.68 | 0.97 | 0.62, 1.52 | 0.95 | |
| Stearic acid | C18:0 | |||||||||||
| All cases | 1.02 | 0.90, 1.17 | 1.00 | Referent | 1.10 | 0.76, 1.59 | 1.23 | 0.84, 1.80 | 1.13 | 0.77, 1.66 | 0.43 | |
| Localized | 1.01 | 0.75, 1.35 | 1.00 | Referent | 1.62 | 0.69, 3.78 | 2.12 | 0.91, 4.93 | 1.36 | 0.54, 3.44 | 0.35 | |
| Advanced | 1.06 | 0.90, 1.24 | 1.00 | Referent | 0.91 | 0.60, 1.38 | 1.04 | 0.66, 1.63 | 1.07 | 0.69, 1.65 | 0.65 | |
| Arachidic acid | C20:0 | |||||||||||
| All cases | 1.00 | 0.88, 1.15 | 1.00 | Referent | 0.83 | 0.58, 1.21 | 1.07 | 0.75, 1.53 | 0.83 | 0.56, 1.22 | 0.53 | |
| Localized | 1.15 | 0.87, 1.52 | 1.00 | Referent | 1.09 | 0.43, 2.74 | 2.29 | 0.99, 5.31 | 1.52 | 0.62, 3.73 | 0.24 | |
| Advanced | 0.95 | 0.80, 1.11 | 1.00 | Referent | 0.81 | 0.54, 1.23 | 0.89 | 0.59, 1.34 | 0.72 | 0.46, 1.12 | 0.20 | |
| Shorter chainf | C4-C10 | |||||||||||
| All cases | 1.13 | 0.98, 1.29 | 1.00 | Referent | 1.05 | 0.72, 1.54 | 1.09 | 0.74, 1.60 | 1.33 | 0.91, 1.93 | 0.12 | |
| Localized | 1.24 | 0.98, 1.29 | 1.00 | Referent | 1.95 | 0.80, 4.75 | 1.30 | 0.51, 3.32 | 2.88 | 1.24, 6.67 | 0.03 | |
| Advanced | 1.12 | 0.95, 1.33 | 1.00 | Referent | 0.75 | 0.48, 1.17 | 1.03 | 0.67, 1.60 | 1.08 | 0.69, 1.70 | 0.32 | |
| Monounsaturated fatty acids | ||||||||||||
| Total monounsaturated fatty acids | ||||||||||||
| All cases | 1.01 | 0.87, 1.17 | 1.00 | Referent | 1.11 | 0.77, 1.61 | 1.12 | 0.77, 1.64 | 1.17 | 0.80, 1.71 | 0.44 | |
| Localized | 1.05 | 0.77, 1.45 | 1.00 | Referent | 1.20 | 0.50, 2.90 | 1.57 | 0.66, 3.71 | 2.03 | 0.87, 4.76 | 0.08 | |
| Advanced | 1.01 | 0.85, 1.21 | 1.00 | Referent | 1.19 | 0.79, 1.80 | 1.07 | 0.70, 1.65 | 1.09 | 0.69, 1.70 | 0.78 | |
| Palmitoleic acid | C16:1 | |||||||||||
| All cases | 1.00 | 0.88, 1.14 | 1.00 | Referent | 0.98 | 0.67, 1.43 | 1.04 | 0.71, 1.51 | 1.07 | 0.73, 1.57 | 0.66 | |
| Localized | 1.01 | 0.75, 1.37 | 1.00 | Referent | 0.46 | 0.16, 1.34 | 1.26 | 0.59, 2.69 | 1.15 | 0.50, 2.64 | 0.37 | |
| Advanced | 1.01 | 0.87, 1.18 | 1.00 | Referent | 0.94 | 0.61, 1.44 | 1.00 | 0.64, 1.56 | 1.05 | 0.68, 1.63 | 0.75 | |
| Oleic acid | C18:1 | |||||||||||
| All cases | 1.01 | 0.89, 1.15 | 1.00 | Referent | 1.12 | 0.77, 1.62 | 1.05 | 0.72, 1.53 | 1.21 | 0.83, 1.76 | 0.37 | |
| Localized | 1.04 | 0.79, 1.38 | 1.00 | Referent | 1.38 | 0.58, 3.27 | 1.30 | 0.54, 3.12 | 2.11 | 0.90, 4.94 | 0.09 | |
| Advanced | 1.01 | 0.86, 1.18 | 1.00 | Referent | 1.13 | 0.74, 1.71 | 1.02 | 0.66, 1.56 | 1.11 | 0.71, 1.73 | 0.71 | |
| Omega-3 polyunsaturated fatty acids | ||||||||||||
| Total n-3 polyunsaturated fatty acids | ||||||||||||
| All cases | 0.98 | 0.86, 1.13 | 1.00 | Referent | 0.92 | 0.64, 1.33 | 0.80 | 0.54, 1.17 | 0.97 | 0.66, 1.41 | 0.81 | |
| Localized | 1.17 | 0.89, 1.55 | 1.00 | Referent | 0.74 | 0.30, 1.80 | 0.74 | 0.31, 1.76 | 1.34 | 0.61, 2.95 | 0.38 | |
| Advanced | 0.94 | 0.80, 1.11 | 1.00 | Referent | 0.88 | 0.58, 1.35 | 0.79 | 0.51, 1.23 | 0.82 | 0.52, 1.30 | 0.40 | |
| Alpha-linolenic acid | C18:3 | |||||||||||
| All cases | 1.00 | 0.88, 1.15 | 1.00 | Referent | 1.18 | 0.82, 1.69 | 0.83 | 0.56, 1.23 | 1.16 | 0.79, 1.69 | 0.77 | |
| Localized | 1.14 | 0.83, 1.55 | 1.00 | Referent | 1.28 | 0.56, 2.92 | 0.86 | 0.34, 2.16 | 1.67 | 0.71, 3.94 | 0.34 | |
| Advanced | 0.94 | 0.80, 1.11 | 1.00 | Referent | 1.16 | 0.76, 1.77 | 0.79 | 0.51, 1.24 | 1.00 | 0.64, 1.57 | 0.68 | |
| Eicosapentaenoic acid | C20:5 | |||||||||||
| All cases | 0.97 | 0.84, 1.12 | 1.00 | Referent | 0.72 | 0.49, 1.05 | 0.69 | 0.47, 1.01 | 0.66 | 0.45, 0.98 | 0.07 | |
| Localized | 1.11 | 0.89, 1.39 | 1.00 | Referent | 0.40 | 0.16, 1.03 | 0.99 | 0.45, 2.16 | 0.73 | 0.32, 1.67 | 0.95 | |
| Advanced | 0.97 | 0.81, 1.16 | 1.00 | Referent | 0.73 | 0.46, 1.14 | 0.53 | 0.34, 0.85 | 0.70 | 0.44, 1.11 | 0.11 | |
| Docosapentaenoic acid | C22:5 | |||||||||||
| All cases | 0.93 | 0.81, 1.08 | 1.00 | Referent | 0.86 | 0.59, 1.25 | 0.79 | 0.54, 1.16 | 0.83 | 0.56, 1.22 | 0.38 | |
| Localized | 0.99 | 0.74, 1.33 | 1.00 | Referent | 1.24 | 0.55, 2.76 | 0.37 | 0.13, 1.11 | 1.19 | 0.53, 2.68 | 0.75 | |
| Advanced | 0.94 | 0.80, 1.12 | 1.00 | Referent | 0.68 | 0.44, 1.06 | 0.85 | 0.56, 1.29 | 0.68 | 0.43, 1.07 | 0.18 | |
| Docosahexaenoic acid | C22:6 | |||||||||||
| All cases | 0.97 | 0.84, 1.12 | 1.00 | Referent | 0.61 | 0.42, 0.88 | 0.76 | 0.53, 1.10 | 0.60 | 0.41, 0.88 | 0.05 | |
| Localized | 1.10 | 0.87, 1.40 | 1.00 | Referent | 0.31 | 0.12, 0.79 | 0.85 | 0.39, 1.86 | 0.55 | 0.25, 1.24 | 0.65 | |
| Advanced | 0.99 | 0.83, 1.18 | 1.00 | Referent | 0.70 | 0.46, 1.08 | 0.67 | 0.44, 1.01 | 0.74 | 0.48, 1.15 | 0.19 | |
| Combined marine fatty acidsg | ||||||||||||
| All cases | 0.97 | 0.84, 1.12 | 1.00 | Referent | 0.57 | 0.39, 0.83 | 0.70 | 0.48, 1.00 | 0.59 | 0.40, 0.87 | 0.04 | |
| Localized | 1.10 | 0.86, 1.40 | 1.00 | Referent | 0.43 | 0.18, 1.02 | 0.73 | 0.32, 1.64 | 0.61 | 0.27, 1.40 | 0.57 | |
| Advanced | 0.98 | 0.82, 1.16 | 1.00 | Referent | 0.58 | 0.37, 0.90 | 0.62 | 0.41, 0.94 | 0.69 | 0.44, 1.07 | 0.18 | |
| Omega-6 polyunsaturated fatty acids | ||||||||||||
| Total n-6 polyunsaturated fatty acids | ||||||||||||
| All cases | 0.95 | 0.83, 1.09 | 1.00 | Referent | 0.88 | 0.61, 1.28 | 0.76 | 0.52, 1.11 | 0.93 | 0.64, 1.36 | 0.71 | |
| Localized | 0.93 | 0.68, 1.27 | 1.00 | Referent | 0.94 | 0.43, 2.08 | 0.65 | 0.27, 1.60 | 0.87 | 0.39, 1.94 | 0.66 | |
| Advanced | 0.91 | 0.76, 1.08 | 1.00 | Referent | 0.70 | 0.46, 1.08 | 0.55 | 0.35, 0.85 | 0.73 | 0.47, 1.13 | 0.23 | |
| Linoleic acid | C18:2 | |||||||||||
| All cases | 0.95 | 0.83, 1.09 | 1.00 | Referent | 0.90 | 0.62, 1.30 | 0.77 | 0.53, 1.12 | 0.91 | 0.63, 1.33 | 0.71 | |
| Localized | 0.94 | 0.69, 1.28 | 1.00 | Referent | 0.91 | 0.41, 2.01 | 0.69 | 0.29, 1.66 | 0.76 | 0.34, 1.74 | 0.50 | |
| Advanced | 0.91 | 0.76, 1.08 | 1.00 | Referent | 0.79 | 0.51, 1.21 | 0.56 | 0.36, 0.87 | 0.77 | 0.50, 1.19 | 0.38 | |
| Arachidonic acid | C20:4 | |||||||||||
| All cases | 0.95 | 0.82, 1.09 | 1.00 | Referent | 0.98 | 0.68, 1.40 | 0.70 | 0.48, 1.04 | 0.89 | 0.61, 1.30 | 0.43 | |
| Localized | 0.88 | 0.65, 1.18 | 1.00 | Referent | 1.28 | 0.60, 2.71 | 0.35 | 0.12, 1.02 | 0.99 | 0.43, 2.27 | 0.67 | |
| Advanced | 0.99 | 0.84, 1.18 | 1.00 | Referent | 0.95 | 0.62, 1.46 | 0.83 | 0.54, 1.27 | 0.91 | 0.59, 1.41 | 0.64 | |
Abbreviation: CI, confidence interval.
a Hazard ratio per 1-standard deviation increase in fatty acid intake; models were adjusted for the covariates listed below.
b Cox proportional hazards models were adjusted for the age at diagnosis (<65, 65–69, 70–74, ≥75 years), family history of prostate cancer (yes/no), smoking status (never, former, current), calendar year (1989–1991, 1992–1994), alcohol intake (nondrinker, <55 g/week, ≥55 g/week), and body mass index (kg/m2).
c Test for trend across quartiles; all tests are 2 sided.
d Localized stage at diagnosis: T0–T2/M0.
e Advanced stage at diagnosis: T0–T4/M1, T3–T4/M0.
f Shorter chain fatty acids may include saturated butyric (C4), valeric (C5), caproic (C6), enanthic (C7), caprylic (C8), pelargonic (C9), and capric (C10) acids.
g The sum of eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid.
Men in the highest versus lowest quartile of marine n-3 EPA and DHA intakes had an approximate 34%–40% significantly reduced risk of disease-specific mortality. These associations remained unchanged after adjustment for dietary vitamin D intake (data not shown). The top quartile of total marine n-3 fatty acids was also associated with a significantly reduced risk of disease-specific mortality (HRQ4 vs. Q1 = 0.59, 95% CI: 0.40, 0.87; Ptrend = 0.04). However, the ratio of n-3 to n-6 fatty acids was not significantly associated with disease-specific mortality when comparing the ratio of total n-3 to total n-6 fatty acids (HRQ4 vs. Q1 = 1.01, 95% CI: 0.69, 1.48) or alpha-linolenic acid to linoleic acid (HRQ4 vs. Q1 = 1.17, 95% CI: 0.80, 1.71), or when stratified by stage at diagnosis.
Analysis of individual fatty acids suggested that dietary intake of any saturated or monounsaturated fatty acid, n-6 fatty acids, or n-3 alpha-linolenic acid was not significantly associated with prostate cancer-specific mortality among all participants (Table 4). There were no statistically significant associations between individual fatty acids and disease-specific mortality in models examining the association per standard deviation increment in intake overall or stratified by stage at diagnosis.
There were no significant associations between intake of individual fatty acids and prostate cancer-specific mortality among men diagnosed with advanced stage prostate cancer (Table 4). However, among men diagnosed with localized disease, those in the highest versus lowest quartile of saturated myristic acid (hazard ratio = 2.39, 95% CI: 1.06, 5.38; Ptrend = 0.04) and the composite variable of shorter chain saturated fatty acids (C4-C10; hazard ratio = 2.88, 95% CI: 1.24, 6.67; Ptrend = 0.03) had a significantly increased risk of death from prostate cancer. Although other saturated fatty acids also appeared adversely related to prostate cancer-specific mortality, estimates did not achieve statistical significance. When analyses were repeated excluding 85 men who died within 2 years of diagnosis, results did not differ appreciably from those of the full analysis.
We retained 3 eigenvectors in the principal components analysis that together accounted for 91% of the total variance in the original 14 variables. The first eigenvector accounted mainly for fatty acids from animal sources, while the second eigenvector represented marine fatty acids. The third eigenvector accounted for saturated shorter chain and myristic fatty acids almost exclusively. A model containing all 3 principal components revealed no significant associations with overall survival or when stratified by stage.
DISCUSSION
Our survival analysis did not find strong associations between overall saturated, monounsaturated, or polyunsaturated fatty acid intake and disease-specific survival. However, several significant associations appeared limited to men with localized disease, including a more than 2-fold increase in disease-specific mortality for men with high versus low intake of saturated myristic acid and shorter chain fatty acids, both found in dairy and animal products and highly correlated (r = 0.98). We also observed a positive association between total fat intake and disease-specific mortality among men diagnosed with localized disease. The strong association between high total fat intake and death from other causes, particularly among men with advanced stage disease, deserves replication. Additionally, future research could investigate the distribution of specific causes of death among men with prostate cancer who also have a high fat intake. In the principal components analysis, the pattern of fatty acid intake did not appear to be associated with prostate cancer survival.
Although dietary EPA and DHA have been associated with a protective effect on prostate cancer (3, 8), including in our analysis, the evidence remains inconclusive (24–26). High blood levels of EPA and DHA appeared to lower prostate cancer risk in several (4, 5, 27), but not all (28–30), studies. Positive associations were reported between serum EPA and DHA and prostate cancer risk (31), as well as between DHA and high grade disease (10), in 2 large studies. An inverse association between marine fatty acids and prostate cancer mortality has been observed in prospective studies (32, 33), while fish consumption may have a modest protective effect on prostate cancer risk and progression (3, 34, 35), as well as disease-specific mortality (12).
Dietary saturated fat has been adversely associated with prostate cancer in studies across different populations (6, 11, 36–38), although others have not confirmed this association (25, 26, 39). Epidemiologic studies previously reported positive associations between saturated myristic acid and risk of prostate cancer (28, 31), although none explored disease-specific mortality. Our findings of increased prostate cancer-specific mortality for high versus low myristic acid intake among men diagnosed with localized disease agree, in general, with those from other studies of myristic acid and prostate cancer risk (29, 37). Myristic acid makes up approximately 11% of fatty acids found in dairy products (40) and may raise cholesterol levels (41). Consumption of dairy products accounts for a large percentage of saturated fats in the Western diet (41) and has been linked to an increased risk of prostate cancer in several studies (42, 43), including the original case-control study from which our study population is drawn (15). It is possible that myristic acid plays a mechanistic role in this association, although further research is needed to elucidate its contribution to prostate carcinogenesis.
Although some studies observed an increased risk of prostate cancer with high levels of alpha-linolenic acid (6–8, 29, 44), the most common n-3 fatty acid and precursor of long chain n-3 fatty acids, we found no association between alpha-linolenic acid and survival. We also did not detect an association between survival and n-6 linoleic acid, consistent with prior studies of prostate cancer risk (26, 45). We found no association between arachidonic acid, a cyclooxygenase-2 substrate and precursor of proinflammatory eicosanoids, and prostate cancer survival, consistent with most reports (19, 24–26, 28, 29, 31, 44).
There are several plausible biologic mechanisms through which fatty acids could influence prostate carcinogenesis and outcome. In vitro evidence suggests that fat intake may affect levels of hormones and insulin-like growth factor 1 (46). Myristic acid may prime polymorphonuclear leukocytes to release reactive oxygen species (47). At high levels, reactive oxygen species can lead to inflammation, oxidative stress, and DNA damage, which may increase prostate cancer risk (48). In addition, high dietary saturated fat intake was associated with biochemical recurrence (49), defined as an increase in prostate-specific antigen (PSA) levels following prostate cancer treatment, which may increase the risk of prostate cancer death (50). Fatty acid intake may also alter cell membrane function and modulation of metabolic processes (51).
Our observation of an increased risk of prostate cancer-specific mortality with high intake of certain saturated fatty acids and total fat intake was restricted to men diagnosed with localized disease. Conversely, the data suggest that men with the lowest dietary intake of these fatty acids have a reduced risk of death from their disease. It is possible that disease outcome may be influenced by dietary factors only while the cancer is still in its early stages. Once a tumor has progressed to an advanced stage or metastasized, dietary modification may no longer influence prognosis. This observation is in line with previous studies of dietary nutrients and prostate cancer survival in this population (16, 52).
Our study has several strengths. Our study population of 525 men was completely followed for up to 20 years. Because the dietary questionnaire was specifically designed for the Swedish diet, we believe that the assessment of foods contributing to dietary fat intake is well captured in our study population. Furthermore, the results of the sensitivity analysis suggest that men with more severe disease did not recall diet differently from men with less severe disease. As participants were recruited before the introduction of prostate cancer screening in Sweden, a large proportion of men had advanced stage tumors, which allowed us to stratify our analysis by stage at diagnosis. During follow-up, over 200 men died from prostate cancer, and 268 from other causes, allowing for sufficient power to detect associations with intake of various fatty acids.
There are also potential limitations to our study. Although our study population is fairly large, the analysis may be underpowered to detect associations of small magnitude, particularly for fatty acids with limited range of intake in this population, including marine n-3 fatty acids, or associations among men with localized cancer, where few deaths occurred. In addition, the modest significant associations we observed would not remain statistically significant after application of a conservative Bonferroni correction for multiple testing, with a corrected P value of 0.001. We did not have information available regarding Gleason grade at diagnosis, which is a strong predictor of prostate cancer outcome, but we do have some information on the degree of tumor cell differentiation (53). However, cell differentiation was not included in the final multivariable models as it may be a mediator on the causal pathway. Recent reports suggest that blood levels of trans-fatty acids may be associated with prostate cancer (10, 33). Future research may investigate an association between trans-fat intake and prostate cancer survival, as we are unable to address this in our study. However, trans-fat intake is substantially lower in Sweden compared with the United States (54), possibly attenuating an association in this population. In addition, we were unable to explore the effect of changing dietary patterns on survival.
In conclusion, high total dietary fat and saturated myristic and shorter chain fatty acid intake were adversely associated with survival following a diagnosis of localized prostate cancer in a population-based cohort of Swedish men. We saw a suggestive decrease in overall disease-specific mortality with high intake of marine n-3 fatty acids despite low levels in this population. These results suggest that early stage tumors may be more responsive to dietary factors and that diet may influence prognosis following a diagnosis of early stage prostate cancer. As one of the few studies examining the relation between dietary fat and prostate cancer survival, our study results warrant replication in other populations.
ACKNOWLEDGMENTS
Author affiliations: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts (Mara M. Epstein, Julie L. Kasperzyk, Lorelei A. Mucci, Edward Giovannucci, Alkes Price, Katja Fall); Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts (Edward Giovannucci); Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts (Alkes Price); Channing Laboratory, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts (Mara M. Epstein, Julie L. Kasperzyk, Lorelei A. Mucci); The Centre for Public Health Services, University of Iceland, Reykjavik, Iceland (Lorelei A. Mucci, Katja Fall); The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (Alicja Wolk, Niclas Håkansson); Clinical Epidemiology and Biostatistics, Örebro University Hospital, Örebro, Sweden (Katja Fall); and Department of Urology, Örebro University Hospital, Örebro, Sweden (Swen-Olof Andersson, Ove Andrén).
This research was supported by National Institutes of Health research training grant R25 CA098566 (M. M. E.) and training grant NIH 5 T32 CA09001-35 (J. L. K.), as well as by the American Institute for Cancer Research (J. L. K.).
The authors would like to thank Dr. Jan-Erik Johansson (Örebro University Hospital, Örebro, Sweden) for his longstanding commitment to this study and his advice for this analysis.
Conflict of interest: none declared.
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