ABSTRACT
Background
Plant-based diets are associated with multiple health benefits and a favorable environmental impact. For prostate cancer, previous studies suggest a beneficial role of specific plant-based foods (e.g., tomatoes) and a potentially harmful role of specific animal-based foods (e.g., meat, dairy). However, less is known about plant-based dietary patterns.
Objectives
We sought to examine the relation between plant-based diet indices and prostate cancer risk, including clinically relevant disease.
Methods
This was a prospective cohort study including 47,239 men in the Health Professionals Follow-Up Study (1986–2014). Overall and healthful plant-based diet indices were calculated from FFQs. Cox proportional hazards models were used to estimate HRs and 95% CIs to examine the risk of incident prostate cancer (total and by clinical category), among men ages <65 and ≥65 y.
Results
Of the 47,239 men, 6655 men were diagnosed with prostate cancer over follow-up, including 515 with advanced-stage disease at diagnosis, 956 with lethal disease (metastasis or death), and 806 prostate cancer deaths. Greater overall plant-based consumption was associated with a significantly lower risk of fatal prostate cancer (HR: 0.81; 95% CI: 0.64, 1.01; P-trend = 0.04). In men aged <65, a higher plant-based diet index was associated with a lower risk of advanced, lethal, and fatal prostate cancer. Moreover, greater consumption of a healthful plant-based diet was associated with lower risks of total (HR: 0.84; 95% CI: 0.73, 0.98; P-trend = 0.046) and lethal prostate cancer (HR: 0.56; 95% CI: 0.34, 0.94; P-trend = 0.03) at age <65. There were no associations between overall or healthful plant-based diet indices with prostate cancer among men ≥65 y. Fewer than 1% of participants followed a strict vegetarian or vegan diet.
Conclusions
This prospective study provides supportive evidence that greater consumption of healthful plant-based foods is associated with a lower risk of aggressive forms of prostate cancer, with stronger benefit among men aged <65 y.
Keywords: prostate cancer, plant-based diet, nutrition, dietary patterns, epidemiology
Introduction
Plant-based dietary patterns are becoming increasingly popular in the United States (1). Healthful plant-based diets, including vegetables, fruits, nuts, legumes, and whole grains, are associated with numerous health benefits, including reductions in diabetes, cardiovascular disease, and overall mortality (2, 3). The benefits of a plant-based diet on health may be due to direct effects of their healthy components (e.g., fiber, antioxidants), reductions in intake of animal products, and potential reductions in obesity. The WHO classifies processed meat as a group 1 carcinogen (causes cancer in humans); red meat is classified as group 2A, probably carcinogenic to humans (4). Notably, this conclusion was primarily based on colorectal cancer risk, although suggestive associations were also seen for pancreatic and prostate cancer. Other benefits of consumption of plant-based diets include animal welfare and environmental protection (5).
Less is known about the relation between plant-based dietary patterns with prostate cancer, the most common cancer and second leading cause of cancer death in US men (6), although there is intriguing evidence supporting a benefit. Experimental studies using prostate cancer xenograft models reported that a diet containing 20% plant protein inhibited tumor weight by 37% compared with a 20% animal dairy protein diet (7).
Epidemiologic evidence also supports a beneficial role for specific plant-based foods with prostate cancer risk. Tomato products and lycopene have been associated with lower risk of prostate cancer, particularly lethal disease (8). Conversely, there is substantial epidemiologic evidence linking dairy and red meat with an increased risk of prostate cancer (9).
Despite previous studies evaluating specific animal- and plant-based foods, there are limited data on the relation of dietary patterns with prostate cancer risk or outcomes. Because it is a public health priority to identify the optimal diet for disease prevention, recent research in nutritional epidemiology has shifted toward evaluation of dietary patterns (10). In a study using data from the NHANES, a greater healthful plant-based diet Index was associated with a significantly lower risk of having an elevated prostate-specific antigen (PSA) level; the study did not examine prostate cancer incidence (11). Our objective was to examine plant-based dietary patterns and prostate cancer risk in the Health Professionals Follow-Up Study (HPFS). We hypothesized that a higher overall and healthful plant-based diet Index is associated with a lower risk of overall and aggressive prostate cancer. We also hypothesized that the impact of plant-based dietary patterns on prostate cancer risk may be differential by age, based on previous studies showing the importance of earlier exposures in prostate carcinogenesis (12, 13).
Subjects and Methods
The HPFS began in 1986 and was designed to evaluate the association between nutritional factors with serious illnesses, including cancer and cardiovascular disease. In HPFS, we performed a prospective cohort analysis with follow-up from 1986 to 2014 to examine the relation of the plant-based diet Index with prostate cancer incidence. Participants completed questionnaires at baseline and every 2 y thereafter to collect information on demographics, lifestyle, medical history, and disease outcomes, and every 4 y for diet. The outcomes of interest were incident prostate cancer overall, as well as clinical subtypes of localized, advanced, lethal, and fatal disease. The study was approved by the institutional review board at the Harvard T.H. Chan School of Public Health and those of participating registries as required.
Study population
Among 51,529 men in the HPFS, we excluded men with a history of cancer (other than nonmelanoma skin cancer) at baseline (n = 2800) or who reported consuming <800 or >4200 kcal/d or were missing more than 70 out of 131–152 items on the FFQ (n = 1490). Following these exclusions, the final sample included 47,239 men.
Dietary assessment
Dietary data were collected with a validated semiquantitative FFQ at baseline and additionally every 4 y. Reliability and validity of these instruments have been previously reported (14). Participants were asked how often, on average, they had consumed a standard portion size of each food item in the past year. We calculated the overall plant-based diet Index, healthful plant-based diet Index, and unhealthful plant-based diet Index using the FFQ data. These indices were developed and reported in previous studies in the HPFS focusing on diabetes and heart disease (3, 15). The full components and scoring of each index are shown in Supplemental Table 1. In brief, healthful plant foods include whole grains, fruits, vegetables, legumes, vegetable oils, tea, and coffee; unhealthful plant-based foods include refined grains, fruit juices, sugar-sweetened beverages, potatoes, sweets, and desserts. We examined all 3 indices due to previous studies in HPFS showing different impacts of healthful and unhealthful plant-based foods for cardiovascular disease. Animal foods included meat, fish and seafood, eggs, dairy, butter or lard, and miscellaneous animal foods. Diet indices were calculated using cumulative averages through follow-up to best represent long-term diet and to minimize within-person variation due to measurement error. Energy intake was computed by multiplying the frequency of consumption of foods by the energy content of the specified portion from the USDA and Harvard University food composition databases. Diet indices were adjusted for total energy intake using the residual method.
Outcome definitions and ascertainment
Incident diagnoses of prostate cancer were reported on biennial questionnaires. Permission was obtained to acquire medical records and pathology reports for review by trained personnel to confirm the cancer diagnosis and clinical features. When records were unavailable, diagnoses were confirmed through linkage to state tumor registries. Biennial disease-specific questionnaires were used to obtain more information about treatment, disease progression, and metastases. Deaths were identified by next-of-kin, the postal service, and linkage with the National Death Index. Dates and causes of death were confirmed by an Endpoints Committee of physicians.
Stage T1a cases were excluded from analyses to reduce detection bias for incidental cases diagnosed in ≤5% of the specimen during transurethral resection of the prostate for benign prostatic hyperplasia. Given the disease's considerable biological heterogeneity in metastatic potential, we classified prostate cancers into the following clinical subgroups at diagnosis: localized (stage T1/T2 and N0, M0 at diagnosis), advanced (stage T3b/T4/N1/M1 at diagnosis), lethal (distant metastasis or prostate cancer death), and fatal (prostate cancer death).
Cox proportional hazards models were used to examine the association between plant-based diet indices (overall, healthful, and unhealthful) with risk of incident prostate cancer (overall and clinical subgroups). The overall and healthful indices were the primary exposures of interest, whereas the unhealthful index was a secondary exposure and is presented in Supplemental tables.
Person-time was calculated from return of baseline questionnaires until prostate cancer diagnosis, death, or end of follow-up, whichever was documented first. In all models, we calculated P values for linear trend by assigning the median score for each quintile to all participants in the quintile. We examined a basic model adjusting for age and calendar time period and multivariable-adjusted models which were further adjusted for self-reported race (white, nonwhite), height (inches; ≤68, >68–70, >70–72, and >72), BMI (in kg/m2); <18.5, 18.5–<25, 25–<30, ≥30), BMI at age 21 (<20, 20–<23, 23–<25, and ≥25), diabetes (yes/no), alcohol (g/d; quintiles), smoking history (never, former, current), physical activity [metabolic equivalents (METs)-h/wk; quintiles], family history of prostate cancer (yes/no), PSA screening in the previous cycle (yes, no), PSA testing in >50% of previous cycles (yes, no), multivitamin use (yes/no), vitamin E supplement use (yes/no), aspirin use (yes, no), and anticholesterol medicine use (yes, no), to include factors from the HPFS surveys that have previously been associated with prostate cancer risk and/or diagnostic activity (13). Time-varying exposures were updated using the cumulative updating approach, and missing data were handled by carrying overexposure data over from the prior questionnaire cycle. We used a 2-y lag between dietary assessment and prostate cancer incidence in the primary analysis to limit potential reverse causation bias. In addition, we modeled longer latency periods (4-, 8-, 12-y lag) in secondary analyses to assess potential etiologic windows of exposure. The analysis was also performed with a priori stratification by current age <65 y compared with ≥65 y since prostate cancer is most frequently diagnosed among men ages 65–74 in the United States and this age cutoff has been used in previous studies (16, 17). All analyses were performed using SAS version 9.4 (SAS Institute Inc.). Statistical tests were 2-sided with P < 0.05 considered statistically significant.
Results
Table 1 shows the demographics of the 47,239 eligible men by quintile of the overall and healthful plant-based diet Index, and Supplemental Table 2 shows the demographics for the unhealthful plant-based diet Index. During a mean follow-up of 20.7 y or 962,896 person-y, 6655 men were diagnosed with prostate cancer, including 4573 with localized, 515 advanced, 956 lethal, and 806 fatal disease. Compared with men in the lowest quintile of the overall plant-based diet Index, men in the highest quintile were more likely to undergo PSA screening, had a lower BMI, were more physically active, consumed less alcohol, and were less likely to smoke and have diabetes. They were also more likely to take aspirin, multivitamins, and a cholesterol-lowering medication.
TABLE 1.
Age-adjusted characteristics of men weighted by person-years according to plant-based diet index and healthful plant-based diet index, in 47,239 men from the Health Professionals Follow-Up Study1
| Plant-based diet index | Healthful plant-based diet index | |||||
|---|---|---|---|---|---|---|
| Q1 (lowest) | Q3 | Q5 (highest) | Q1 (lowest) | Q3 | Q5 (highest) | |
| Median score | −1.3 | 0 | 1.3 | −1.3 | 0 | 1.3 |
| Age, y | 63.1 ± 10.7 | 65.3 ± 11.0 | 65.3 ± 11.0 | 62.2 ± 10.8 | 65.2 ± 11.0 | 66.4 ± 10.7 |
| White, % | 91.1 | 90.6 | 90.8 | 91.2 | 90.6 | 90.5 |
| Height, inches | 70.2 ± 3.6 | 70.1 ± 3.5 | 69.9 ± 3.5 | 70.1 ± 3.2 | 70.2 ± 3.6 | 70 ± 3.6 |
| BMI at age 21 y | 22.2 ± 5.7 | 22.1 ± 5.4 | 21.9 ± 5.3 | 21.9 ± 5.4 | 22.1 ± 5.5 | 22.3 ± 5.6 |
| Smoking status, % | ||||||
| Never | 56.0 | 58.1 | 58.9 | 60.5 | 56.7 | 55.6 |
| Former | 36.9 | 37.4 | 38.4 | 33.2 | 38.7 | 41.3 |
| Current | 7.1 | 4.5 | 2.8 | 6.3 | 4.6 | 3.2 |
| Family history of prostate cancer, % | 11.7 | 12.0 | 11.4 | 11.8 | 11.5 | 11.3 |
| PSA screening in 1994, % | 31.6 | 37.3 | 41.1 | 32.9 | 37.2 | 40.4 |
| PSA screening in 2008, % | 48.2 | 55.1 | 53.9 | 51.6 | 54.9 | 52.3 |
| Multivitamin use, % | 49.4 | 53.8 | 54.6 | 48.8 | 54.0 | 56.3 |
| Alcohol consumption, g/d | 14.1 ± 18.7 | 11 ± 14.7 | 9 ± 12.0 | 9.5 ± 13.3 | 11.7 ± 15.4 | 12.2 ± 16.2 |
| Physical activity, METs-h/wk | 29.5 ± 25.9 | 32.6 ± 27.9 | 35.8 ± 29.9 | 28.9 ± 24.9 | 32.4 ± 27.9 | 37.4 ± 31.2 |
| Aspirin use, % | 40.4 | 44.9 | 46.6 | 41.1 | 46.0 | 44.9 |
| Anticholesterol medication, % | 14.4 | 18.6 | 18.7 | 16.2 | 18.8 | 17.2 |
| Year (total energy intake in kcal/d) | 1987 (6712) | 1973 (630) | 1998 (576) | 1974 (589) | 1968 (637) | 2017 (646) |
| BMI | 26.8 ± 4.2 | 26.1 ± 3.7 | 25.3 ± 3.4 | 26.4 ± 4.1 | 26.2 ± 3.7 | 25.6 ± 3.7 |
| Diabetes, % | 10.8 | 7.9 | 5.3 | 7.6 | 7.8 | 8.3 |
| Carbohydrates, g/d | 216.1 ± 43.3 | 246.3 ± 39.7 | 274 ± 39.8 | 236 ± 38.8 | 243.1 ± 43.5 | 261.7 ± 49.8 |
| Animal protein, g/d | 71.7 ± 19.2 | 62.3 ± 16.5 | 53.1 ± 16.8 | 64.6 ± 16.4 | 62.8 ± 17.4 | 58.3 ± 21.1 |
| Vegetable protein, g/d | 22.5 ± 5.8 | 26.9 ± 5.9 | 31.6 ± 7.4 | 22.8 ± 4.9 | 26.6 ± 5.7 | 32.3 ± 8.2 |
| Animal fat, g/d | 45 ± 13.6 | 35 ± 11.2 | 26.7 ± 10.5 | 41.9 ± 12.4 | 35.8 ± 12.2 | 27.9 ± 12.3 |
| Vegetable fat, g/d | 31.1 ± 11.7 | 34.1 ± 11.5 | 35.4 ± 12.0 | 32.5 ± 10.0 | 33.9 ± 11.5 | 34.7 ± 13.9 |
1Values presented as means ±SDs for continuous variables. All variables other than age are standardized to the age distribution of all participants. MET, metabolic equivalent of task; PSA, prostate-specific antigen; Q, quintile.
As shown in Table 2, there was no significant association between the plant-based diet Index and total prostate cancer or localized disease. However, there was a lower risk of fatal prostate cancer among men with a higher plant-based diet index (HR: 0.81; 95% CI: 0.64, 1.01 for quintile 5 compared with quintile 1; P-trend = 0.04). The healthful plant-based diet Index was associated with a significantly lower risk of localized prostate cancer in the overall population.
TABLE 2.
HR and 95% CIs for the associations between plant-based diet index and prostate cancer risk in 47,239 men from the Health Professionals Follow-Up Study (1986–2014)1
| Q 1 | Q 2 | Q 3 | Q 4 | Q 5 | P-trend | |
|---|---|---|---|---|---|---|
| Plant-based diet index | ||||||
| Total prostate cancer | ||||||
| Cases, n | 1178 | 1383 | 1371 | 1384 | 1339 | |
| Age adjusted | 1 [Reference] | 1.12 (1.04, 1.21) | 1.08 (1.00, 1.17) | 1.07 (0.99, 1.15) | 1.03 (0.95, 1.11) | 0.99 |
| Multivariable adjusted | 1 [Reference] | 1.08 (1.00, 1.17) | 1.03 (0.95, 1.12) | 1.01 (0.94, 1.10) | 0.97 (0.90, 1.05) | 0.17 |
| Localized prostate cancer2 | ||||||
| Cases, n | 793 | 970 | 944 | 981 | 885 | |
| Age adjusted | 1 [Reference] | 1.17 (1.06, 1.29) | 1.11 (1.01, 1.22) | 1.14 (1.03, 1.25) | 1.04 (0.95, 1.15) | 0.64 |
| Multivariable adjusted | 1 [Reference] | 1.11 (1.01, 1.22) | 1.03 (0.94, 1.14) | 1.05 (0.95, 1.16) | 0.96 (0.87, 1.06) | 0.18 |
| Advanced prostate cancer2 | ||||||
| Cases, n | 102 | 101 | 122 | 92 | 98 | |
| Age adjusted | 1 [Reference] | 0.96 (0.72, 1.26) | 1.13 (0.86, 1.47) | 0.84 (0.63, 1.11) | 0.79 (0.60, 1.05) | 0.07 |
| Multivariable adjusted | 1 [Reference] | 0.94 (0.71, 1.24) | 1.12 (0.86, 1.46) | 0.83 (0.62, 1.10) | 0.78 (0.59, 1.04) | 0.06 |
| Lethal prostate cancer2 | ||||||
| Cases, n | 190 | 187 | 187 | 192 | 200 | |
| Age adjusted | 1 [Reference] | 0.91 (0.74, 1.12) | 0.88 (0.72, 1.08) | 0.86 (0.70, 1.06) | 0.81 (0.66, 0.99) | 0.04 |
| Multivariable adjusted | 1 [Reference] | 0.92 (0.75, 1.12) | 0.90 (0.73, 1.11) | 0.88 (0.71, 1.08) | 0.83 (0.67, 1.02) | 0.07 |
| Fatal prostate cancer2 | ||||||
| Cases, n | 167 | 160 | 157 | 152 | 170 | |
| Age adjusted | 1 [Reference] | 0.89 (0.71, 1.11) | 0.83 (0.67, 1.04) | 0.77 (0.62, 0.97) | 0.78 (0.63, 0.97) | 0.01 |
| Multivariable adjusted | 1 [Reference] | 0.89 (0.72, 1.11) | 0.86 (0.69, 1.08) | 0.80 (0.64, 1.00) | 0.81 (0.64, 1.01) | 0.04 |
| Healthful plant-based diet index | ||||||
| Total prostate cancer | ||||||
| Cases, n | 1173 | 1263 | 1453 | 1356 | 1410 | |
| Age adjusted | 1 [Reference] | 0.98 (0.90, 1.06) | 1.08 (1.00, 1.17) | 0.96 (0.89, 1.04) | 0.97 (0.90, 1.05) | 0.36 |
| Multivariable adjusted | 1 [Reference] | 0.96 (0.88, 1.04) | 1.05 (0.97, 1.14) | 0.93 (0.86, 1.01) | 0.95 (0.87, 1.02) | 0.11 |
| Localized prostate cancer2 | ||||||
| Cases, n | 822 | 886 | 1019 | 902 | 944 | |
| Age adjusted | 1 [Reference] | 0.98 (0.89, 1.08) | 1.09 (0.99, 1.20) | 0.94 (0.85, 1.03) | 0.97 (0.88, 1.06) | 0.29 |
| Multivariable adjusted | 1 [Reference] | 0.95 (0.86, 1.05) | 1.04 (0.95, 1.14) | 0.88 (0.80, 0.97) | 0.91 (0.83, 1.01) | 0.02 |
| Advanced prostate cancer2 | ||||||
| Cases, n | 89 | 100 | 97 | 121 | 108 | |
| Age adjusted | 1 [Reference] | 1.07 (0.80, 1.43) | 0.98 (0.74, 1.32) | 1.14 (0.86, 1.50) | 0.90 (0.68, 1.20) | 0.57 |
| Multivariable adjusted | 1 [Reference] | 1.07 (0.80, 1.42) | 0.99 (0.74, 1.33) | 1.15 (0.87, 1.52) | 0.93 (0.70, 1.25) | 0.75 |
| Lethal prostate cancer2 | ||||||
| Cases, n | 151 | 176 | 216 | 195 | 218 | |
| Age adjusted | 1 [Reference] | 1.01 (0.81, 1.26) | 1.17 (0.95, 1.44) | 0.94 (0.76, 1.17) | 0.95 (0.77, 1.18) | 0.41 |
| Multivariable adjusted | 1 [Reference] | 1.01 (0.81, 1.26) | 1.18 (0.95, 1.46) | 0.96 (0.77, 1.19) | 0.98 (0.79, 1.21) | 0.60 |
| Fatal prostate cancer2 | ||||||
| Cases, n | 136 | 140 | 185 | 164 | 181 | |
| Age adjusted | 1 [Reference] | 0.88 (0.70, 1.12) | 1.10 (0.88, 1.38) | 0.88 (0.70, 1.10) | 0.87 (0.69, 1.09) | 0.21 |
| Multivariable adjusted | 1 [Reference] | 0.89 (0.70, 1.13) | 1.12 (0.89, 1.40) | 0.89 (0.71, 1.13) | 0.89 (0.71, 1.13) | 0.35 |
1Values are presented as HRs (95% Cis) unless otherwise indicated. Diet indices were adjusted for total energy intake using the residual method. Age-adjusted Cox proportional hazards models stratified by age and time period. Multivariable-adjusted Cox proportional hazards models stratified by age and time period, and adjusted for race (white, nonwhite), height (in; ≤68, >68–70, >70–72, >72), BMI (≤18.5, 18.5–<25, 25–<30, ≥30), BMI at age 21 (kg/m2; ≤20, 21–<23, 23–<25, ≥25), smoking status (never, former, current), family history of prostate cancer (yes, no), PSA test in previous cycle (yes, no), PSA testing in >50% of previous cycles (yes, no), multivitamin use (yes, no), vitamin E supplement use (yes/no), alcohol intake (g/d; quintiles), physical activity (METs-h/wk; quintiles), aspirin use (yes, no), anti-cholesterol medication (yes, no), and diabetes (yes, no). P values for linear trend calculated by assigning the median score for each quintile to all participants in the quintile. MET, metabolic equivalent of task; PSA, prostate-specific antigen; Q, quintile.
2Localized prostate cancer: stage T1/T2 and N0, M0 at diagnosis; advanced prostate cancer: stage T3b/T4/N1/M1 at diagnosis is lethal prostate cancer: prostate cancer death or distant metastasis; fatal prostate cancer: prostate cancer death.
We hypothesized that diet might be more strongly associated with prostate cancer risk in younger men based on previous studies on the importance of earlier exposures (12, 13). Supplemental Table 3 shows the distribution of macronutrients for plant-based diet indices by age. Multivariable-adjusted results are presented in Table 3 stratified by age. Among men age <65 y at diagnosis, there was no significant association of the plant-based diet Index with total prostate cancer. However, men with a higher plant-based diet Index had a 42% lower risk of advanced prostate cancer (HR: 0.58; 95% CI: 0.35, 0.94 for quintile 5 compared with quintile 1; P-trend = 0.005, P-interaction = 0.06). Compared with the reference group with the lowest plant-based diet Index, a higher plant-based diet Index was associated with a reduction in lethal and fatal prostate cancer, although the results were not linear. Finally, latency analyses showed that a higher plant-based diet Index had a stronger protective association against fatal prostate cancer when we included a longer time lag (Supplemental Table 4).
TABLE 3.
Multivariable-adjusted HR and 95% CI of the associations of overall and healthful plant-based diet indices and prostate cancer risk, stratified by age, in 47,239 men from the Health Professionals Follow-Up Study1
| Q1 | Q 2 | Q 3 | Q 4 | Q 5 | P-trend | P-interaction | |
|---|---|---|---|---|---|---|---|
| Plant-based diet index | |||||||
| Total prostate cancer2 | 0.58 | ||||||
| Age <65 y (n = 1882) | 1 [Reference] | 1.09 (0.95, 1.25) | 0.94 (0.82, 1.09) | 0.94 (0.81, 1.09) | 0.94 (0.81, 1.09) | 0.12 | |
| Age ≥65 y (n = 4773) | 1 [Reference] | 1.08 (0.99, 1.19) | 1.07 (0.98, 1.18) | 1.05 (0.95, 1.15) | 0.99 (0.90, 1.09) | 0.56 | |
| Localized prostate cancer2 | 0.43 | ||||||
| Age <65 y (n = 1332) | 1 [Reference] | 1.15 (0.98, 1.36) | 0.99 (0.84, 1.18) | 1.00 (0.84, 1.19) | 0.90 (0.75, 1.08) | 0.12 | |
| Age ≥65 y (n = 3241) | 1 [Reference] | 1.10 (0.98, 1.23) | 1.06 (0.94, 1.19) | 1.07 (0.96, 1.20) | 0.99 (0.88, 1.11) | 0.62 | |
| Advanced prostate cancer2 | 0.06 | ||||||
| Age <65 y (n = 150) | 1 [Reference] | 0.65 (0.40, 1.03) | 0.65 (0.41, 1.04) | 0.36 (0.20, 0.65) | 0.58 (0.35, 0.94) | 0.005 | |
| Age ≥65 y (n = 365) | 1 [Reference] | 1.16 (0.81, 1.66) | 1.47 (1.05, 2.06) | 1.16 (0.81, 1.65) | 0.94 (0.65, 1.35) | 0.62 | |
| Lethal prostate cancer2 | 0.14 | ||||||
| Age <65 y (n = 208) | 1 [Reference] | 0.56 (0.37, 0.85) | 0.64 (0.42, 0.97) | 0.61 (0.40, 0.94) | 0.62 (0.41, 0.95) | 0.03 | |
| Age ≥65 y (n = 748) | 1 [Reference] | 1.08 (0.85, 1.37) | 1.02 (0.80, 1.31) | 1.00 (0.78, 1.27) | 0.92 (0.72, 1.18) | 0.35 | |
| Fatal prostate cancer2 | 0.14 | ||||||
| Age <65 y (n = 177) | 1 [Reference] | 0.56 (0.36, 0.88) | 0.62 (0.40, 0.98) | 0.52 (0.32, 0.84) | 0.62 (0.40, 0.97) | 0.02 | |
| Age ≥65 y (n = 629) | 1 [Reference] | 1.05 (0.81, 1.36) | 0.98 (0.75, 1.27) | 0.92 (0.71, 1.20) | 0.89 (0.69, 1.16) | 0.24 | |
| Healthful plant-based diet index | |||||||
| Total prostate cancer2 | 0.19 | ||||||
| Age <65 y (n = 1882) | 1 [Reference] | 0.93 (0.81, 1.07) | 1.03 (0.90, 1.18) | 0.93 (0.80, 1.07) | 0.84 (0.73, 0.98) | 0.046 | |
| Age ≥65 y (n = 4773) | 1 [Reference] | 0.98 (0.88, 1.08) | 1.07 (0.97, 1.18) | 0.95 (0.86, 1.04) | 0.99 (0.90, 1.09) | 0.59 | |
| Localized prostate cancer2 | 0.02 | ||||||
| Age <65 y (n = 1332) | 1 [Reference] | 0.91 (0.77, 1.06) | 0.95 (0.80, 1.11) | 0.88 (0.74, 1.04) | 0.74 (0.62, 0.89) | 0.002 | |
| Age ≥65 y (n = 3241) | 1 [Reference] | 0.98 (0.87, 1.11) | 1.10 (0.98, 1.23) | 0.90 (0.80, 1.02) | 1.00 (0.89, 1.12) | 0.50 | |
| Advanced prostate cancer2 | 0.51 | ||||||
| Age <65 y (n = 150) | 1 [Reference] | 0.94 (0.55, 1.59) | 1.27 (0.77, 2.09) | 1.25 (0.75, 2.08) | 0.97 (0.57, 1.65) | 0.78 | |
| Age ≥65 y (n = 365) | 1 [Reference] | 1.13 (0.80, 1.60) | 0.88 (0.62, 1.27) | 1.11 (0.79, 1.55) | 0.91 (0.64, 1.28) | 0.53 | |
| Lethal prostate cancer2 | 0.04 | ||||||
| Age <65 y (n = 208) | 1 [Reference] | 0.93 (0.60, 1.45) | 1.10 (0.71, 1.69) | 0.80 (0.50, 1.28) | 0.56 (0.34, 0.94) | 0.03 | |
| Age ≥65 y (n = 748) | 1 [Reference] | 1.03 (0.79, 1.34) | 1.22 (0.95, 1.57) | 1.01 (0.78, 1.30) | 1.10 (0.85, 1.41) | 0.65 | |
| Fatal prostate cancer2 | 0.06 | ||||||
| Age <65 y 65 (n = 177) | 1 [Reference] | 0.99 (0.66, 1.49) | 1.12 (0.75, 1.68) | 0.86 (0.56, 1.33) | 0.62 (0.38, 0.99) | 0.048 | |
| Age ≥65 y (n = 629) | 1 [Reference] | 0.88 (0.66, 1.17) | 1.14 (0.87, 1.48) | 0.93 (0.71, 1.22) | 1.00 (0.76, 1.30) | 0.93 |
1Values are presented as HRs (95% Cis) unless otherwise indicated. Diet scores were adjusted for total energy intake using the residual method. Multivariable-adjusted Cox proportional hazards models stratified by age and time period, and adjusted for race, height, BMI, BMI at age 21, smoking, family history of prostate cancer, PSA test in previous cycle, PSA testing in >50% of previous cycles, multivitamin use, vitamin E supplement use, alcohol intake, physical activity, aspirin use, anti-cholesterol medication, and diabetes. We calculated P values for linear trend by assigning the median score for each quintile to all participants in the quintile. MET, metabolic equivalent of task; PSA, prostate-specific antigen; Q, quintile.
2Localized prostate cancer: stage T1/T2 and N0, M0 at diagnosis; advanced prostate cancer: stage T3b/T4/N1/M1 at diagnosis; lethal prostate cancer: prostate cancer death or distant metastasis; fatal prostate cancer: prostate cancer death.
Multivariable analysis was also performed for both the healthful and unhealthful plant-based diet index, stratified by age. A higher healthful plant-based diet index was associated with a lower risk of total (HR: 0.84; 95% CI: 0.73, 0.98 for quintile 5 compared with quintile 1, P-trend = 0.046), lethal (HR: 0.56; 95% CI: 0.34, 0.94 for quintile 5 compared with quintile 1, P-trend = 0.03), and fatal prostate cancer (HR: 0.62; 95% CI: 0.38, 0.99 for quintile 5 compared with quintile 1, P-trend = 0.048) among men aged <65 y (Table 3). These associations were null among older men. Notably, a higher unhealthful plant-based diet index was also associated with a lower risk of lethal and fatal prostate cancer among men age ≥65 y (Supplemental Table 5). Table 4 shows the association between animal, healthful plant, and unhealthful plant food groups and prostate cancer risk by age, mutually adjusted. This analysis showed that healthful plant-based foods were associated with a lower risk of total, localized advanced, lethal, and fatal prostate cancer in men aged <65 y.
TABLE 4.
HR of animal, healthful plant, and unhealthful plant-based foods, mutually adjusted, and prostate cancer risk by age subgroup in 47,239 men from the Health Professionals Follow-Up Study1
| Q 1 | Q 2 | Q 3 | Q 4 | Q 5 | P-trend | |
|---|---|---|---|---|---|---|
| Age <65 y | ||||||
| Total prostate cancer2 | ||||||
| Animal | 1 [Reference] | 1.21 (1.03, 1.41) | 1.30 (1.10, 1.53) | 1.28 (1.08, 1.53) | 1.13 (0.92, 1.38) | 0.52 |
| Healthful plant | 1 [Reference] | 0.95 (0.83, 1.09) | 0.80 (0.69, 0.93) | 0.79 (0.68, 0.93) | 0.81 (0.68, 0.96) | 0.002 |
| Unhealthful plant | 1 [Reference] | 1.00 (0.86, 1.16) | 0.93 (0.79, 1.09) | 0.93 (0.79, 1.09) | 0.88 (0.72, 1.08) | 0.14 |
| Localized prostate cancer2 | ||||||
| Animal | 1 [Reference] | 1.19 (0.99, 1.43) | 1.38 (1.14, 1.67) | 1.27 (1.03, 1.57) | 1.06 (0.83, 1.36) | 0.98 |
| Healthful plant | 1 [Reference] | 0.94 (0.80, 1.10) | 0.82 (0.69, 0.98) | 0.80 (0.66, 0.96) | 0.74 (0.60, 0.91) | 0.001 |
| Unhealthful plant | 1 [Reference] | 1.09 (0.91, 1.31) | 1.04 (0.85, 1.27) | 0.98 (0.79, 1.22) | 1.05 (0.82, 1.34) | 0.94 |
| Advanced prostate cancer2 | ||||||
| Animal | 1 [Reference] | 1.43 (0.79, 2.58) | 1.48 (0.79, 2.75) | 1.52 (0.79, 2.94) | 1.53 (0.75, 3.13) | 0.38 |
| Healthful plant | 1 [Reference] | 1.04 (0.64, 1.68) | 0.81 (0.48, 1.36) | 0.57 (0.32, 1.02) | 0.63 (0.34, 1.14) | 0.04 |
| Unhealthful plant | 1 [Reference] | 0.86 (0.52, 1.41) | 0.63 (0.36, 1.10) | 0.54 (0.29, 0.99) | 0.42 (0.21, 0.85) | 0.01 |
| Lethal prostate cancer2 | ||||||
| Animal | 1 [Reference] | 1.68 (1.02, 2.77) | 1.40 (0.81, 2.39) | 1.54 (0.89, 2.69) | 1.49 (0.82, 2.72) | 0.46 |
| Healthful plant | 1 [Reference] | 0.87 (0.58, 1.31) | 0.69 (0.45, 1.07) | 0.59 (0.37, 0.94) | 0.58 (0.35, 0.95) | 0.01 |
| Unhealthful plant | 1 [Reference] | 0.70 (0.46, 1.08) | 0.53 (0.33, 0.87) | 0.66 (0.40, 1.08) | 0.55 (0.31, 0.97) | 0.08 |
| Fatal prostate cancer2 | ||||||
| Animal | 1 [Reference] | 1.69 (0.98, 2.91) | 1.52 (0.85, 2.71) | 1.52 (0.83, 2.78) | 1.50 (0.78, 2.87) | 0.53 |
| Healthful plant | 1 [Reference] | 0.82 (0.52, 1.28) | 0.67 (0.42, 1.07) | 0.58 (0.35, 0.96) | 0.61 (0.36, 1.03) | 0.04 |
| Unhealthful plant | 1 [Reference] | 0.69 (0.43, 1.10) | 0.54 (0.32, 0.92) | 0.62 (0.36, 1.07) | 0.62 (0.34, 1.13) | 0.20 |
| Age ≥65 y | ||||||
| Total prostate cancer2 | ||||||
| Animal | 1 [Reference] | 0.97 (0.89, 1.07) | 1.07 (0.97, 1.19) | 1.11 (1.00, 1.24) | 1.02 (0.90, 1.15) | 0.51 |
| Healthful plant | 1 [Reference] | 0.96 (0.87, 1.06) | 1.02 (0.92, 1.13) | 1.00 (0.91, 1.11) | 0.97 (0.86, 1.08) | 0.64 |
| Unhealthful plant | 1 [Reference] | 1.04 (0.95, 1.15) | 1.07 (0.97, 1.18) | 1.01 (0.90, 1.13) | 0.98 (0.86, 1.10) | 0.37 |
| Localized prostate cancer2 | ||||||
| Animal | 1 [Reference] | 0.96 (0.86, 1.08) | 1.06 (0.94, 1.20) | 1.08 (0.95, 1.24) | 0.97 (0.83, 1.13) | 0.92 |
| Healthful plant | 1 [Reference] | 0.97 (0.83, 1.13) | 1.04 (0.92, 1.17) | 1.01 (0.89, 1.15) | 0.98 (0.86, 1.13) | 0.72 |
| Unhealthful plant | 1 [Reference] | 1.05 (0.93, 1.18) | 1.08 (0.95, 1.22) | 1.04 (0.91, 1.19) | 1.04 (0.91, 1.19) | 0.66 |
| Advanced prostate cancer2 | ||||||
| Animal | 1 [Reference] | 1.07 (0.75, 1.53) | 1.09 (0.75, 1.58) | 1.05 (0.70, 1.58) | 1.32 (0.86, 2.03) | 0.19 |
| Healthful plant | 1 [Reference] | 1.15 (0.79, 1.67) | 1.42 (0.98, 2.04) | 1.18 (0.80, 1.74) | 1.03 (0.68, 1.56) | 0.81 |
| Unhealthful plant | 1 [Reference] | 1.09 (0.77, 1.53) | 1.03 (0.72, 1.47) | 0.94 (0.64, 1.38) | 0.85 (0.55, 1.31) | 0.33 |
| Lethal prostate cancer2 | ||||||
| Animal | 1 [Reference] | 1.01 (0.79, 1.29) | 1.10 (0.85, 1.43) | 1.09 (0.83, 1.44) | 1.17 (0.87, 1.59) | 0.29 |
| Healthful plant | 1 [Reference] | 0.94 (0.73, 1.22) | 1.10 (0.86, 1.42) | 1.01 (0.78, 1.32) | 1.06 (0.80, 1.40) | 0.64 |
| Unhealthful plant | 1 [Reference] | 1.08 (0.86, 1.35) | 0.96 (0.75, 1.23) | 0.89 (0.68, 1.17) | 0.78 (0.57, 1.06) | 0.05 |
| Fatal prostate cancer2 | ||||||
| Animal | 1 [Reference] | 1.04 (0.79, 1.36) | 1.09 (0.83, 1.45) | 1.15 (0.85, 1.55) | 1.16 (0.83, 1.62) | 0.36 |
| Healthful plant | 1 [Reference] | 0.83 (0.63, 1.09) | 0.99 (0.75, 1.29) | 0.94 (0.71, 1.25) | 0.95 (0.70, 1.28) | 0.99 |
| Unhealthful plant | 1 [Reference] | 1.12 (0.87, 1.44) | 1.02 (0.78, 1.34) | 0.86 (0.64, 1.16) | 0.75 (0.54, 1.05) | 0.03 |
1Values are presented as HRs (95% Cis) unless otherwise indicated. The healthful plant-based foods from Satija et al. (3)include whole grains, fruits, vegetables, nuts, legumes, vegetable oils, tea, and coffee; whereas, unhealthful plant-based foods include potatoes, refined grains, fruit juices, sugar-sweetened beverages, sweets, and desserts. Q, quintile.
2Localized prostate cancer: stage T1/T2 and N0, M0 at diagnosis; advanced prostate cancer: stage T3b/T4/N1/M1 at diagnosis; lethal prostate cancer: prostate cancer death or distant metastasis; fatal prostate cancer: prostate cancer death.
Discussion
We found that greater consumption of plant-based foods was associated with a lower risk of fatal prostate cancer. A higher overall and healthful plant-based diet index was associated with a lower risk of lethal and fatal prostate cancer for men age <65 y. Surprisingly, more unhealthful plant-based food was associated with a lower risk of lethal and fatal prostate cancer in men age ≥65 y. The absence of any detrimental impact of plant-based dietary consumption for prostate cancer risk is important in light of its many other documented health and environmental benefits.
There are several possible mechanisms through which greater consumption of plant-based foods and lower consumption of animal-based foods may influence prostate cancer risk. These includes greater intake of antioxidants and anti-inflammatory components in fruits and vegetables and reducing potentially harmful exposures associated with animal-based foods, such as hormones and heterocyclic amines created during high-temperature cooking (18). Diets high in animal protein may increase insulin resistance and insulin levels (19, 20), and milk and dairy increase levels of IGF1, which are associated with prostate cancer risk (21). These results are also aligned with ecological data reporting positive associations between country-level intake of animal foods with prevalence and mortality from multiple neoplasms including prostate cancer (22, 23).
It is noteworthy that the impact of plant-based dietary consumption with prostate cancer risk appeared to be differential by age. Previous studies have suggested the importance of exposures earlier in life with prostate cancer risk (24). For example, a large-pooled analysis showed that higher IGF1 levels were much more strongly associated with prostate cancer risk in men age <60 y (RR: 1.80; 95% CI: 1.34, 2.42) than in men age >70 y (RR: 1.20; 95% CI: 0.13, 1.38; P for heterogeneity = 0.051) (12). Similarly, hyperinsulinemic and inflammatory dietary patterns (e.g., including some overlapping components such as red and processed meat) have been associated with a higher risk of aggressive prostate cancer among men age <65 y (13). Although not all were statistically significant, our results suggest that plant-based foods reduce risk and animal foods increase risk of fatal and lethal prostate cancer in men age <65 y.
Our results build upon those of numerous previous studies on the health effects of increasing plant-based food consumption for other disease outcomes. Satija et al. initially developed the plant-based diet indices to study the association with risk of type 2 diabetes, finding a significant inverse association between overall and healthful plant-based diet index with type 2 diabetes (3). In a follow-up study, these authors similarly found that the plant-based diet index, and particularly the healthful plant-based diet index, were inversely associated with incident coronary heart disease (15).
More recently, Baden et al. examined the association between changes in the plant-based diet index over a 12-y period and risk of all-cause and cause-specific mortality (2). They found that increased intake of a healthful plant-based diet was associated with a reduction in cardiovascular and total mortality. They also reported a reduction in prostate cancer mortality with an increased plant-based diet index (HR: 0.73; 95% CI: 0.55, 0.96). Unlike the current study, the study by Baden et al. did not adjust for important factors that influence prostate cancer mortality, such as PSA screening history, and they did not examine prostate cancer incidence.
Sustainability and environmental impact are other important factors to consider when developing dietary guidelines and recommendations. A recent modeling study reported that a healthy vegetarian eating pattern results in substantially less land use, freshwater eutrophication, marine eutrophication, particulate matter, and climate change compared with a healthy Mediterranean or US-style dietary pattern (5). Another recent study found that replacing half of all animal-based foods (e.g., dairy, meat, and fish) in the United States would save 224 million metric tons of carbon/y, equivalent to 47.5 million passenger vehicles (25).
Notably, the current study was specifically undertaken to evaluate the relation of the plant-based diet index with incidence of prostate cancer. We did not examine the association of the plant-based diet index with oncologic or functional outcomes among men already diagnosed with prostate cancer; however, this is an important direction for future study.
A limitation of this study is that the healthful and unhealthful plant-based diet Indices were developed in studies of diabetes and cardiovascular disease (3, 15), rather than cancer or prostate cancer specifically. For example, some foods that are considered in the “unhealthful” plant-based category, such as potatoes, do not have a known link to prostate cancer risk or adverse oncologic outcomes. Furthermore, all factors are weighted equally in these indices and it is possible that some food categories are more impactful than others with respect to risk of prostate cancer. That notwithstanding, we chose to employ this classification to align our work with previous studies showing a positive impact of healthful plant-based diet for diabetes, cardiovascular disease, and overall mortality (2). However, the use of this classification scheme which is not specific to prostate cancer may underlie some of our unexpected findings such as lower risk of fatal prostate cancer among men age >65 y consuming more unhealthful plant-based foods.
Another key limitation of our study is that <1% of participants did not consume meat or fish at baseline; therefore, we are unable to assess the impact of a vegan or strict vegetarian dietary pattern. Even in the highest quintile of the plant-based diet indices, the vast majority of participants consumed some animal-based products. There was a moderate inverse correlation between the overall plant-based diet index and animal protein (−0.38) and the percentage of energy from animal protein was about 11–12% in the highest quintile of the plant-based diet indices. Therefore, we are unable to examine the association of a vegetarian or vegan dietary pattern with risk of prostate cancer. Screening with PSA is a key confounder in epidemiologic studies of prostate cancer risk, which we accounted for in our multivariable models. Nonetheless, as with any observational study, we cannot rule out the possibility of residual or unmeasured confounding by PSA screening or other factors. Lastly, participants in this study were health professionals and primarily white, potentially limiting the generalizability of these findings to more socioeconomically and racially/ethnically diverse populations. An assessment of the relations between plant-based dietary patterns on risk of prostate cancer in racially diverse populations is an important direction for further study.
Strengths of this study include the large sample size, high rate of follow-up, and repeated assessment of dietary intake and other lifestyle factors with updating of exposure. In addition, the study had a large number of clinically relevant prostate cancer cases, which is critical given the biologic heterogeneity of prostate cancer. To our knowledge, this study is also among the first to examine the relation of dietary patterns rather than individual dietary factors with prostate cancer risk. This research question is particularly timely given the demonstrated benefits of plant-based diets for overall health and the environment. The EAT-Lancet Commission and other recent reports highlight a shift toward plant-based diets as a critical step in order to meet climate targets and preserve biodiversity (26, 27). Correspondingly, a greater understanding of the impact of plant-based dietary patterns on health outcomes, including prostate cancer risk, is important. In conclusion, plant-based diets have many important benefits for human health and ecological sustainability. Our study found a significantly lower risk of fatal prostate cancer among men consuming more plant-based foods. These results build upon previous studies showing a lower risk of elevated PSA with greater consumption of healthy plant-based foods. Men should be counseled that consuming more plant-based foods is associated with a lower risk of fatal prostate cancer along with other health benefits.
Supplementary Material
Acknowledgments
SL and LAM are supported by the Prostate Cancer Foundation. SL is also supported by Tricia and Michael Berns. SAK is supported by the Helen Diller Family Chair in Population Science for Urologic Cancer. This work was supported by grants from the National Institutes of Health (U01 CA167552, T32 CA009001). SRB is supported by grant 1K12DK111028 from the National Institute of Diabetes, Digestive, and Kidney Disorders. We thank the participants and staff of the Health Professionals Follow-Up Study for their valuable contributions, as well as the following US state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY.
The authors’ responsibilities were as follows—SL, BCF, SAK, and LAM: designed the research; SL, BCF, and LAM: conducted the research; ELG and LAM: provided databases; BCF: statistical analysis and interpretation (all) statistics; SL, BCF, and LAM: wrote initial paper; SRB, CHP, JMC, ELVB, ELG, and SAK: critical revisions; and all authors: read and approved the final manuscript. SAK reports equity in Fellow Health Inc. SRB has been paid by Myovant Sciences, Inc., for consulting work related to developing patient education materials for lifestyle modifications among men with prostate cancer. All other authors report no conflicts of interest.
Notes
Supported by grants from the National Institutes of Health (U01 CA167552, T32 CA009001).
SL and BCF contributed equally as first authors and SAK and LAM contributed equally as senior authors.
Supplemental Tables 1–5 are available from the “Supplementary data” link in the online posting of the article at https://academic.oup.com/ajcn/.
Abbreviations used: HPFS, Health Professionals Follow-Up Study; MET, metabolic equivalent of task; PSA, prostate-specific antigen.
Contributor Information
Stacy Loeb, Department of Urology and Population Health, New York University and Manhattan Veterans Affairs, New York, NY, USA.
Benjamin C Fu, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Scott R Bauer, Department of Medicine and Urology, UCSF; Division of General Internal Medicine, San Francisco, CA, USA.
Claire H Pernar, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
June M Chan, Departments of Epidemiology and Biostatistics, and Urology, University of California, San Francisco, San Francisco, CA, USA.
Erin L Van Blarigan, Departments of Epidemiology and Biostatistics, and Urology, University of California, San Francisco, San Francisco, CA, USA.
Edward L Giovannucci, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Stacey A Kenfield, Departments of Epidemiology and Biostatistics, and Urology, University of California, San Francisco, San Francisco, CA, USA.
Lorelei A Mucci, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Data Availability
Data described in the manuscript, code book, and analytic code may be made available upon application to and approval by the Harvard T.H. Chan School of Public Health. Further information including the procedures to obtain and access data from the Health Professionals Follow-Up Study is described at https://sites.sph.harvard.edu/hpfs/for-collaborators/.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data described in the manuscript, code book, and analytic code may be made available upon application to and approval by the Harvard T.H. Chan School of Public Health. Further information including the procedures to obtain and access data from the Health Professionals Follow-Up Study is described at https://sites.sph.harvard.edu/hpfs/for-collaborators/.