Background
Prostate cancer is the most common cancer in men in Europe, and the second most frequently diagnosed cancer in men worldwide [
1]. While relatively little is known about prostate cancer aetiology, hormones have been implicated; for example, circulating insulin-like growth factor I (IGF-I) concentrations are associated with prostate cancer risk [
2]. A relatively large body size has been proposed to influence several metabolic and hormonal mechanisms that can promote cancer development [
3]. With increasing global rates of overweight and obesity [
4], the potential role of obesity in carcinogenesis has become a significant public health concern.
Several prospective studies have investigated the association of body size with the development of prostate cancer [
3,
5‐
11]. The results have suggested differences in associations of body size with risk according to prostate tumour characteristics [
12], but relatively few studies have investigated whether body size is related to a higher risk of clinically relevant aggressive prostate cancer [
3,
7‐
9]. The latest World Cancer Research Fund meta-analysis reported that height was related to total prostate cancer and ‘advanced’ prostate cancer, including as ‘advanced’ prostate cancer various aggressive forms of the disease, but not differentiating between stage, grade and prostate cancer death because of the small number of available studies with data on these separate outcomes [
12]. This meta-analysis also reported that obesity was associated with ‘advanced’ prostate cancer. The latest meta-analysis published in a peer-reviewed journal classified incident prostate cases into two categories (‘localised’ or ‘advanced’) using a combination of Gleason score, World Health Organization (WHO) grading system, tumour node metastasis (TNM) stage, Jewett–Whitmore staging system and prostate-specific antigen (PSA) levels [
13]. Therefore, more studies of the association of body size with prostate cancer separately by both grade and stage are needed.
The current study is an extended analysis of the association between body size and prostate cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC), with an additional 5 years of follow-up (13.9 compared to 8.5 years in the previous publication) and almost three times the number of incident cases (7024 compared to 2446 cases, including 726 compared to 580 high grade, and 1388 compared to 499 advanced stage cases), and a substantial number of deaths from prostate cancer (
n = 934) [
14]. Herein, we sought to examine the association of height and adiposity at baseline with both prostate cancer risk by tumour characteristics and with prostate cancer death.
Results
After an average of 13.9 years of follow-up, a total of 7024 men were diagnosed with prostate cancer among the 141,896 men included in this study. Among the total cases, there were 934 deaths from prostate cancer. The mean age at diagnosis was 67.8 years (range, 41–95 years). The main baseline characteristics of the participants according to categories of BMI (<25, 25–29.9 and ≥ 30 kg/m
2) are shown in Table
1 (and by height and waist circumference in Additional file
1: Tables S3 and S4; the distribution of the study participants and of prostate cancer cases by country is shown in Additional file
1: Table S5). Participants with obesity at baseline were more likely to be older, former smokers, moderately inactive and with a lower level of education than were men of normal BMI. Men with obesity were more likely to be missing information on marital status, but of those men who provided information on marital status at recruitment, men with obesity were more likely to be married.
Table 1
Baseline characteristics of male participants according to body mass index (BMI) categories in the European Prospective Investigation into Cancer and Nutrition (EPIC) study
Characteristic | <25 | 25–29.9 | ≥30 |
Number of men | 50,678 | 68,736 | 21,698 |
Age at baseline,a years | 50.0 (11.2) | 52.5 (9.4) | 53.3 (8.9) |
Age at diagnosis,a years | 67.7 (6.9) | 68.0 (6.5) | 67.7 (6.3) |
Smoking status, N (%) |
Never smoker | 19,156 (37.8) | 21,354 (31.1) | 5914 (27.3) |
Former smoker | 15,113 (29.8) | 26,916 (39.2) | 9162 (42.2) |
Current smoker | 15,749 (31.1) | 19,480 (28.3) | 6327 (29.2) |
Unknown | 660 (1.3) | 986 (1.4) | 295 (1.4) |
Physical activity, N (%) |
Inactive | 8141 (16.1) | 12,998 (18.9) | 5309 (24.5) |
Moderately inactive | 15,452 (30.5) | 21,203 (30.8) | 6506 (30.0) |
Moderately active | 12,597 (24.9) | 16,636 (24.2) | 5046 (23.3) |
Active | 13,135 (25.9) | 16,487 (24.0) | 4539 (20.9) |
Unknown | 1353 (2.7) | 1412 (2.1) | 298 (1.4) |
Diabetes at baseline, N (%) |
No | 48,380 (95.5) | 64,886 (94.4) | 19,692 (90.8) |
Yes | 1088 (2.1) | 2424 (3.5) | 1542 (7.1) |
Unknown | 1210 (2.4) | 1426 (2.1) | 464 (2.1) |
Education, N (%) |
Below degree level | 32,488 (64.1) | 50,091 (72.9) | 17,485 (80.6) |
Degree level | 16,644 (32.8) | 16,919 (24.6) | 3730 (17.2) |
Unknown | 1546 (3.1) | 1726 (2.5) | 483 (2.2) |
Marital status, N (%) |
Married | 29,318 (57.9) | 38,540 (56.1) | 11,029 (50.8) |
Not married | 9154 (18.1) | 7209 (10.5) | 2099 (9.7) |
Unknown | 12,206 (24.1) | 22,987 (33.4) | 8570 (39.5) |
Height,a cm | 176.2 (7.2) | 174.3 (7.2) | 172.6 (7.6) |
BMI,a kg/m2
| 23.0 (1.6) | 27.2 (1.4) | 32.6 (2.7) |
Weight,a kg | 71.3 (7.3) | 82.7 (7.7) | 97.3 (11.4) |
Waist circumference,a cm | 85.8 (6.2) | 96.2 (6.2) | 109.0 (8.2) |
Hip circumference,a cm | 95.6 (4.6) | 101.6 (4.7) | 109.7 (6.6) |
Waist to hip ratioa
| 0.899 (0.056) | 0.948 (0.054) | 0.995 (0.057) |
The relationship of height with prostate cancer risk is shown in Table
2. When we compared the highest fifth with the lowest, height was not associated with total prostate cancer risk (HR = 1.06, 95% CI, 0.97–1.15;
P
trend = 0.3). There was evidence of heterogeneity by tumour grade (
P
heterogeneity = 0.002), with height being positively associated with high-grade disease (HR = 1.54, 1.18–2.03;
P
trend = 0.006), but not low-intermediate-grade disease (HR = 0.96, 0.86–1.08;
P
trend = 0.2). Taller height was also associated with a higher risk for prostate cancer death (HR = 1.43, 1.14–1.80;
P
trend = 0.001). The risks of high-grade disease and prostate cancer death increased by 21% (HR = 1.21, 1.06–1.38) and 17% (HR = 1.17, 1.04–1.31), respectively, with every 10 cm increment in height.
Table 2
Multivariable-adjusted hazard ratios (95% CI) for prostate cancer in relation to height at recruitment in men from the European Prospective Investigation into Cancer and Nutrition (EPIC) study
Median (range) | | 165.2 (115.0–168.5) | 171.0 (168.5–173.0) | 175.0 (173.0–176.7) | 178.9 (176.7–181.0) | 184.2 (181.0–210.0) | | | |
Total prostate cancer | 7010 | 1.00 ref | 1.04 (0.96–1.12) | 1.02 (0.94–1.10) | 1.02 (0.94–1.10) | 1.06 (0.97–1.15) | 0.3 | | 1.02 (0.98–1.06) |
Grade |
Low-intermediate | 3740 | 1.00 ref | 0.96 (0.87–1.06) | 0.97 (0.88–1.08) | 0.91 (0.82–1.01) | 0.96 (0.86–1.08) | 0.2 | | 0.97 (0.92–1.03) |
High | 726 | 1.00 ref | 1.30 (1.02–1.66) | 1.39 (1.08–1.79) | 1.35 (1.04–1.74) | 1.54 (1.18–2.03) | 0.006 | 0.002 | 1.21 (1.06–1.38) |
Stage |
Localised | 2632 | 1.00 ref | 1.02 (0.91–1.15) | 1.01 (0.89–1.14) | 0.93 (0.82–1.06) | 1.01 (0.88–1.16) | 0.7 | | 0.98 (0.92–1.05) |
Advanced | 1387 | 1.00 ref | 1.04 (0.88–1.24) | 1.11 (0.92–1.32) | 1.13 (0.95–1.35) | 1.09 (0.90–1.32) | 0.4 | 0.2 | 1.06 (0.96–1.16) |
Prostate cancer deaths | 932 | 1.00 ref | 1.13 (0.92–1.39) | 1.17 (0.94–1.46) | 1.13 (0.91–1.41) | 1.43 (1.14–1.80) | 0.001 | | 1.17 (1.04–1.31) |
Total prostate cancer risk was inversely related to BMI and waist circumference (Table
3); the HRs for highest fifth versus lowest were 0.90 (0.83–0.97,
P
trend < 0.001) for BMI and 0.92 (0.84–1.00,
P
trend = 0.01) for waist circumference. However, the association of BMI and waist circumference with prostate cancer risk was found to differ between different prostate cancer tumour characteristics. For BMI and prostate cancer risk, there was evidence of heterogeneity by tumour grade (
P
heterogeneity = 0.01; HR = 0.89, 0.79–0.99 for low-intermediate-grade and HR = 1.32, 1.01–1.72 for high-grade cancer) and stage (
P
heterogeneity = 0.01; HR = 0.86, 0.75–0.99 for localised stage and HR = 1.11, 0.92–1.33 for advanced stage). Similarly, there was significant heterogeneity in the association with waist circumference by tumour grade (
P
heterogeneity = 0.002; HR = 0.87, 0.77–0.99 for low-intermediate-grade and HR = 1.43, 1.07–1.92 for high-grade cancer), but not by tumour stage (
P
heterogeneity = 0.1). There were statistically significant positive associations of prostate cancer death with BMI (HR = 1.35, 1.09–1.68) and waist circumference (HR = 1.55, 1.23–1.96).
Table 3
Multivariable-adjusted hazard ratios (95% CI) for prostate cancer in relation to body mass index (BMI) and waist circumference at recruitment in men from the European Prospective Investigation into Cancer and Nutrition (EPIC) study
BMI, kg/m2
| | | | | | | | | Continuous per 5 kg/m2
|
Median (range) | | 22.2 (12.7–23.5) | 24.5 (23.5–25.3) | 26.1 (25.3–27.0) | 28.0 (27.0–29.2) | 31.1 (29.2–68.4) | | | |
Total prostate cancer | 6991 | 1.00 ref | 0.99 (0.92–1.07) | 1.04 (0.96–1.12) | 0.94 (0.87–1.01) | 0.90 (0.83–0.97) | <0.001 | | 0.94 (0.90–0.98) |
Grade |
Low-intermediate | 3727 | 1.00 ref | 0.98 (0.88–1.09) | 1.08 (0.97–1.20) | 0.90 (0.80–1.00) | 0.89 (0.79–0.99) | 0.001 | | 0.92 (0.87–0.98) |
High | 720 | 1.00 ref | 1.38 (1.07–1.77) | 1.30 (1.01–1.68) | 1.32 (1.02–1.71) | 1.32 (1.01–1.72) | 0.07 | 0.01 | 1.10 (0.97–1.25) |
Stage |
Localised | 2622 | 1.00 ref | 1.03 (0.91–1.17) | 1.00 (0.88–1.14) | 0.91 (0.80–1.03) | 0.86 (0.75–0.99) | 0.001 | | 0.90 (0.84–0.97) |
Advanced | 1384 | 1.00 ref | 1.04 (0.87–1.24) | 1.24 (1.05–1.48) | 1.08 (0.90–1.29) | 1.11 (0.92–1.33) | 0.3 | 0.01 | 1.05 (0.96–1.15) |
Prostate cancer deaths | 931 | 1.00 ref | 1.15 (0.93–1.42) | 1.20 (0.97–1.48) | 1.05 (0.84–1.31) | 1.35 (1.09–1.68) | 0.01 | | 1.14 (1.02–1.27) |
Waist, cm | | | | | | | | | Continuous per 10 cm |
Median (range) | | 82.5 (51.0–86.0) | 89.0 (86.0–91.9) | 94.0 (91.9–96.5) | 99.5 (96.5–103.0) | 108.0 (103.0–180.0) | | | |
Total prostate cancer | 6352 | 1.00 ref | 1.01 (0.93–1.09) | 1.00 (0.93–1.09) | 0.99 (0.91–1.07) | 0.92 (0.84–1.00) | 0.01 | | 0.97 (0.94–1.00) |
Grade |
Low-intermediate | 3251 | 1.00 ref | 0.97 (0.87–1.09) | 0.97 (0.86–1.09) | 0.95 (0.85–1.06) | 0.87 (0.77–0.99) | 0.003 | | 0.95 (0.91–0.99) |
High | 641 | 1.00 ref | 1.36 (1.02–1.81) | 1.26 (0.94–1.67) | 1.58 (1.20–2.08) | 1.43 (1.07–1.92) | 0.001 | 0.002 | 1.13 (1.03–1.25) |
Stage |
Localised | 2075 | 1.00 ref | 0.96 (0.82–1.11) | 0.96 (0.83–1.11) | 0.93 (0.80–1.08) | 0.89 (0.76–1.03) | 0.03 | | 0.96 (0.91–1.01) |
Advanced | 1291 | 1.00 ref | 1.20 (1.00–1.46) | 1.17 (0.97–1.41) | 1.30 (1.08–1.56) | 1.08 (0.89–1.32) | 0.2 | 0.1 | 1.03 (0.96–1.10) |
Prostate cancer deaths | 877 | 1.00 ref | 1.21 (0.96–1.53) | 1.03 (0.81–1.31) | 1.28 (1.02–1.61) | 1.55 (1.23–1.96) | <0.001 | | 1.18 (1.08–1.28) |
The associations of hip circumference and WHR with prostate cancer risk are shown in Additional file
1: Table S6. Total prostate cancer was inversely associated with hip circumference (HR for highest versus lowest fifth 0.86, 0.79–0.94). There was significant heterogeneity for hip circumference by tumour grade (
P
heterogeneity < 0.001; HR = 0.84, 0.75–0.95 for low-intermediate-grade and HR = 1.37, 1.04–1.80 for high-grade cancer). WHR was not associated with total prostate cancer incidence. However, there was evidence of heterogeneity by cancer grade (
P
heterogeneity = 0.004) and stage (
P
heterogeneity = 0.02); WHR was positively associated with high-grade (HR = 1.46, 1.09–1.94,
P
trend = 0.004) and advanced stage (HR = 1.29, 1.05–1.58,
P
trend = 0.01), but not with low-intermediate-grade and localised prostate cancer. Hip circumference was significantly associated with risk of death from prostate cancer (HR for highest versus lowest fifth 1.43, 1.14–1.79), but no association between WHR and prostate cancer death was observed.
When BMI, waist circumference and WHR were categorised according to the WHO cut-off points, the results were broadly similar to those for these variables categorised in fifths (Additional file
1: Table S7).
There was no evidence of heterogeneity for the associations of height, BMI and waist circumference with high-grade prostate cancer and prostate cancer death by age at recruitment (<60, ≥ 60 years), age at diagnosis (<65, ≥ 65 years), or time between recruitment and diagnosis (<5, ≥ 5 years) (Additional file
1: Tables S8 (height), S9 (BMI) and S10 (waist circumference)).
The significant positive association of height, BMI and waist circumference with high-grade prostate cancer and prostate cancer death remained largely unchanged in the sensitivity analysis. After excluding men with missing data for covariates, we observed that the association of waist circumference with both high-grade prostate cancer and prostate cancer death was slightly larger, although the associations of height and BMI with risk were somewhat attenuated and were no longer statistically significant. When we used waist circumference-adjusted residuals of BMI as the exposure, the positive association between BMI and prostate cancer death was no longer statistically significant and the direction was reversed (HR = 0.80, 0.51–1.25). When we used BMI-adjusted residuals of waist circumference as the exposure the association between waist circumference and prostate cancer death was essentially unchanged.
Discussion
In this prospective analysis, men who were taller and with greater adiposity had an elevated risk of high-grade prostate cancer and death from prostate cancer. The associations were strongest for height and waist circumference.
Previous studies have found a positive association between height and risk of prostate cancer [
3,
5,
12,
25‐
30]. In our study, this positive association was only significant for high-grade prostate cancer and death from prostate cancer. While several prospective studies have found a positive association between height and death from prostate cancer [
3,
27,
28], to our knowledge, no previous study has found a positive association between height and high-grade prostate cancer risk [
3,
29,
30]. However, this might be due to the fact that not many studies have differentiated between prostate cancer stage and grade of the disease [
12]. The mechanisms underlying this association of height with aggressive disease are not fully understood. Height is partly determined by genetic factors and it might also be a marker of cumulative early-life growth factor exposures, such as high IGF-I or childhood nutrition, which may increase the risk of prostate cancer [
2]. Taller men have more cells (including stem cells) and larger prostate volumes [
31]. However, men with smaller prostates have been found to have more high-grade/advanced disease and higher progression rates [
32].
Results from previous prospective studies have suggested that the association between obesity and prostate cancer may vary significantly across tumour characteristics [
3,
6‐
9], with a positive association between adiposity and risk of aggressive (advanced stage and high grade combined) prostate cancer [
3,
6‐
9]. The association between genetically determined adiposity and prostate cancer risk has also recently been examined in a large Mendelian randomisation study [
33]. No association was observed between genetic score for adult BMI and WHR for total and aggressive prostate cancer (defined as a Gleason score of ≥ 8, a disease stage of ‘distant’, a PSA level of > 100 ng/mL or death from prostate cancer); however, associations were not examined separately by tumour stage and grade [
33]. In our analysis, adiposity tended to be positively associated with risk for high-grade tumours and prostate cancer death, and inversely related to non-aggressive prostate cancer tumours and total prostate cancer, which is in accordance with previous reports [
9,
11,
34]. The association of obesity with death might be for a specific tumour subtype such as tumours with the TMPRSS2:ERG gene fusion [
35]. BMI adjusted for waist circumference probably reflects lean body mass rather than adiposity. The positive association between waist circumference and prostate cancer death was the only one maintained in all of the multiple sensitivity analyses. Although waist circumference and BMI are highly correlated, waist circumference has been proposed as a better marker of adiposity for men [
36].
In our analysis, adiposity markers tended to be positively associated with aggressive tumours and prostate cancer mortality, and inversely related to non-aggressive prostate cancer tumours and total prostate cancer. These different associations by tumour characteristics may be partly due to differences in prostate cancer detection in men with obesity. Such men may be less likely to be diagnosed with prostate cancer overall, and in particular with early prostate cancer, because they have lower PSA concentrations (perhaps due to an increased blood volume since the total amount of PSA in blood does not differ by body mass), are less likely to undergo a biopsy, and are also likely to have larger prostates, making cancer detection more difficult [
37]. It may be also more difficult to perform a thorough digital rectal examination on men with obesity. A reduced likelihood of early detection and treatment might in turn lead to an elevated incidence of aggressive disease and high prostate cancer mortality in men with obesity [
38]. However, several possible biological mechanisms that may underlie the association between obesity and prostate cancer death have been proposed, including mechanisms that involve insulin and the IGF-I axis, sex hormones, and inflammatory and oxidative stress pathways. Obesity is associated with disturbances in the IGF-I axis; an inverted U-shaped association between BMI and IGF-I has been observed, while BMI and concentrations of IGFBP-1 and -2 have been shown to be inversely associated [
39]. High circulating IGF-I levels are associated with an increased prostate cancer incidence in this cohort [
40] and in an individual participant meta-analysis of prospective studies [
2]. Participants with obesity normally suffer from hyperinsulinemia, which has been linked to prostate cancer risk [
41] and prostate cancer mortality [
42]. Obesity is also related to a decrease in free testosterone and changes in other sex hormone concentrations [
38]. Moreover, excess adiposity may contribute to the activation of proinflammatory signalling pathways [
43] and higher oxidative stress [
44], both of which have been suggested to be linked to higher prostate cancer risk [
45,
46].
This study has several strengths and also some limitations. The strengths include its prospective design, detailed information on potential confounders, long follow-up, the large sample size and number of incident cases, and the availability of data on prostate cancer tumour characteristics and mortality. Analyses by time to diagnosis showed no evidence that the observed associations were due to reverse causality. Although measurements of fat mass were not available in this study, previous investigations have shown that both BMI and waist circumference are strongly correlated with total fat mass [
47]. Participants in this cohort might be considered to be late middle-aged adults, since their mean age at recruitment was 52 years. In this age group, and especially in older adults, the use of BMI as a measure of overweight and obesity might be less sensitive because ageing is associated with a decrease in muscle mass and height [
48]. It might therefore be argued that the use of BMI in our cohort may lead to an underestimate in the prevalence of obesity; however, we also use waist circumference, which has been found to be a better predictor of total body fat, and especially of abdominal adiposity in men, than BMI, because waist circumference is less influenced by muscle mass [
48]. The lack of screening data is a limitation of this analysis. Information on tumour characteristics was only available for a subset of cases (24.8% of prostate cancer cases did not have any data on tumour characteristics) and men with obesity were less likely to have missing data on tumour stage and grade than were men who were not overweight. Data on early-life factors, including anthropometry, which may influence prostate cancer occurrence [
26,
49], were not available in the current study.
Acknowledgements
We thank all participants in the EPIC cohort for their contribution to the study.