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Associations between Metabolic Syndrome (MetS) components and prostate cancer development have not been studied comprehensively; results have been divergent. Using the National Cholesterol Education Program Adult Treatment panel III (NCEP) and International Diabetes Federation (IDF) definitions of the MetS we investigated such associations taking competing risks of death into consideration.
In the prospective Uppsala Longitudinal Study of Adult Men (ULSAM) of 2322 Caucasian men with 34 years of follow-up baseline MetS-measurements at age 50 were used. Cumulative incidence of prostate cancer and death with/without the MetS were calculated. Competing risk of dying was taken into account by calculating the conditional probability of prostate cancer with/without the MetS.
Two-hundred-and- thirty-seven prostate cancers were identified. Prostate cancer probability by age 80 with baseline MetS compared to without the MetS was non-significantly higher, 5.2 percent-units (CI -0.8%-11.3%, (NCEP), 2.7 percent-units (CI -2.7%-8.0%) (IDF), cumulative incidence proportions of death was significantly higher, 19.3 percent-units (CI 13.4%-25.3%) (NCEP), 15.3 percent-units (CI 9.5%-21.1%) (IDF) and conditional probability of prostate cancer considering death from other causes was significantly higher, 7.3 percent-units (CI 0.2%-14.5%) odds ratio(OR) of 1.64 (CI 1.03-2.23). (NCEP), and non-significantly higher 5.0 percent-units (CI -1.6%-11.6%) OR 1.43 (CI 0.89-1.90). (IDF).
The MetS by the NCEP definition is associated with prostate cancer taking the competing risk of early death from other causes into account.
The results further highlight the public health impact of the increasing prevalence of MetS, and the importance of considering competing risks when studying risk factors for cancer.
Previous studies of an association between the metabolic syndrome (MetS) and prostate cancer have shown divergent results. The studies differ in size, baseline characteristics of those included, methodology used in analyses and length of follow up (1). Few studies have considered the full MetS. Among those that have, some have found a positive association in Scandianvians (2, 3) and in African Americans (4, 5) while others found an inverse association in a mixed population (6) or no relationship in Scandinavians (7) or whites in the US (6).
Most studies have analyzed the association between prostate cancer and selected components of the MetS rather than the full syndrome (8, 9, 10, 11). Some studies found more pronounced associations between components of the MetS and aggressive prostate cancer; examples being insulin resistance (12) and adiposity or high BMI (8, 13, 14, 15, 16) while others showed an association between components of the MetS and prognosis or mortality in prostate cancer. Such associations have been shown for obesity and high plasma C-peptide concentration (17), high BMI (18, 19), hyperinsulinemia and insulin resistance (20).
The Uppsala Longitudinal Study of Adult Men (ULSAM) (24) has characterized a cohort of men in detail with regard to the MetS (25). In the ULSAM cohort with more than three decades of follow-up, we investigated whether the MetS following two accepted definitions or components of the MetS and life style factors at baseline at the age of 50 influence the risk of developing clinically relevant prostate cancer. As the MetS is a risk factor for premature death and may be associated with smoking, we included the competing risks of early death and smoking in our analysis.
The source population used in the present study is the Uppsala Longitudinal Study of Adult Men (ULSAM). In 1970-1974, all men resident in Uppsala county born in 1920-24 (n=2841) were invited to take part in a prospective health survey to identify risk factors for diabetes and cardiovascular disease (CVD). Eighty two percent (n=2322) of the invited men participated at baseline, for all men at age 50, forming the ULSAM cohort (21). The study was approved by the Ethics Committee of the Faculty of Medicine at Uppsala University and individual informed consent was obtained.
For all analyses we used the two clinically oriented definitions of the MetS recommended by the National Cholesterol Education Program Adult Treatment panel III (NCEP) (22) and the International Diabetes Federation (IDF) (23), definitions which were both previously applied in relation to CVD in ULSAM (25).
The NCEP defines the MetS as established if three or more of the following components are present: elevated fasting plasma glucose level (≥6.1 mmol/L), elevated blood pressure (≥130/85 mm/Hg) or pharmacological treatment for hypertension, elevated triglyceride level (≥1.7 mmol/L), lowered HDL cholesterol level (<1.03 mmol/L for males) and large waist circumference (>102 cm for males).
The IDF defines the MetS as established if the absolute criterion abdominal obesity (waist circumference ≥94 cm in Caucasian males)is present and at least two of the following; elevated fasting plasma glucose level (≥5.6 mmol/L) or pharmacological treatment for type 2 diabetes, hypertension (≥130/85 mmHg) or pharmacological treatment for hypertension, elevated triglyceride level (≥1.7 mmol/L) or pharmacological treatment thereof, lower than normal levels of HDL cholesterol (< 1.0 mmol/L for males) or pharmacological treatment thereof. As waist circumference was only measured in a sub-sample of the men, the definitions were modified using a BMI cut point. Waist circumferences of 102 cm (NCEP) and 94 cm (IDF) correspond to BMIs of 29.4 and 27.4 respectively in a linear regression analysis. This is similar to BMI cut points used in previous modified definitions of the MetS (25, 26). The men for whom results of blood sample analyses and body measurements for the determination of the MetS (NCEP and/or IDF) were available constitute our study base.
The men were characterized as smokers or non-smokers/ex-smokers as per interview at age 50. At the ULSAM baseline examination at age 50, enzyme assays to measure fasting plasma glucose, high density lipoproteins (HDL) cholesterol and triglyceride concentrations of serum were used and waist and BMI measurements were performed as has been described before (25), including coding of smoking using baseline interview reports.
Follow-up started at the baseline examination in 1970-74 at 50 years of age of the participants and the censoring date for the present study was December 31, 2003, with a median of 30.3 years of observation for the cohort of 2184 men (NCEP) and with 1071 men then still alive. Total number of years of follow-up was 56 600. The age of the men still alive at the end of follow-up was thus between 79 and 83 years. Follow-up to identify prostate cancer and cause of death was achieved by linking the unique personal registration numbers to nationwide registers in Sweden: the Population Register, the Cancer Register (CR), the Hospital Discharge Register (HDR) and the Causes of Death Register (CDR).
Diagnosis of invasive prostate cancer (ICD-10, C61) was considered an event. Both the CR and the CDR started in 1958 while the HDR is available for all somatic inpatient health care since 1987. Reporting to these registries is compulsory and the coverage of prostate cancer in the CR is more than 95% (27). Mortality data from the CDR and the HDR have been shown to be an efficient validated alternative to revised hospital discharge notes and death certificates (28, 29). Confirmation of prostate cancer events identified using national registries was made through systematically reviewing the medical records for men reported with prostate cancer. Clinical tumor characteristics of the confirmed prostate cancer cases were then obtained from their respective medical records (cf. table 2). In nine cases where the medical records could not be retrieved, the diagnosis was verified by crosschecking with data in the National Prostate Cancer Registry, a nationwide clinical data base started in 1997 and detailing stage of disease and treatment (30). Men without prostate cancer were censored at the time of death from a cause other than prostate cancer or if alive at end of follow-up. Recommendations for PSA testing were restrictive -and thus practice limited- during the period of follow up, both nationally and in the region of the University Hospital of Uppsala. General screening is currently still not recommended and not common in men who are over the age of 70.
Absolute risks of prostate cancer and of death without a diagnosis of prostate cancer were calculated by means of cumulative incidence proportions (31), where the events of prostate cancer and of death, whichever came first, was considered as competing events, censoring for end of follow-up.
The probability of being diagnosed with prostate cancer was calculated as one minus the Kaplan Meier estimate of prostate cancer free survival, censoring for both death and end of follow up.
The conditional probability of prostate cancer given that death did not occur was calculated as the fraction of the cumulative incidence of prostate cancer divided by one minus the cumulative incidence of death without prostate cancer and confidence intervals were calculated according to Pepe (32) using R-code (33, 34). Relative risks in the conditional probability setting were calculated as odds ratios with 95% bootstrap confidence intervals.
To our knowledge, this is the first study using the methodology according to Pepe when analyzing the longitudinal relationship between the metabolic syndrome and prostate cancer as the outcome taking competing risk of mortality into account.
Relative risks of prostate cancer and death was calculated by means of Cox proportional hazard models(35). In the analysis of death, we censored for occurrence of prostate cancer. Similarly, in the analysis of prostate cancer we censored for death.
In the ULSAM cohort, 2183 men had measurements allowing a classification according to NCEP and 2287 allowing a classification according to IDF. In the cohort 237 prostate cancers were identified for 226 of which we had data to determine status according to the NCEP definition and for 234 according to the IDF definition.
Table 1 presents the distribution of the components of the MetS and smoking at baseline, age 50. Data for the men in the study base unclassifiable by NCEP (n=137) and IDF (n=34) criteria are also presented. Presence of the MetS as defined by NCEP, IDF and their components did not significantly influence the relative risk of prostate cancer, not considering competing risks. Smoking did not influence the risk of prostate cancer. The presence of MetS, all of its components and smoking conferred a statistically significant higher risk of death without prostate cancer compared to non-presence of these factors. The most common cause of death in ULSAM is CVD (24).
Table 2 shows the clinical characteristics of the men with prostate cancer by presence or absence of the MetS (NCEP/IDF) at age 50. The median age at prostate cancer diagnosis was 73 years. The majority (76% of all 237) of the men had their cancer detected subsequent to lower urinary tract symptoms or other symptoms (e.g. skeletal pain), signaling a clinically relevant or advanced disease. The majority of men were diagnosed with advanced stages of disease: the percentage of men diagnosed with Tumor stage T2 and above was 64.1 %, with another 9.7 % unclassified as regards stage. There was no clear association between presence of the MetS and TNM status at diagnosis, mode of detection or Gleason score. None of the men presented with a combination of a PSA-value of <10, a Gleason sum < 7 and a T-stage of less or equal to T2 which would be typical for screening–detected cancers.
Figure 1A-D illustrates the probability of prostate cancer censoring for end of follow-up without events and considering occurrence of prostate cancer and death as competing events. Men fulfilling the NCEP MetS criteria (figure 1A) and, slightly less so, men fulfilling the IDF MetS criteria (figure 1B) have a modestly higher risk of developing prostate cancer than men not fulfilling any of these criteria at baseline. However, when men reach age 80 the difference is not statistically significant: 4.4 percent units (CI -1.7%-10.5%) (NCEP), 1.7 percent units (CI -3.5%-6.9%) (IDF). We show two examples of components of the MetS: men with abdominal obesity (NCEP) at age 50 (figure 1C) also appeared to have a higher probability of developing clinically relevant prostate cancer (n.s. at age 80), while high fasting plasma glucose levels(IDF) (figure 1D) did not affect the probability of being diagnosed with prostate cancer.
Figure 2A-D shows the cumulative incidence proportion of death from all causes censored for a diagnosis of prostate cancer, which was at age 80, 19.2 percent units (CI 13.3%-25.3%) higher in the men diagnosed with the MetS-NCEP (figure 2A) and 15.8 percent units (CI 10.5%-21.7%) higher in men diagnosed with MetS-IDF (figure 2B). In men with abdominal obesity (NCEP) (figure 2C) and in men with high fasting plasma glucose (IDF) (figure 2D) cumulative incidence proportion of death was also significantly higher. Presence of any components of the MetS (high blood pressure (NCEP, IDF) high triglycerides (NCEP, IDF) and low HDL cholesterol (NCEP, IDF) or being a smoker was associated with a significantly higher cumulative incidence proportion of death from all causes than non-presence of the factors (not shown).
As presence of the MetS at age 50 in our cohort is associated with a higher RR of death without prostate cancer we assessed the risk of prostate cancer in men with the MetS independently of the early risk of death by estimating risk of prostate cancer conditioned on survival at a given time (figure 3A-D).
In figure 3A the conditional probability of being diagnosed with prostate cancer at age 80 is statistically significantly higher in the men with the MetS-NCEP at age 50 with a 7.3 percent units (CI 0.2%-14.5%) higher absolute risk in the MetS (NCEP) group translating into an odds ratio(OR) of 1.64 (CI 1.03-2.23). The same tendency is seen in figure 3B for men with the MetS-IDF at age 50 who, at age 80, had a 5.0 percent units (CI -1.6%-11.6%) higher conditional probability of being diagnosed with prostate cancer than men without the MetS, OR 1.43 (CI 0.89-1.90). Abdominal obesity (NCEP) (figure 3C) is likewise associated with a non-significantly higher conditional probability of 8.1 percent units (CI -1.3-17.5), OR 1.71 (CI 0.95-2.78), while high fasting plasma glucose (IDF) did not influence the conditional probability of being diagnosed with prostate cancer in men up to 80 years of age (fig 3D), the difference being 1.5 percent units (CI -4.6%-7.6%) giving an OR of 1.12 (CI 0.69-1.68). High triglycerides (NCEP, IDF) increased the risk of prostate cancer non-significantly by 3.0 percent units (CI -0.8%-6.8%), OR 1.26 (CI 0.94-1.55) (not shown in figure) while high blood pressure (NCEP, IDF) and low HDL cholesterol (NCEP, IDF) were only marginally associated with a higher risk of prostate cancer (not shown in figures). Smoking non-significantly increased the conditional probability of later prostate cancer.
We show that the presence of the full MetS according to the NCEP definition at age 50 is a risk factor for clinically relevant or advanced stages of prostate cancer over 34 years of follow-up. Results for the MetS according to the IDF definition were of similar magnitude, however not statistically significant. Few of the men in the study presented with clinically non-advanced or non-aggressive prostate cancer. The components of the MetS predominately responsible for the finding appear to be abdominal obesity, and a high serum triglyceride level. The findings become more evident when accounting for the competing risk of early death due to the MetS. High fasting blood glucose, high blood pressure and a low HDL cholesterol level are only marginally associated with the conditional probability of prostate cancer whereas smoking is not.
The ULSAM cohort used in this study is population based, homogeneous as regards ethnic background and standardized for age of the participants at baseline. The participants have been thoroughly characterized regarding the components of the MetS, smoking status and occurrence of prostate cancer. The participation rate is high and the data on individual follow-up of up to 34 years is almost complete through linkage to personal hospital records and nationwide registers with high coverage. In addition, less than 2% of the prostate cancer cases are screening detected and our results thus mainly pertain to clinically relevant prostate cancer with a high risk of progressive disease.
While the ULSAM cohort is relatively small and modest or weak associations may go undetected, its annotation is unprecedented in details and precision. It is indeed similar in size to other studies published on the relationship between a fully characterized MetS and prostate cancer and the follow-up is considerably longer. The measurements for diagnosing the full MetS used for the present study were made at only one point in time, on average 25 years before diagnosis, a design feature shared with most studies in the field. However, several of the components of the MetS reflect long-term life style habits which will not likely vary significantly over time, once established in middle aged men. Any misclassification of men who after the age of 50 have established the MetS would most probably lead to an underestimation of the risks observed rather than overestimate them.
There may be several reasons why previous cohort studies have come to divergent conclusions regarding the MetS and prostate cancer risk. This may be attributed to a number of factors, among these, the different definitions of the MetS used and the effects of competing factors are probably the most important. The four generally accepted definitions used to define the MetS have been put forth by the World Health Organization (WHO), NCEP, the European Group for the Study of Insulin Resistance (EGIR) and IDF. None of these can yet be considered the gold standard, since they emphasize different aspects of the MetS. This may in part explain differences in the results in the various studies. Furthermore, several investigators used modified versions of these definitions (2, 5, 7) or only selected parts of these definitions (4). We feel that a more important reason for equivocal results is the lack of consideration given to the effect of competing risks; many men with the MetS will not live to an age when prostate cancer risk is highest but will die early from other causes leaving an excess risk of risk of prostate cancer undetected.
The commonly used statistical analyses assume that censored individuals have the same risk of the event under study as those observed until the endpoint (35). When an exposure is associated both with risk of early death and the disease under study, especially when the outcome is increasing in frequency with age, this criterion is not fulfilled (35). We used a conditional probability method described by Pepe (32) to try to circumvent such a possible violation of the assumptions underlying the standard techniques and revealed that the full metabolic syndrome and key elements of the MetS are linked to prostate cancer risk.
Further reasons for diverging results in previous studies may be differences in age at baseline measurement and length of follow-up, e.g. measurements vary from those done early in life (7) to those in the elderly close to or at the time of diagnosis of prostate cancer (4). Some of the published studies on prostate cancer detected outside PSA screening end their follow-up before the mean age of diagnosis for non-screening detected prostate cancer (2, 3, 7), thereby studying only a younger part of the prostate cancer spectrum.
Our findings are in line with those of Laukkanen et al (3) who in their younger cohort found that men with a modified WHO definition of the MetS had a 1.9 fold higher relative risk (CI 1.1-3.5) of developing clinically relevant prostate cancer later in life. They considered the effects on the estimates due to high morbidity and mortality in men with diabetes and excluded these men. Lund-Håheim et al (2) studied modified components of the MetS according to NCEP in a large cohort and found a weak positive relation to prostate cancer with an increased relative risk of 1.56 (CI: 1.21-2.00). The weak associations may be due to this cohort being young. The median age at the end of follow-up was 73, which is below the mean age of diagnosis for clinically detected prostate cancer in our cohort. Tande et al (6) observed in a cohort study on comparatively young and overweight American men, a lower relative risk of developing prostate cancer of 0.77 (CI: 0.60-0.98) in men with the MetS (NCEP). The study had a 50% participation rate. The cases were identified by a combination of questionnaire and registry findings and the prostate cancers were to an unknown extent screening detected.
Martin et al (7) used a revised NCEP definition of the MetS and found little evidence of a relationship between the MetS or most of the components thereof and later clinically relevant prostate cancer, RR= 0.91 (CI: 0.77-1.09). Their study included 29 364 men with an average age of 50 years followed for a mean of 9.3 years, i.e. mainly men of ages with low prostate cancer risk. Competing risks were not considered. The only significant finding was a positive relationship between elevated blood pressure and prostate cancer. Prostate cancer in the young may in 30-40% of cases be associated with dominantly inherited genetic traits with high penetrance (36) and less influenced by metabolic factors. In two previous studies on the relationship between type 2 diabetes mellitus and prostate cancer risk, even though they did not take competing risk of mortality into consideration an increased risk of prostate cancer was observed in men with lower BMI in one study (37) but not in the other one (38). These studies did not take competing risk of death into account when analysing the relationship to prostate cancer which is a cancer typically diagnosed at higher ages and further that type 2 diabetes is a condition with an expected shorter life span due to an increased risk of cardiovascular death mediated by elevated blood glucose.
Our results indicate that life style factors giving rise to the metabolic syndrome according to either the NCEP or the IDF definition, in particular abdominal obesity, increase the risk of clinically relevant prostate cancer once the competing risk of dying from other outcomes of the MetS has been taken into account. If this is substantiated in further studies, it will not only be an important public health message, but will also prompt research to further understand the underlying mechanisms and to find out whether a reversal of the MetS components, e.g. obesity, will attenuate the risk. The findings also call for a methodological development to better analyze competing risks for risk factors with complex effects, e.g. our findings indicate that smoking is indeed a risk factor for prostate cancer which is still unclear (39, 40) plausibly owing to its being a relatively weak risk factor in a disease that mainly occurs late in life while also leading to a high risk of premature death from other causes as CVD and lung cancer.
Financial support: This work was supported by grants from the Ernfors Family(BZ), the Thuring(BZ), the Thuréus(BZ) and the Åke Wiberg(BZ) Foundations, the Swedish Diabetes Association Research Fund(BZ), the Swedish Medical Products Agency(BG, BZ), The Swedish Cancer Society (BG, LH), Cancer Research UK (HG, LH), the Prostate Cancer Foundation(ML), the National Cancer Institute (RO1CA131945, P50 CA90381) (ML), the Dana Farber Cancer Institute -Novartis Drug Development Program (ML) and the Linda and Arthur Gelb Center for Translational Research, a gift from Nuclea Biomarkers(ML).