The association between metabolic syndrome and the risk of prostate cancer, high-grade prostate cancer, advanced prostate cancer, prostate cancer-specific mortality and biochemical recurrence

In men, prostate cancer (PCa) is the most frequently diagnosed malignancy in industrialized countries [1] and it is the second most commonly diagnosed cancer and the sixth leading cause of cancer death worldwide [2]. There is a clear need for a better understanding of the risk factors related to PCa development and progression. Age, race and family history are the only established prostate cancer risk factors and these factors are all non-modifiable. Recently, modifiable lifestyle factors such as physical activity and diet have been investigated. Because a higher incidence of PCa was associated with a higher prevalence of “western” lifestyle, it has been suggested that these lifestyle factors play a significant role in the pathogenesis of PCa [3].

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes hypertension, diabetes mellitus, obesity, hypertriglyceridemia, and low high-density lipoprotein cholesterol, with insulin resistance as the underlying hallmark feature [4]. The prevalence of MetS has been increasing worldwide and has become a major public health problem in many western countries. For example, 35%-41% of adults in the USA are reported to exhibit MetS [5]. Recently, increasing evidences suggests that MetS may be involved in the development and progression of certain types of cancer as an independent etiologic factor including breast cancer [6], endometrial cancer [7], colorectal cancer [8], pancreatic cancer [9] and prostate cancer [10]. MetS was firstly observed as a composite factor associated with prostate cancer risk in 2004 [11], and more studies have since reported the association between MetS and prostate cancer. However, the studies investigating the association between MetS and prostate cancer risk have reported inconsistent findings [12‐21].

It is crucial to review and evaluate the magnitude to which MetS affects the development and progression of PCa, as proper management of this modifiable lifestyle factor may help improve PCa outcomes.

A recently performed meta-analysis study summarized the association between MetS and the incidence of some common cancer types, including prostate cancer. The results, based on 14 databases, revealed that MetS was not associated with prostate cancer risk [22]. However, a new investigation on MetS and prostate cancer risk was published recently [19], and much increasing evidence in the latest investigations suggests that MetS may be associated with the aggressiveness and progression of PCa; prostate cancer patients with MetS may suffer more aggressive disease and adverse clinical outcomes [19, 23‐27]. However, inverse results [28] or no significant associations [14, 20, 29, 30] have been reported in other studies. Therefore, to thoroughly investigate the nature of this association, we focused on longitudinal cohort studies and conducted a new meta-analysis to confirm the association between MetS and prostate cancer risk by searching the latest literature. Subsequently, we performed another meta-analysis to quantitatively summarize several parameters of PCa aggressiveness and progression, including Gleason score, clinical stage, biochemical recurrence and prostate cancer-specific mortality associated with MetS.

In 2007, Hsing et al. summarized five studies on MetS and prostate cancer risk and concluded that the epidemiologic evidence was insufficient to suggest a link between MetS and PCa [37]. In 2012, Esposito et al. performed a systematical review and meta-analysis on the association of MetS and cancer risk including prostate cancer. The authors also concluded that MetS was not associated with prostate cancer risk too [22]. In the present study, we updated the data and used the current evidence to analyze whether MetS is associated with prostate cancer risk. We observed the same result as previous meta-analysis; no association could be detected between Mets and prostate cancer.

We believe the result is reliable for two reasons. Firstly, only longitudinal cohort studies were included in this analysis, imparting strong evidence for our conclusions. In addition, the association between MetS and prostate cancer may be affected by several factors, including heterogeneity among the individual studies. The heterogeneity may arise from differences in age, race, the definition of MetS [22], and geographic factors [26]. Further, MetS is a syndrome composed of at least 3 components, and the individual component may exert antagonistic functions on one another Thus the syndrome may represent an integrated outcome that combines neutralizing positive and negative functions. For example, a meta-analysis revealed that diabetes mellitus was significantly negatively associated with prostate cancer risk in population-based studies (RR = 0.72, 95% CI: 0.64-0.81) and cohort studies conducted in the USA (RR = 0.79, 95% CI: 0.73, 0.86) [38]. Furthermore, several genome-wide association studies suggest that diabetes mellitus and prostate cancer share certain genetic factors, including the HNF1β and JAZF1 genes, and a previous study suggested that JAZF1 might represent a potential target against diabetes and obesity [39]. Although hypertension was found to be positively associated with prostate cancer risk [33, 40‐42], Obesity is negatively with localized prostate cancer (0.94, 95% CI, 0.91-0.97) and positively associated with advanced prostate cancer risk (1.07, 95% CI 1.01-1.13) [43].

However, after analyses of several parameters of PCa aggressiveness and progression, we found MetS to be significantly associated with an increased risk of prostate cancer with a high-Gleason score or advanced clinical stage, with biochemical recurrence after primary treatment and with prostate cancer-specific mortality. If confirmed by more investigations, this finding may open a new research field on PCa development and progression, potentially leading to new strategies or methods for PCa treatment. MetS is a major public health problem and prostate cancer is the most prevalent solid organ tumor, accounts for 29% of all cancer cases and the second most common cause of death by cancer among men in the USA [44]. Therefore we believe that there is a compelling need to investigate this association between MetS and prostate cancer although the association is not strong.

Nevertheless, the reliability of these results is limited. First, Gleason score and clinical stage data were extracted from cross-sectional studies not longitudinal cohort studies. Second, there exists a small difference among studies on the definition of high-grade Gleason PCa, some authors defined a high Gleason score ≥ 7 whereas others defined a high score as >7. Third, the pathological stage data in some studies were from biopsy not radical prostatectomy specimens. Last but not least, to date there remains limited studies focusing on this association, although many of the available studies are well designed case-control or longitudinal cohort studies.

In addition to the limitations listed above, another limitation for the analyses of the association between MetS and prostate cancer risk or prostate cancer parameters is that we did not perform a meta-regression to attempt to explain the heterogeneity of the study because of the varying adjustments in the individual studies. The result of a recent meta-analysis on 9 cross-sectional studies of metabolic syndrome in adult cancer survivors increases the weight of this suspicion, as it revealed that no significant association was found for non-hematologic malignancies, including testicular tumor, prostate cancer, sarcoma, and epithelial ovarian [45]. Therefore, there is an urgent future need to confirm this association and to find potential mechanisms to explain how metabolic factors affect the development or progression of PCa.

Based on the current findings, MetS is not associated with prostate cancer risk, but preliminary evidences demonstrates that men with MetS more frequently suffer high-grade prostate cancer, more advanced disease and are at greater risk of progression after radical prostatectomy and prostate cancer-specific death. Together, these findings indicate that MetS may be associated with the progression of prostate cancer and adverse clinical outcomes. Further studies with adjustment for appropriate confounders and larger, prospective, multicenter investigations are required in the future.