Metabolic syndrome is associated with advanced prostate cancer in patients treated with radical retropubic prostatectomy: results from a multicentre prospective study

Background Prostate cancer (PCa) is the most common non-skin cancer in USA and the second leading cause of cancer death in Western Countries. Despite the high mortality associated with PCa, the only established risk factors are age, race and family history. A possible association between metabolic syndrome (MetS) and PCa was firstly described in 2004 and several subsequent studies in biopsy cohorts have shown conflicting results. Aim of our multicentre prospective study was to investigate the association between MetS and PCa in men undergoing radical prostatectomy (RP). Methods From January 2012 to June 2015, 349 consecutive men undergoing RP for PCa at three centres in Italy were enrolled into a prospective database. Body Mass Index (BMI) as well as waist circumference was measured before RP. Blood samples were also collected and tested for total PSA, fasting glucose, triglycerides and HDLs. Blood pressure was also recorded. We evaluated the association between MetS, defined according to Adult Treatment Panel III, PCa stage (advanced stage defined as pT ≥ 3 or N1) and grade (high grade defined as Gleason Score ≥ 4 + 3) using logistic regression analyses. Results Median age and preoperative PSA levels were 66 years (IQR: 61-69) and 7 ng/ml (IQR: 5-10), respectively. Median BMI was 26.12 kg/m2 (IQR 24-29) with 56 (16 %) obese (BMI ≥ 30 kg/m2) patients and 87 (25 %) patients with MetS. At pathological evaluation, advanced PCa and high-grade disease were present in 126 (36 %) and 145 (41.5 %) patients, respectively. MetS was significantly associated with advanced PCa (45/87, 51 % vs 81/262, 31 %; p = 0.008) and high-grade disease (47/87, 54 % vs 98/262, 37 %; p = 0.001). On multivariable analysis, MetS was an independent predictor of pathological stage ≥ pT3a or N1 (OR: 2.227; CI: 1.273-3.893; p = 0.005) and Gleason score ≥ 4 + 3 (OR: 2.007, CI: 1.175-3.428; p = 0.011). Conclusions We firstly demonstrated in a European radical retropubic prostatectomy cohort study that MetS is associated with an increased risk of high-grade and advanced prostate cancer. Further studies with long term follow-up should evaluate the impact of Mets on PCa survival.


Background
Prostate cancer (PCa) represents the most common non-skin cancer in Western Countries and the second leading cause of cancer death. Notwithstanding the high mortality rate associated with PCa, the only established risk factors are age, race, and family history [1]. Large geographic disparity in PCa risk suggests that lifestyle factors may contribute to the aetiology of the disease. In fact, Asian men have incidence rates 10-to 15-fold lower than those observed in Western Countries, however PCa incidence in Eastern Countries and in emigrants has increased rapidly in the last years, suggesting that Westernization may represent an important etiologic factor [2].
Metabolic syndrome (MetS) was firstly described by Reaven in 1988 as complex disorder (Syndrome X), namely a constellation of metabolic abnormalities that increases the risk of coronary artery disease, cardiovascular atherosclerotic diseases and diabetes mellitus type 2 (DMT2) [3]. MetS has become a major public health problem in many Western Countries since its prevalence has been increasing; 35-41 % of adults in the USA are diagnosed with MetS [4]. According to the most widely accepted definition, proposed by the National Cholesterol Education Program's Adult Treatment Panel III (ATPIII), patients with at least 3 of the following factors are considered to have MetS: abdominal obesity (waist circumference >102 cm in men or >88 cm in women), hypertriglyceridemia (>150 mg/dl), low high density lipoprotein (HDL) cholesterol (<40 mg/dl in men and <50 mg/dl in women), high blood pressure (>130/85 mm Hg) and a high fasting blood glucose level (>110 mg/dl) [1,5].
Aim of our multicentre prospective study was to evaluate the association between MetS, defined according to the ATPIII criteria, and PCa among a consecutive series of men undergoing radical prostatectomy (RP).

Methods
From January 2012 to June 2015 a consecutive series of men undergoing RP for PCa at three centres in Italy were enrolled into a prospective database. The study was approved by the Ethics committee of the coordinator centre (Ospedale Sant' Andrea, La Sapienza University of Rome) and then of the Regina Elena National Cancer Institute, Rome, and San Giovanni Bosco Hospital, Turin. All patients signed a dedicated informed consent.
Age and anthropometric parameters including waist circumference and body mass index (BMI) were assessed according to standardized methods and recorded from all patients. Waist circumference was measured, using a standard measurement strip with the patients standing and breathing normally, at the midway between the lowest rib margin and iliac crest [19]. BMI was calculated as weight in kilograms divided by height in meters, squared (kg/m 2 ). Obesity was defined as BMI ≥30 kg/m 2 . Additionally, resting blood pressure was recorded as the first and fifth Korotkof sounds by auscultation methods [20]. Moreover, fasting (8 hours) blood samples were drawn from all patients during the preoperative assessment evaluation and analysed for blood glucose, HDL cholesterol, triglycerides, total Prostate Specific Antigen (PSA) [1]. Data were used to define a binary variable for the presence or absence of MetS, according to ATPIII [5]. Finally, prostate volume was evaluated before surgery by means of trans-rectal ultrasound.
As per European Association of Urology (EAU) Guidelines [21], surgical treatment was recommended to patients with a life expectancy of at least 10 years and a bioptic diagnosis of PCa, clinically localized or advanced (cT1-T3). Indication to surgery, independently from the presence of MetS, was proposed by a local muldisciplinary uro-oncology team evaluating all the prostate cancer cases diagnosed or referred to each hospital. One dedicated uro-pathologist in each centre performed the histological examinations of the RP specimens.
Pathologic report was standardized [22] according to the histological/architectural thresholds proposed by the World Health Organization (WHO) classification of tumor of the urinary system and male genital organs [23].

Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS v.21, IBM Corp., Armonk, NY, USA). Evaluation of data distribution using the Kolmogorov-Smirnov test showed a non-normal distribution of the study data set. Differences between groups of patients in medians for quantitative variables and differences in distributions for categorical variables were tested with the Kruskal Wallis one-way analysis of variance and chi-square test, respectively. Using multiple logistic regression with the enter method, the statistical significant variables assessed in the univariate analysis were entered and investigated as predictors of advanced PCa (pathological Tumor stage ≥ pT3a and/or N1) versus localized PCA, and in a separate model predictors of high grade (Gleason score ≥ 4 + 3) versus low grade were compared. The logistic regression analysis was carried out using data from patients for whom complete data were available. In order to reduce the risk of redundant variables and subsequent multicollinearity, the variables included in the definition of the MetS were excluded from the multivariate analysis. An alpha value of 5 % was considered as threshold for significance. Data are presented as median (Inter quartile range (IQR)) and mean ± standard deviation (SD). Odds ratios (OR) and 95 % Confidence Intervals (CI) were calculated for the parameters in each model.  Table 2).

Discussion
In our series older patients with higher PSA levels and lower prostate volumes presented an increased risk of advanced and high grade PCa. These data were similar to previous experiences from our centre and from other studies demonstrating a negative correlation between    [1,[25][26][27][28][29]. Specifically, Freedland et al reported a significantly higher incidence of advanced disease in men with small prostates [25]; Kassouf et al described that more poorly differentiated tumors were found at RP in subjects with small prostate volumes than in those with larger glands [28]. The biological mechanism accountable for the inverse association between prostate volume and cancer aggressiveness remains to be explicated. Since more PSA diffuses into the circulation from cancerous cells than from benign prostatic tissues, it is theorized that men with higher PSA density may have an increased risk of harbouring high-grade/advanced-stage PCa [30].
In the present study we observed that MetS is a common condition (87/349, 25 %) among patients undergoing RP and is more prevalent than obesity (56/349, 16 %). In a previous experience, we reported that MetS was even more prevalent (44 %) in patients at risk of PCa for an elevated PSA or an abnormal digital rectal examination and we also showed that MetS was associated with an increased risk (OR: 3.8; 95 % CI 1.33-10.9) of Gleason score ≥ 7 in patients with PCa at biopsy [1]. Our results have been later confirmed by Morote et al [14] (OR 1.75; 95 % CI 1.26-2.41) and Kayaly et al [12] (OR 1.8; 95 % CI 0.87-3.74) on similar bioptic studies. Notwithstanding all these studies, the association between MetS and PCa is still controversial. Most of the studies conducted on the European population have demonstrated a positive association between MetS and PCa incidence, aggressiveness and outcomes [9,11,13]. Similar cohort studies performed on Americans revealed null [17] or inverse [16] associations. Making a comparison between our series and the USA one may be misleading because of heterogeneity in age, race and BMI distribution. Our cohort is entirely Caucasian with neither Africans nor Hispanics and, although in line with the average Italian population, it is less obese (16 % vs 34 %) and older (median age 66 vs 62 years) when compared to other experience from USA series [1,6,31]. In 2013, Xiang et al conducted a meta-analysis confirming a weak association between MetS and PCa risk, although men with MetS appeared more likely to have a grater risk of biochemical progression after RP and a higher cancer-specific mortality [18]. Bhindi and colleagues recently highlighted that no individual MetS component is independently associated with PCa outcomes, however a correlation between the number of MetS components and the odds of PCa diagnosis exists, with a biologic gradient present [10]. Finally, data from a recent study based on the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) population confirmed that having two or three to four MetS features was associated with increased risk of high-grade PCa (OR 1.35 and 1.94 respectively) [15].
One of the most important limitations and criticisms of the available evidence on the relationship between PCa and MetS is the lack of confirmatory studies on RP as most of the studies were performed on prostate biopsy cohorts where a significant percentage of patients with a negative biopsy unfortunately harbour a PCa. In order to overcome these limitations, we designed the first prospective multicentre study conducted on a consecutive series of patients undergoing RP using a standardized definition of MetS as the one proposed by ATPIII [5]. We observed that MetS is significantly associated with advanced PCa: patients with MetS presented a 2-fold increased risk of advanced stage and high-grade cancer. Our results are also supported by the retrospective single centre study presented by Kheterpal E et al [32], although data are not comparable since the author defined the presence of MetS using the criteria proposed by the International Diabetes Federation.
The biological mechanisms explaining these findings remain unknown. MetS features are known to accompany a pro-inflammatory state (elevated levels of C-reactive protein, TNF-α, interleukin 8, 6, 1β), which in turn has been related to prostate cancer risk [33][34][35][36]. Moreover, men with MetS are commonly diagnosed with hyperinsulinemia that has been associated with increased risk of PCa death. Finally, elevated circulating levels of IGF-1, leptin and adiponectin, commonly encountered in MetS patients, have all been associated with prostate cancer risk. However, current knowledge probably represents a minimal part of the biological mechanisms behind these associations and forthcoming studies are awaited [6].
We must acknowledge some limitations of our study. This is a multicentre study of patients with prostate cancer undergoing radical retropubic prostatectomy with a limited population of Caucasian men with no Africans or Hispanics; so far, our results cannot be extended to all patients with prostate cancer. Furthermore, a comprehensive evaluation of the association between MetS and PCa should include data on the different therapeutic options available for the management of T1-T3 PCa patients. However, although a trial investigating the impact of MetS in patients treated with External Beam Radio Therapy is ongoing in one of our centres and data will be soon available, the current study did not evaluate other possible treatment options. Considering the conflicting results reported by different authors when investigating the association between MetS and PCa in non-European populations, confirmatory findings from multicentre studies based on larger cohorts of patients of different ethnicities, receiving different treatment, are warranted.
Another limitation derives from the lack of information in the current study regarding physical activity or diet, which are associated with MetS, risk of PCa and potentially cancer grade at diagnosis [6]. Finally the lack of long-term oncologic outcomes, including at least biochemical recurrence free and metastasis free survivals does not allow supporting MetS as an independent predictor of poor oncologic outcomes. However this study is ongoing and results will be available in the near future.
Notwithstanding all these limitations, our study is the first prospective study evaluating patients treated with RP using the ATPIII criteria to define the presence of MetS. Our results, if confirmed, could open new issues in the management of patients with PCa and MetS as well as new studies investigating the role of physical activity, diet and medical treatment for MetS on PCa development and progression.

Conclusions
In our multi centre study, we firstly observed that MetS is associated with an increased risk of high-grade pathological Gleason score and advanced pathological stage in patients with PCa treated with RP. Even though the molecular pathways are yet to be understood, it is assumable that metabolic factors should be considered as possible drivers of PCa differentiation and progression.