Diabetes and beta-adrenergic blockage are risk factors for metastatic prostate cancer

Prostate cancer (PCa) is the second most common cancer and third most leading cause of death of men in the western world [1]. Correct risk stratification is crucial for optimal of high-risk patients and avoiding overtreatment in low-risk patients. Risk stratification is based on histologic analysis of invasive prostate biopsies, which are indicated by elevated prostate-specific antigen (PSA) levels or suspicious digital rectal examination (DRE) findings. Several risk classification tools exist for pretherapeutic stratification such as Kattan normograms [2], D’Amico score [3, 4] or CAPRA (Cancer of Prostate Risk Assessment) score [5‐7]. All scores are based primarily on PSA levels (ng/ml), Gleason score, and age (years) and have biochemical recurrence within 5 years after radical prostatectomy as primary endpoint. The mentioned scores stratify patients into low-, intermediate-, and high-risk groups. However, identifying patients with preexisting lymph node metastases (cN1) or non-organ defined tumors (R1) remains difficult, but these parameters significantly determine the therapeutic strategy. Imaging which provide detailed information for cN status and R status, such as magnetic resonance imaging (MRI) or positron emission computer tomography (PET/CT) (e.g., PSMA-PET/CT), cannot be performed in every patient for economic and availability reasons. cN1 status would require extended lymphadenectomy during radical prostatectomy or extended field radiation in primary radiation therapy. Extended staging using MRI is recommended for high-risk patients with PSA > 10 ng/ml or Gleason score ≥ 8–10 [8] only in the European guidelines for prostate cancer. In order to find further risk stratifier, comorbidities have come into the focus with possible implications on cancer genesis, stage, progression, and therapy [9, 10]. Data are still conflicting, and exact mechanism regarding stage and prognosis are not understood. Among the comorbidities, diabetes is one of the better examined and most common diseases with an estimated 269 million people affected worldwide [11]. Interestingly, a reduced risk for developing PCa has been described for diabetes patients [11]; however, little is known about the impact on cancer stage. We have therefore used our electronic patient chart to generate the prostate cancer patients’ comorbidity profile by the self-medication during hospitalization for radical prostatectomy. We assessed the comorbidity profile’s impact on cancer stage at diagnosis represented by R status and pN status as the key determinants of primary and adjuvant therapeutical strategy.

Four hundred fifty-four prostate cancer patients after radical prostatectomy were analyzed in this study. Patients’ median age was 66.0 years (IQR 61.0–70.0) and median iPSA 8.55 ng/ml (IQR 5.67–14.43). 18.5% (85/454), 39.88% (181/454), and 41.41% (188/454) showed CAPRA score 1–2, 3–5 and 6–10, respectively. Histopathology from prostatectomy and lymphadenectomy showed in 11.7% (53/454), 62.33% (283/454), and 25.99% (118/454) Gleason score 6, 7, and 8–10 (Table 1). Rates for pN1 and R1 were 21.37% (97/454) and 29.30% (133/454), respectively (Table 1).

A median of 2 (IQR 1–4) medications from 2 (IQR 1–4) comorbidity level 1 classes were taken per patient. 14.9% (68/454), 54.2% (246/454), 29.7% (135/454), and 1.1% (5/454) of the patients took 0, 1–3, 4–9, and 10–15 medications (Table 5). From clinical parameters such as age (years), PSA (ng/ml), Gleason score, and CAPRA score, we identified CAPRA score and Gleason score as significant risk factors for N1 (OR 3.200, p = 0.001/OR 3.454, p = 0.001) and CAPRA score for R1 (OR 2.916, p = 0.004) (Table 4). Patients with diabetes showed no statistically significant difference in Gleason score (p = 0.499), CAPRA score (p = 0.495), PSA (p = 0.668), and age (p = 0.537) compared to non-diabetic patients.

Patients took 157 different types of medications from 9 major comorbidity classes according to the ATC code level 1 [12] (Table 2). 14.89% (68/454), 54.19% (246/454), 29.74% (135/454), and 1.1% (5/454) took 0, 1–3, 4–9, and greater 10 medications at time of radical prostatectomy. Patients took medication for cardiovascular system (C) 68.28% (310/454), alimentary tract (A) 33.70% (153/454), blood system (B) 27.53% (125/454), genitourinary system (G) 12.78% (58/454), hormonal system (H) 10.35% (47/454), nervous system (N) 8.81% (40/454), respiratory system (R) 3.52% (16/454), sensory system (S) 3.08% (14/454), and immune system (L) 0.66% (3/454) (Table 2).

Analysis of the ATC code on level 2 showed top 10 medications to be renin angiotensin system (C09) 44.49% (202/454), beta-blockers (C07) 32.28% (147(454), antithrombosis (B01) 27.53% (125/454), lipid modifyers (C10) 26.21% (110/454), acid disorders (A02) 23.57% (107/454), calcium channel blockers (C08) 17.18% (78/454), diuretics (C03) 14.32% (65/454), urologicals (G04) 12.78% (58/454), thyroid therapy (H03) 10.13%(46/454), and diabetes (A10) 9.25% (42/454) (Table 3).

Logistic regression analysis on ATC code level 1 did not show significantly increased risk for pN1 or R1 status whereas regression analysis on ATC code level 2 did show significantly increased risk for pN1 in patients with diabetes (OR 2.869, p = 0.004) and beta1 blockers for R1 (OR 1.929, p = 0.020). Subgroup analysis showed significantly increased risk for N1 in patients taking metformin (OR 2.989, p = 0.010) and R1 for patients taking beta1 selective blocker metoprolol (OR 2.400, p = 0.010). The number of medications per patient and the number of medicated organ systems per patient did not show statistically significant risk increase for either N1 or R1 (Table 3).

In this study, we identified diabetes (OR 2.869) and beta-blockage (OR 1.929) as significant risk factors for the existence of lymph metastases (pN1) and non-organ confined (R1) prostate cancer in patients at radical prostatectomy. The comorbidity profile of each patient was defined as the self-medication, which is not associated to hospitalization. More comorbidities might have been present within the cohort, which were missed by this method. However, our methods allow for a detailed analysis of the comorbidities on the organ system level down to single medications utilizing the WHO ATC code. Within the diabetes group, e.g., we identified metformin and in the beta1 selective blockage group metoprolol as single risk factors for pN1 and R1, respectively.

Comorbidities have been associated with tumor genesis and progression, results however remain controversial. Several studies show that the effect can be protective or associated with increased cancer risk in different organs [17]. Especially, diabetes and beta-adrenergic signaling have been associated with carcinogenesis for a long time.

Lipscomb et al. [18] showed that diabetic women (n = 6115) have an increased risk (OR 1.16) for developing lymph node positive breast cancer. Obesity or increased BMI are not associated with increased risk for lymph node metastases [19] in breast cancer. We could not identify a study, which specifically analyzed the association between diabetes and nodal status of prostate cancer in a PubMed search until today.

Several studies describe a medication inferred decreased risk for developing prostate cancer: Margel et al. [20] showed in 12,000 prostate cancer patients that, e.g., metformin users had decreased risk (OR 0.66) for developing prostate cancer. Preston et al. [21] showed in 120,000 diabetic men that metformin was not associated with decreased risk for developing prostate cancer in general or high-grade prostate cancer. A meta-analysis by Bansal et al. [22] concluded from 8.1 million patients including 120,000 prostate cancer patients that diabetes significantly lowers the risk (RR 0.86) for developing prostate cancer. Li et al. [23] report opposite results in a cohort of 22,000 men with increased risk for developing high-grade prostate cancer in men with diabetes.

Despite the high numbers of studies showing a protective effect of diabetes on cancer genesis, little is known about the influence of diabetes in men with prostate cancer. Also, on the mechanistic level, it was shown that diabetes alters the lymphatic vessel architecture and promotes vessel evasion of the tumor cells [24]. Our clinical findings could be explained by the latter results (Table 4). However, further studies have to validate our findings.

Also, beta-adrenergic signaling has been associated with advanced prostate cancer [25] and beta-blockers have been associated reduced mortality in various tumor types [25]. The prostate, especially the peripheral zone where most of the tumors originate, shows high adrenergic innervation [25]. Especially, beta2 receptor subtypes were detected in the peripheral zone. This could explain a possible protective effect by unselective beta-blockage such as carvedilol; however, the effect in our analysis was statistically not significant. The luminal epithelial cells which are suspected as the originating cells for prostate cancer show high expression for beta-adrenergic receptors in the malignant and benign state and thus connect the nervous system to the tumor [26]. Magnon et al. [27] showed that beta-adrenergic and cholinergic nerves play an important role in prostate cancer genesis and progression, by actively infiltrating the tumor. Perineural nerve sheath infiltration by the tumor also serves as an independent negative predictor for disease free survival [28]. Furthermore, beta-blockers were associated, we improved survival in prostate cancer patients [29]. Even though beta-blockers seem to have protective effects on long term survival, the underlying disease with an activated adrenergic system could well explain the increased risk for R1 disease in prostate cancer patients in our cohort. Further studies will have validate our results. Only scarce data is available upon alpha-adrenergic signaling and cancer. Some studies show inhibitory effects on cancer cells by alpha-adrenergic blockage [30‐32].

Limitation of this study is the fact that comorbidities were defined only by self-medication. Additional comorbidities not reflected by the medication were not analyzed. Furthermore, dosage and duration of the medications were not considered.

We were able to show that together with the established stratification markers such as Gleason score or the CAPRA score, medication profiles can further aid in identifying men at high risk for advanced and aggressive prostate cancer (Table 5).

Diabetes and beta-blockage are major risk factors for advanced prostate cancer, which should be incorporated into the pretherapeutic staging strategy and into the planning of definite therapy to allow for optimal results for our patients. The usage of electronic patient charts represent a powerful tool to analyze risk structures within patient cohorts. They could also be used to incorporate medication-based risk factors, which will automatically alert the physicians for high-risk patients.