1 INTRODUCTION

Prostate cancer and hypertension are both common and complex conditions among men world-wide. While prostate cancer is one of the most common cancers in men and its incidence continues to rise, systolic blood pressure (BP) above 115 mmHg is ranked as a leading risk factor for the global burden of disease.1 The global age-standardized prevalence of elevated BP (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) in men was estimated as ≥20% in 2015.2 Of note, high BP may last for several decades ahead of any disease development, reflecting a long-lasting cumulative exposure and exposure time of interest in an ageing-related disease as prostate cancer.

Hypertension has been linked to inflammation, and inflammation is one of the hallmarks of cancer development.3 Inflammatory cells in the prostate microenvironment associated with precursor lesions for prostate cancer in the prostate gland, termed proliferative inflammatory atrophy, have been observed.4 Recently, we observed that systemic prediagnostic inflammatory biomarkers including high sensitive C-reactive protein (hs-CRP) and white blood cells were associated with prostate cancer development, and our results are supported by others linking systemic inflammatory biomarkers to prostate cancer development.5

Results from previous studies of the association between hypertension and prostate cancer development have been inconsistent.6-8 Neither the European Prospective Investigation into Cancer and Nutrition (EPIC) nor a meta-analysis observed any association between hypertension and risk of prostate cancer.7, 8 However, a meta-analysis including case–control and cohort studies support that hypertension may increase prostate cancer risk.6 Moreover, in a longitudinal case–control study, men (aged 40–58 years at study entry) in the highest quartile of systolic BP (>150 mmHg) had an increased prostate cancer risk.9 Hypertension was also associated with increased risk of biochemical recurrence after radical prostatectomy, independent of age at diagnosis and tumor pathological features.10 Whether long-lasting, raised diastolic hypertension influences prostate cancer development and prognosis has not been much studied. Use of antihypertensive medication does not seem to have any effect on cancer risk.11 Thus, the importance of elevated BP may show variation by age at onset of hypertension, exposure time, age when diagnosed with prostate cancer, and aggressiveness of disease.12

Whether long-lasting, modern, prostate cancer treatments interact with systolic and diastolic BP of importance for survival has not been much studied.13 Androgen deprivation therapy (ADT) has a key role in adjuvant prostate cancer treatment combined with radiation therapy, as well as in the lifelong treatment of metastatic prostate cancer.14, 15 However, important side effects from ADT include a higher risk of later cardiovascular disease (CVD).16 Men with prostate cancer, aged ≥40 years, who underwent ADT, were observed to have a higher risk of developing hypertension.17 However, there is a knowledge gap regarding elevated BP before, during, and after prostate cancer treatment. Furthermore, we lack information about the importance of a pre-existing hypertension on the risk for future CVD events after initiating ADT among patients with prostate cancer.

The aim of the present study was, therefore, to study whether prediagnostic systolic and diastolic BP were associated with prostate cancer risk, if prediagnostic systolic and diastolic BP were associated with overall mortality among patients with prostate cancer, and if such associations vary by age and type of prostate cancer treatment.

2 METHOD 2.1 Study design, settings, and participants

The Prostate Cancer Study throughout life (PROCA-life) includes all men older than 25 years at study entry who were enrolled in the population-based Tromsø Study in 1994/1995 (Tromsø 4).18, 19 The procedures and assessments were performed by trained research technicians at one study site. All age-eligible men in the Tromsø municipality were invited to participate with a personal written invitation, and nonresponders were given one reminder. The attendance proportion for men included in the present study was 69.6% of those invited.19

2.2 Questionnaire and assessments of lifestyle factors

The questionnaire was checked for completeness and inconsistency and included questions about medical history, lifestyle factors, and use of medication including antihypertensive drugs. Educational level was categorical (1 = secondary school only, 5 = college/university for 4 or more years). Alcohol use was defined as more than 1 unit of alcohol per month, defined by others in this cohort.20, 21 We defined being physically active as more than 1 h/week of strenuous exercise, or any leisure time exercise more than 2–3 times/week.

2.3 Assessments of systolic and diastolic blood pressure and clinical assessments

Systolic and diastolic BP (mmHg) were measured by using an automatic device (Dinamap Vital Signs Monitor 1846; Critikon Inc.). Participants rested for 2 min in a sitting position, then three readings were taken on the upper right arm, separated by 1-min intervals, and the average of the last two readings was used.22

Height and weight were measured on a regularly calibrated electronic scale with the participants wearing light clothing and no shoes. Height was measured to the nearest centimeter (cm) and weight to the nearest kilogram (kg). Body mass index (BMI) was calculated using the formula weight/height2 (kg/m2).

2.4 Assessment of serum samples

Blood samples (nonfasting) were drawn by trained research assistants on attendance. Analyses of serum samples were done at the Department of Laboratory Medicine, University Hospital of Northern Norway (UNN).18 Prostate-specific antigen (PSA) measurements were done for cancer cases only, as part of clinical routine in diagnosis and follow-up (1990–1994 Stratus® PSA Fluorometric Enzyme Immunoassay, 1994–2001 AxSYM Psa Reagent Pack, Abbot®, 2001 Bayer® PSA Reagens Pack Immuno I [Prod. Nr.T01-3450-51], Technicon Immuno I). For patients with prostate cancer diagnosed or treated in other institutions (n = 21), PSA values from their local laboratories were recorded.

2.5 Identification of patients with prostate cancer during follow-up

Patients with prostate cancer diagnosed during follow-up (until December 31, 2018) were identified by using the unique national 11-digit identification number through linkage with the Cancer Registry of Norway. We excluded all men who had a previous history of cancer (n = 382), or who emigrated, died, or were diagnosed with cancer within the first year after study entry (n = 128), to account for the possibility that undiagnosed cancer or severe illness could influence our results. Participants with missing measurement of BP at study entry were also excluded (n = 24) leaving a final study population of 12,271 men (Figure S1).

A total of 811 men developed prostate cancer during follow-up between 1994 and 2018. There were no ongoing screening programs for prostate cancer in Norway during the study period. Causes of death were identified by linkage to the Norwegian Cause of Death Registry, and dates of emigration were obtained from the Population Registry of Norway.

Detailed information from medical records were obtained by trained physicians (TK, MS, and ES) and included prostate cancer treatments and recurrence. A total of 153 patients with prostate cancer had missing data in treatment details or follow-up but were still included if baseline data; data about diagnosis and data on cause of death were complete (Figure S1).

Histopathological information for the patients with prostate cancer was obtained from histopathological records and were in addition re-examined by the same specialized pathologist (ER) and classified according to the latest International Society of Urological Pathology (ISUP) guidelines on Gleason score and ISUP grade group.23 Patients with prostate cancer were divided into four risk groups based on PSA level at diagnosis, highest ISUP grade group and clinical T-stage, similar to the European Association of Urology-classification (EAU) guidelines.14 Risk group 1 (low) was defined as PSA <10 µg/L, clinical T-stage (cT-) 1, and ISUP grade group 1. Risk group 2 (intermediate) was defined as PSA: 10–20 µg/L, cT-stage 2, or ISUP grade group 2–3. Risk group 3 (high) was defined as PSA: >20–100 µg/L, cT-stage 3, or ISUP grade group 4–5. Risk group 4 (metastatic) was defined as PSA >100 µg/L, or with radiological evidence of metastatic disease. ISUP grade group was reported after reclassification when available. PSA values above 100 were not included in calculation of mean or median PSA.

2.6 Statistical methods

Descriptive characteristics of the study population were presented as means (standard deviation) or percent (numbers). Multivariable Cox proportional hazard models, with follow-up time as timescale, were used to investigate whether prediagnostic systolic or diastolic BP were independently associated with prostate cancer risk and mortality. To study the importance of the variation, prediagnostic systolic and diastolic BP were split in four levels based on international categories: systolic BP (mmHg): <130, 130–139.9, 140–149.9, ≥150 mmHg, diastolic BP (mmHg): <80, 80–89.9, 90–99.9, ≥100 mmHg.

Associations between baseline BP and prostate cancer incidence have been studied in the full cohort (n = 12,271), and associations between baseline BP and overall mortality have been studied in men diagnosed with prostate cancer (the PCa-cohort, n = 811). Follow-up to incidence of prostate cancer was calculated from the date of entry into the study to the date of prostate cancer diagnosis, date of emigration, date of death, or end of follow-up (December 31, 2018), whichever event occurred first. Follow-up to mortality after prostate cancer diagnosis was calculated from the date of prostate cancer diagnosis to date of death, emigration, or end of follow-up (December 31, 2018). Based on biological mechanisms hypothesized and previous observations suggesting that risk factors for prostate cancer may vary by time period during lifetime and by length of exposure,24 separate analyses on prostate cancer incidence were performed in two age groups (age at entry <45 years and age >45 years). Furthermore, to study whether the association between prediagnostic BP and mortality varied by the type of prostate cancer treatment, analyses were performed by type of treatment, curative or endocrine, within the PCa-cohort.

Several variables were assessed as potential confounders based on suggested biological mechanisms influencing systolic and diastolic BP and/or prostate cancer risk and prognosis. Age at entry (continuous), BMI (continuous), alcohol habits (categorical), smoking (categorical), physical activity (categorical), educational level (categorical), and diabetes (yes/no) were included as covariates in the final models. Use of lipid-lowering and/or antihypertensive medication were included but did not influence the results and were excluded in the final models.

Kaplan–Meier survival curves of prostate cancer incidence and of total mortality were presented for the full cohort and for the PCa cohort, respectively. The proportional hazard assumption was verified by assessing the parallelism between log minus log survival curves for categories of BP and also formal tests based on Schoenfeld residuals. All statistical tests were two-sided using a significance level of p < 0.05 and conducted with STATA/MP version 16 (StataCorp LLC).

3 RESULTS

At study entry, the cohort participants had the following means: age at entry 45.6 years (SD 14.2), prediagnostic systolic BP 134.1 mmHg and prediagnostic diastolic BP 77.5 mmHg (Table 1). During follow-up, a total of 811 men developed prostate cancer with a mean age at diagnosis of 69.4 years. A total of 18.0% of the patients with prostate cancer were in the low-risk group, and 21.7% were in the high-risk group at the time of diagnosis. A total of 265 patients with prostate cancer (32.7%) died during 7.1 years of follow-up, of whom 41.9% (n = 111) were classified as prostate cancer death, 12.5% (n = 33) as cardiovascular death and 45.7% (n = 121) other causes of death (Table 1, Table S2).

TABLE 1. Distribution of selected prediagnostic characteristics for men with prostate cancer (cases) and without prostate cancer (non-cases) in the PROCA-life Study (1994–2018) Characteristics Non-cases (n = 11,460) Prostate cancer cases (n = 811) Age at entry (years) 45.6 (14.2) 54.4 (10.8) Observation time (years) 21.0 (6.0) 14.0 (6.1) Clinical variables, mean (SD) Systolic blood pressure (mmHg) 134.1 (16.8) 137.9 (18.9) Diastolic blood pressure (mmHg) 77.5 (11.6) 80.8 (11.7) Body mass index (kg/m2) 25.6 (3.3) 25.9 (3.2) Serum samples at study entry mean (SD) Total cholesterol (mmol/L) 6.02 (1.2) 6.32 (1.2) Hs-CRP (mg/L)a 2.97 (7.4) 2.57 (4.7) White blood cells (×109/L) 7.07 (2.0) 6.98 (1.8) Lifestyle factors (%) Lipid-lowering drugs, current use 1.0 1.4 User of blood pressure–lowering medication 7.2 9.3 Current smokers 36.8 31.0 Physically active 37.6 36.0 Alcohol user 66.5 66.8 Characteristics among patients with prostate cancer Age at diagnosis, mean (SD) (years) 69.4 (9.0) PSA at diagnosis, median (μg/L)b 10.9 Observation time after diagnosis (years) 7.1 Cancer-specific mortality, % of all death (n) 41.9 (111) Cardiovascular death, % of all death (n) 12.5 (33) Other causes, % of all death (n) 45.7 (121) Tumor characteristics T-stage, % (n) T1 42.4 (344) T2 24.4 (198) T3 13.1 (106) T4 3.8 (31) Tx 16.2 (132) ISUP Grade Group, % (n) 1 (Gleason 3+3) 39.1 (317) 2 (Gleason 3+4) 19.5 (158) 3 (Gleason 4+3) 8.5 (69) 4 (Gleason 4+4) 6.9 (56) 5 (Gleason 4+5/5+4/5+5) 7.4 (60) ISUP missing 16.8 (151) Risk group, % (n) Low 18.0 (146) Intermediate 32.9 (267) High 21.7 (176) Metastatic 9.0 (73) Unknown 18.4 (149) Prostate cancer treatment characteristics, % (n) Curative intended treatment 58.7 (476) Endocrine treatment, overall 36.0 (292) Endocrine treatment, curative 19.2 (156) Numbers may vary due to missing information. Values are mean (standard deviation) unless otherwise specified. Prostate cancer risk group definitions: Low: PSA <10 µg/L, clinical T-stage (cT-) 1, and ISUP grade group 1. Intermediate: PSA: 10–20 µg/L, cT-stage 2, or ISUP grade group 2–3. High: PSA: >20–100 µg/L, cT-stage 3, or ISUP grade group 4–5. Metastatic: PSA >100 µg/L, or with radiological evidence of metastatic disease. Abbreviations: Hs-CRP, high-sensitivity C-reactive protein; PSA, prostate-specific antigen; ISUP, International Society of Urological Pathology. 3.1 Prediagnostic systolic and diastolic blood pressure and prostate cancer risk

We observed an increased incidence of prostate cancer among men in the upper level of both systolic and diastolic BP (systolic BP ≥150 mmHg, diastolic BP ≥100 mmHg) in crude data (Figure 1). Among men aged >45 years at study entry, we observed, when adjusted for potential confounding factors, a positive dose–response association between prediagnostic systolic BP and prostate cancer risk (HR 1.07 per SD increase, 95% CI 1.00–1.16). Furthermore, men with a prediagnostic systolic BP >150 mmHg had a 35% increased risk of prostate cancer compared with men with prediagnostic systolic BP <130 mmHg (HR 1.35, 95% CI 1.08 −1.69). We observed an overall positive dose–response relationship between prediagnostic diastolic BP and risk of prostate cancer (HR 1.08 per SD increase, 95% CI 1.01–1.17) (Table 2, Figure 1). Associations between BP and incidence of different risk-groups of prostate cancer has been tested but did not provide statistically significant results.

Kaplan–Meier survival curves of prostate cancer incidence according to prediagnostic systolic (A) and diastolic (B) blood pressure (bp)

TABLE 2. Multivariable adjusted hazard ratios (HRs) for incident prostate cancer according to the levels of prediagnostic systolic and diastolic blood pressure by age-group (≤/>45 years). The PROCA-life study (1994–2018) All age ( patients with prostate cancer n = 811) ≤45 years at baseline (patients with prostate cancer n = 183) >45 years at baseline ( patients with prostate cancer n = 628) HR (95%CI) HR (95%CI) HR (95%CI) Number of cases Multivariablea Number of cases Multivariablea Number of cases Multivariablea Systolic blood pressure (mmHg) <130 296 1.00 (ref.) 95 1.00 (ref.) 201 1.00 (ref.) 130–139.9 221 1.20 (1.01–1.43) 56 1.13 (0.81–1.58) 165 1.28 (1.04–1.58) 140–149.9 121 0.99 (0.80–1.23) 23 1.03 (0.65–1.64) 98 1.08 (0.84–1.38) ≥150 173 1.13 (0.92–1.39) 9 0.87 (0.43–1.74) 164 1.35 (1.08–1.69) p for trendb 0.41 0.967 0.025 Per SD increase 1.00 (0.93–1.08) 0.94 (0.76–1.16) 1.07 (1.00–1.16) Diastolic blood pressure (mmHg) <80 404 1.00 (ref.) 132 1.00 (ref.) 272 1.00 (ref.) 80–89.9 227 0.99 (0.83–1.16) 37 0.80 (0.55–1.15) 190 0.93 (0.77–1.13) 90–99.9 132 1.25 (1.02–1.54) 11 0.79 (0.42–1.49) 121 1.20 (0.96–1.50) ≥100 48 1.20 (0.88–1.64) 3 0.76 (0.24–2.40) 45 1.15 (0.83–1.59) p for trendb 0.056 0.223 0.165 Per SD increase 1.08 (1.01–1.17) 0.88 (0.74–1.06) 1.05 (0.97–1.15) Statistically significant (p-value < 0.05) hazard ratios are marked in bold letters. p-value for linear trend in blood pressure categories are marked in italic letters. 3.2 Prediagnostic systolic and diastolic blood pressure and survival

After 7.1 years of follow-up after being diagnosed with prostate cancer, there was among patients with prostate cancer a positive dose–response association between prediagnostic systolic BP and overall mortality (HR 1.14 per SD increase, 95% CI 1.03–1.27) and prediagnostic diastolic BP and overall mortality (HR 1.17 per SD increase, 95% CI 1.03–1.32). Patients with prostate cancer with a prediagnostic diastolic BP ≥100 mmHg, had an 85% increased overall mortality compared with patients with prostate cancer with diastolic BP <80 mmHg (HR 1.85, 95% CI 1.22–2.82). Patients with prostate cancer treated with curative intention and with a high prediagnostic diastolic BP (≥100 mmHg) had a threefold higher overall mortality risk compared with the patients with prostate cancer with a prediagnostic diastolic BP <80 mmHg (HR 3.05, 95% CI 1.42–6.55). Among patients with prostate cancer receiving endocrine treatment, those with a high prediagnostic diastolic BP (≥100 mmHg) at study entry had a twofold increase in overall mortality risk compared with those with a prediagnostic diastolic BP <80 mmHg (HR 2.15, 95% CI 1.25–3.69) (Table 3).

TABLE 3. Multivariable adjusted hazard ratios (HRs) for all-cause mortality according to prediagnostic systolic and diastolic blood pressure among patients with prostate cancer by the type of treatment (curative and endocrine prostate cancer treatment). The PROCA-life study (1994–2018) All prostate cancer Curative treatment Endocrine treatment Number of deaths/cases 265/798 Number of deaths/cases 86/476 Number of deaths/cases 168/292 HR (95% CI) HR (95% CI) HR (95% CI) Systolic blood pressure (mmHg) <130 67/296 1.00 (reference) 22/196 1.00 (reference) 44/94 1.00 (reference) 130–139.9 60/221 1.08 (0.75–1.55) 21/112 1.11 (0.59–2.08) 40/72 0.87 (0.55–1.36) 140–149.9 46/121 0.97 (0.65–1.47) 17/70 1.58 (0.81–3.10) 30/48 0.91 (0.55–1.51) ≥150 92/173 1.35 (0.96–1.90) 26/82 1.83 (0.99–3.40) 54/78 1.11 (0.73–1.71) p for trendb 0.091 0.029 0.51 Per SD increase 1.14 (1.03–1.27) 1.26 (1.03–1.55) 1.14 (0.99–1.31) Diastolic blood pressure (mmHg) <80 110/404 1.00 (reference) 32/238 1.00 (reference) 74/125 1.00 (reference) 80–89.9 75/227 1.08 (0.80–1.45) 24/134 1.10 (0.64–1.88) 48/94 0.98 (0.67–1.42) 90–99.9 50/132 1.24 (0.87–1.75) 20/80 1.75 (0.97–3.14) 26/49 0.91 (0.57–1.45) ≥100 30/48 1.85 (1.22–2.82) 10/24 3.05 (1.42–6.55) 20/24 2.15 (1.25–3.69) p for trendb 0.009 0.004 0.13 Per SD increase 1.17 (1.03–1.32) 1.43 (1.17–1.75) 1.12 (0.97–1.30) Statistically significant (p-value < 0.05) hazard ratios are marked in bold letters. p-value for linear trend in blood pressure categories are marked in italic letters.

After 10 years of follow-up, we observed that among patients with prostate cancer, 49% of those with a prediagnostic systolic BP ≥150 mmHg were alive, compared with 66% of patients with prostate cancer with a normal prediagnostic systolic BP (<130 mmHg). Among those with a prediagnosti