Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis.
Patients and Methods
Using the complementary DNA–mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases.
We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006).
Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.
Although dietary fat has been associated with prostate cancer risk, the association between specific fatty acids and prostate cancer survival remains unclear. Dietary intake of 14 fatty acids was analyzed in a population-based cohort of 525 Swedish men with prostate cancer in Örebro County (1989–1994). Multivariable hazard ratios and 95% confidence intervals for time to prostate cancer death by quartile and per standard deviation increase in intake were estimated by Cox proportional hazards regression. Additional models examined the association by stage at diagnosis (localized: T0-T2/M0; advanced: T0-T4/M1, T3-T4/M0). Among all men, those with the highest omega-3 docosahexaenoic acid and total marine fatty acid intakes were 40% less likely to die from prostate cancer (Ptrend = 0.05 and 0.04, respectively). Among men with localized prostate cancer, hazard ratios of 2.07 (95% confidence interval: 0.93, 4.59; Ptrend = 0.03) for elevated total fat, 2.39 (95% confidence interval: 1.06, 5.38) for saturated myristic acid, and 2.88 (95% confidence interval: 1.24, 6.67) for shorter chain (C4-C10) fatty acid intakes demonstrated increased risk for disease-specific mortality for the highest quartile compared with the lowest quartile. This study suggests that high intake of total fat and certain saturated fatty acids may worsen prostate cancer survival, particularly among men with localized disease. In contrast, high marine omega-3 fatty acid intake may improve disease-specific survival for all men.
fatty acids; prostatic neoplasms; survival analysis
Anti-adhesion mucins have proven to play an important part in the biology of several types of cancer. Therefore, we test the hypothesis that altered expression of MUC-1 is associated with prostate cancer progression. We retrieved archival tumour tissue from a population-based cohort of 195 men with localised prostate cancer (T1a-b, Nx, M0) that has been followed for up to 20 years with watchful waiting. Semi-automated, quantitative immunohistochemistry was undertaken to evaluate MUC-1 expression. We modelled prostate cancer-specific death as a function of MUC-1 levels accounting for age, Gleason grade and tumour extent, and calculated age-adjusted and multivariate adjusted hazard ratios (HR). Men that had tumours with an MUC-intensity lower or higher than normal tissue had a higher risk of dying in prostate cancer, independent of tumour extent and Gleason score (HR 5.1 and 4.5, respectively). Adjustment for Gleason grade and tumour stage did not alter the results. Men with a Gleason score ⩾7 and MUC-1 deviating from the normal had a 17 (RR=17.1 95% confidence interval=2.3–128) times higher risk to die in prostate cancer compared with men with Gleason score <7 and normal MUC-1 intensity. In summary, our data show that MUC-1 is an independent prognostic marker for prostate cancer death.
prostate cancer; MUC-1; population-based; prognostic marker; twenty year follow-up; anti-adhesion
To evaluate the relationship between testosterone levels and the development of high-risk prostate cancer, by prospectively examining serum androgen concentrations in a well-studied cohort, as the role of testosterone in prostate cancer progression is debated.
PATIENTS AND METHODS
The study comprised 781 men in the Baltimore Longitudinal Study of Aging who had sex steroid measurements before a diagnosis of prostate cancer, or at their last visit for those without cancer (no cancer, 636; cancer, not high risk, 109; cancer, high risk, 36). High-risk cancer was defined as death from prostate cancer, a prostate specific antigen (PSA) level of ≥20 ng/mL at diagnosis, or a Gleason score of ≥8. The hazard ratio (HR) of high-risk disease was determined using a Cox proportional hazards regression model with simple updating, and risk rates were stratified by age and tercile for androgens of interest based on the proportional hazards analyses.
The likelihood of high-risk prostate cancer doubled per unit (0.1) increase in the free testosterone index (FTI) for patients aged >65 years (HR 2.07, 95% confidence interval, CI, 1.01–4.23; P = 0.047); the likelihood for men aged ≤65 years was inversely related to the FTI (HR 0.96, 95% CI 0.35–2.6; P = 0.9). The risk rate per person-years increased from lowest to highest tercile of FTI for the oldest men (age >70 years) but this trend was not apparent among younger men.
Higher levels of serum free testosterone are associated with an increased risk of aggressive prostate cancer among older men. These data highlight the importance of prospective trials to insure the safety of testosterone-replacement therapy.
prostate cancer; testosterone; high-risk
The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up.
From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided.
During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001).
Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.
The cause of death in prostate cancer patients is examined using the Swedish Family-Cancer Database. Prostate cancer patients were found to have a higher risk for dying from various causes other than prostate cancer, including external causes and heart failure.
A recent rise in the incidence of prostate cancer and a more favorable outcome have increased the proportions of other causes of death in affected men. Extending the survival of prostate cancer patients thus requires knowledge of all causes of death.
Data on the population, cancers, and causes of death were gathered from the nationwide Swedish Family-Cancer Database. A Cox regression model, comparing prostate cancer patients with all other men, was applied. Hazard ratios (HR) were calculated both for the underlying cause and for dying with a specific cause listed among multiple causes of death.
Among 686,500 observed deaths, 62,500 were prostate cancer patients. For underlying causes other than prostate cancer, the highest cause-specific HRs were found for external causes (HR, 1.24; 95% confidence interval [CI], 1.16–1.31), diseases of the pulmonary circulation (HR, 1.22; 95% CI, 1.09–1.37), and heart failure (HR, 1.18; 95% CI, 1.11–1.24). For specific multiple causes, the highest HRs were found for anemia (HR, 2.28; 95% CI, 2.14–2.42), diseases of the pulmonary circulation (HR, 1.61; 95% CI, 1.55–1.68), and urinary system disease (HR, 1.90; 95% CI, 1.84–1.96).
Prostate cancer patients have a higher risk for dying from various causes other than prostate cancer, including external causes and heart failure. Mechanisms have been proposed linking these elevated risks to both cancer and treatment. More attention should be paid to comorbidities in men with prostate cancer. The present study fulfills a gap in the knowledge of death causes in prostate cancer patients.
Prostate cancer; Cause of death; Comorbidity; Regression analysis
Current prostate cancer prognostic models are based on pre-treatment prostate specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models.
We analyzed a Swedish Watchful Waiting cohort with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL) method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP) samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer and men who survived more than 10 years without metastases (lethals and indolents, respectively). Several statistical and machine learning models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases.
Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors.
The determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses making the development of molecular biomarkers for prostate cancer progression challenging.
Prostate specific antigen testing is common in the elderly despite evidence that older men without aggressive prostate cancer are unlikely to benefit from diagnosis and treatment. We evaluated the relationship between prostate specific antigen and the risk of aggressive prostate cancer developing in men of various ages.
Materials and Methods
This longitudinal cohort study consisted of 849 men (122 with and 727 without prostate cancer) with serial prostate specific antigen measurements participating in the Baltimore Longitudinal Study of Aging. The primary outcome measure was the proportion of men by prostate specific antigen and age who died of prostate cancer or in whom aggressive prostate cancer developed (death from prostate cancer, a prostate specific antigen 20 ng/ml or greater, or Gleason score 8 or greater).
No participants between 75 and 80 years old with a prostate specific antigen less than 3.0 ng/ml died of prostate cancer. In contrast, men of all ages with a prostate specific antigen of 3.0 ng/ml or greater had a continually increasing probability of death from prostate cancer (Fisher’s exact test p <0.001). The time to death or diagnosis of aggressive prostate cancer after age 75 years was not significantly different between the prostate specific antigen categories of 3 to 3.9 and 4 to 9.9 ng/ml (p = 0.634), whereas the time to death or diagnosis of high risk prostate cancer was significantly longer for the prostate specific antigen category of less than 3 vs 3 ng/ml or greater (p = 0.019).
Men 75 to 80 years old with a prostate specific antigen less than 3 ng/ml are unlikely to die of or experience aggressive prostate cancer during their remaining life, suggesting that prostate specific antigen testing might be safely discontinued for these men.
prostate-specific antigen; early detection of cancer; prostatic neoplasms; aged
A diagnosis of prostate cancer may distract attention from routine prevention and treatment of other diseases in older men. We assessed survival and cause of death in men aged 65 and older diagnosed with prostate cancer, and in a non-cancer control population.
Retrospective cohort from population-based tumor registry linked to Medicare claims data.
Eleven regions of the Surveillance, Epidemiology and End Results (SEER) Tumor Registry.
208,601 men aged 65–84 diagnosed with prostate cancer from 1988 through 2002 formed the basis for different analytic cohorts.
Survival as a function of stage and tumor grade (low, Gleason grade < 7; moderate, grade = 7; and high, grade = 8–10) compared to men without any cancer, was assessed with Cox proportional hazards regression. Cause of death by stage and tumor grade were compared using chi square statistics.
Men with early stage prostate cancer and with low to moderate grade tumors (59.1% of the entire sample) experienced a survival not substantially worse than men without prostate cancer. In those men, cardiovascular disease and other cancers were the leading causes of death.
The excellent survival of older men with early stage, low to moderate grade prostate cancer, along with the patterns of causes of death, implies that this population would be well served by an ongoing focus on screening and prevention of cardiovascular disease and other cancers.
Prostate Cancer; Mortality; Survival and comorbidities
Whether milk and dairy intake after a prostate cancer diagnosis is associated with a poorer prognosis is unknown. We investigated post-diagnostic milk and dairy intake in relation to risk of lethal prostate cancer (metastases and prostate cancer death) among participants in the Health Professionals Follow-Up Study.
The cohort consisted of 3,918 men diagnosed with apparently localized prostate cancer between 1986 and 2006, and followed to 2008. Data on milk and dairy intake were available from repeated questionnaires. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) of the association between post-diagnostic milk and dairy intake and prostate cancer outcomes.
We ascertained 229 prostate cancer deaths and an additional 69 metastases during follow-up. In multivariate analysis, total milk and dairy intakes after diagnosis were not associated with a greater risk of lethal prostate cancer. Men with the highest versus lowest intake of whole milk were at an increased risk of progression (HR 2.15; 95% CI: 1.28-3.60; P trend<0.01). Men in the highest versus lowest quintile of low-fat dairy intake were at a decreased risk of progression (HR 0.62; 95% CI: 0.40-0.95; P trend=0.07).
With the exception of whole milk, our results suggest that milk and dairy intake after a prostate cancer diagnosis is not associated with an increased risk of lethal prostate cancer.
This is the first larger prospective study investigating the relation between post-diagnostic milk and dairy intake and risk of lethal prostate cancer.
Fusion of the TMPRSS2 prostate-specific gene with the ERG transcription factor is a putatively oncogenic gene rearrangement that is commonly found in prostate cancer tissue from men undergoing prostatectomy. However, the prevalence of the fusion was less common in TURP samples from a Swedish cohort of incidental prostate cancer patients followed by watchful waiting, raising the question as to whether the high prevalence in prostatectomy specimens reflects selection bias. We sought to determine the prevalence of TMPRSS2-ERG gene fusion among PSA-screened men undergoing prostate biopsy in the United States.
We studied 140 prostate biopsies from the same number of patients for TMPRSS2-ERG fusion status with a FISH assay. 134 (100 cancer and 34 benign) were assessable.
ERG gene rearrangement was detected in 46% prostate biopsies that were found to have prostate cancer and in 0% of benign prostate biopsies (p<0.0001). Evaluation of morphological features showed that cribriform growth, blue-tinged mucin, macronucleoli and collagenous micronodules were significantly more frequent in TMPRSS2-ERG fusion positive prostate cancer biopsies than gene fusion negative prostate cancer biopsies (p≤0.04). No significant association with Gleason score was detected. In addition, non-Caucasian patients were less likely to have positive fusion status (p=0.02).
This is the first prospective North American multi-center study to characterize the TMPRSS2-ERG prostate cancer prevalence in a cohort of patients undergoing needle biopsy irrespective of whether or not they subsequently undergo prostatectomy. Our results show that this gene rearrangement is common among North American men who have prostate cancer on biopsy, is absent in benign prostate biopsy, and is associated with specific morphological features. These findings indicate a need for prospective studies to evaluate the relationship of TMPRSS2-ERG rearrangement with clinical course of screening-detected prostate cancer in North American men, and development of non-invasive screening tests to detect TMPRSS2-ERG rearrangement.
In the Scandinavian Prostate Cancer Group Trial Number 4 (SPCG-4), 347 men were randomly assigned to radical prostatectomy and 348 to watchful waiting. In the most recent analysis (median follow-up time = 12.8 years), the cumulative mortality curves had been stable over the follow-up. At 15 years, the absolute risk reduction of dying from prostate cancer was 6.1% following randomization to radical prostatectomy, compared with watchful waiting. Hence, 17 need to be randomized to operation to avert one death. Data on self-reported symptoms, stress from symptoms, and quality of life were collected at 4 and 12.2 years of median follow-up. These questionnaire studies show an intricate pattern of symptoms evolving after surgery, hormonal treatments, signs of tumor progression, and also from natural aging. This article discusses some of the main findings of the SPCG-4 study.
To determine whether the number of times the prostate-specific antigen (PSA) velocity (PSAV) exceeds a threshold (PSAV risk count) is predictive of high-risk prostate cancer.
The PSAV was determined in 717 men (606 without prostate cancer; 32 with high-risk prostate cancer defined as death from cancer, PSA level of 20 ng/mL or more, or a Gleason score of 8 or more; and 79 with prostate cancer who were alive or dead of another cause). Multiple PSAVs determined from three repeated measures from each subject during 10 to 20 years were used to determine the risk count by summing the number of times a subject exceeded a PSAV threshold. Cox proportional hazards regression analysis was used to evaluate the associations between the risk count and the probability of high-risk disease. The statistical tests were two-sided.
The probability of high-risk disease increased directly with the risk count. After adjusting for age, PSA level, PSAV, and date of diagnosis, the PSAV risk count was significantly associated with the development of high-risk prostate cancer (relative risk 1.41, 95% confidence interval 1.25 to 1.59 for a PSAV cutpoint 0.2 ng/mL/yr; relative risk 1.49, 95% confidence interval 1.29 to 1.71 for a PSAV cutpoint of 0.4 ng/mL/yr; P <0.001).
The PSAV risk count could be a useful method of interpreting a PSA history to help identify those men who will benefit from a diagnosis of prostate cancer at PSA levels associated with curable disease.
High cholesterol may be a modifiable risk factor for prostate cancer but results have been inconsistent and subject to potential "reverse causality" where undetected disease modifies cholesterol prior to diagnosis.
We conducted a prospective cohort study of 12,926 men who were enrolled in the Midspan studies between 1970 and 1976 and followed up to 31st December 2007. We used Cox-Proportional Hazards Models to evaluate the association between baseline plasma cholesterol and Gleason grade-specific prostate cancer incidence. We excluded cancers detected within at least 5 years of cholesterol assay.
650 men developed prostate cancer in up to 37 years' follow-up. Baseline plasma cholesterol was positively associated with hazard of high grade (Gleason score≥8) prostate cancer incidence (n = 119). The association was greatest among men in the 2nd highest quintile for cholesterol, 6.1 to < 6.69 mmol/l, Hazard Ratio 2.28, 95% CI 1.27 to 4.10, compared with the baseline of < 5.05 mmol/l. This association remained significant after adjustment for body mass index, smoking and socioeconomic status.
Men with higher cholesterol are at greater risk of developing high-grade prostate cancer but not overall risk of prostate cancer. Interventions to minimise metabolic risk factors may have a role in reducing incidence of aggressive prostate cancer.
Cholesterol; Prostate cancer; Incidence; Gleason grade
The majority of prostate cancers harbor gene fusions of the 5′-untranslated region of the androgen-regulated transmembrane protease, serine 2 (TMPRSS2) promoter with erythroblast transformation specific (ETS) transcription factor family members. The common v-ets erythroblastosis virus E26 oncogene homolog [avian] (TMPRSS2–ERG) fusion is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion.
We used cDNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987–1999) and the US-based Physicians Health Study cohort (1983–2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor–negative (NCI-H660) and –positive (VCaP-ERβ) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided.
We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P<.001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERβ agonist (ERβ agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERα agonist treatment (ERα agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERβ agonist treatment (fold change over internal control, ERβ agonist vs vehicle at 24 hours, NCI H660, mean = 0.57-fold vs 1.0-fold, difference = 0.43, 95% CI = 0.29-fold to 0.57-fold) and increased after ERα agonist treatment (ERα agonist vs vehicle at 24 hours, mean = 5.63-fold vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34-fold to 4.92-fold).
TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.
OBJECTIVES: The incidence of prostate cancer is increasing, as is the number of diagnostic and therapeutic interventions to manage this disease. We developed a Markov state-transition model--the Montreal Prostate Cancer Model--for improved forecasting of the health care requirements and outcomes associated with prostate cancer. We then validated the model by comparing its forecasted outcomes with published observations for various cohorts of men. METHODS: We combined aggregate data on the age-specific incidence of prostate cancer, the distribution of diagnosed tumours according to patient age, clinical stage and tumour grade, initial treatment, treatment complications, and progression rates to metastatic disease and death. Five treatments were considered: prostatectomy, radiation therapy, hormonal therapies, combination therapies and watchful waiting. The resulting model was used to calculate age-, stage-, grade- and treatment-specific clinical outcomes such as expected age at prostate cancer diagnosis and death, and metastasis-free, disease-specific and overall survival. RESULTS: We compared the model's forecasts with available cohort data from the Surveillance, Epidemiology and End Results (SEER) Program, based on over 59,000 cases of localized prostate cancer. Among the SEER cases, the 10-year disease-specific survival rates following prostatectomy for tumour grades 1, 2 and 3 were 98%, 91% and 76% respectively, as compared with the model's estimates of 96%, 92% and 84%. We also compared the model's forecasts with the grade-specific survival among patients from the Connecticut Tumor Registry (CTR). The 10-year disease-specific survival among the CTR cases for grades 1, 2 and 3 were 91%, 76% and 54%, as compared with the model's estimates of 91%, 73% and 37%. INTERPRETATION: The Montreal Prostate Cancer Model can be used to support health policy decision-making for the management of prostate cancer. The model can also be used to forecast clinical outcomes for individual men who have prostate cancer or are at risk of the disease.
Greater exposure to retinol (vitamin A) may prevent prostate cancer, although under some conditions it could promote cell growth and de-differentiation. The authors prospectively examined prostate cancer risk and serum retinol levels, measured by using high-performance liquid chromatography, at baseline (n = 29,104) and after 3 years (n = 22,843) in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Cox proportional hazards models were used to estimate the relative risk of total (n = 2,041) and aggressive (n = 461) prostate cancer by quintiles of baseline and 3-year serum retinol concentrations and by change in serum retinol levels from baseline to 3 years. Men with higher retinol concentrations at baseline were more likely to develop prostate cancer (quintile 5 vs. quintile 1 hazard ratio = 1.19, 95% confidence interval: 1.03, 1.36; Ptrend = 0.009). The results were similar for aggressive disease. Joint categorization based on baseline and 3-year retinol levels showed that men who were in the highest quintile at both time points had the greatest increased risk (baseline/3-year quintile 5/quintile 5 vs. quintile 1/quintile 1 hazard ratio = 1.31, 95% confidence interval: 1.08, 1.59). In this largest study to date of vitamin A status and subsequent risk of prostate cancer, higher serum retinol was associated with elevated risk, with sustained high exposure conferring the greatest risk. Future studies may clarify the underlying biologic mechanisms of the retinol-prostate cancer association.
cohort studies; prospective studies; prostatic neoplasms; vitamin A
Recent studies suggest variation in genes along the vitamin D pathway, as well as vitamin D receptor (VDR) protein levels, may be associated with prostate cancer. As serum vitamin D levels vary by season, we sought to determine whether expression of genes on the vitamin D pathway, assessed in prostate tumor tissue, do the same.
Our study incorporates mRNA expression data from 362 men in the Swedish Watchful Waiting cohort, diagnosed between 1977 and 1999, and 106 men enrolled in the US Physicians’ Health Study (PHS) diagnosed between 1983 and 2004. We also assayed for VDR protein expression among 832 men in the PHS and Health Professionals Follow-up Study cohorts. Season was characterized by date of initial tissue specimen collection categorically and by average monthly ultraviolet radiation levels. One-way analysis of variance was used to examine variation in expression levels of six genes on the vitamin D pathway – VDR, GC, CYP27A1, CYP27B1, RXRα, CYP24A1 – and VDR protein by season, adjusted for age at diagnosis and Gleason grade. Variation was also examined separately among lethal and nonlethal cases.
Tumor expression levels of the six genes did not significantly vary by season of tissue collection. No consistent patterns emerged from subgroup analyses by lethal versus nonlethal cases.
Unlike circulating levels of 25-OH vitamin D, expression levels of genes on the vitamin D pathway and VDR protein did not vary overall by season of tissue collection. Epidemiological analyses of vitamin D gene expression may not be biased by seasonality.
Vitamin D; Vitamin D receptor; prostate cancer; gene expression; seasonality; biomarkers
Reports on biochemical recurrence after prostate cancer (PCa) primary therapy have shown differences between Gleason 4+3 and 3+4 tumors. These findings have not been explored for PCa-specific mortality (PCSM). In this population-based cohort, we determine PCa outcomes at different Gleason scores, in particular the different Gleason 7 patterns.
Men aged 40–64 diagnosed with PCa between 1993–1996 in King County, Washington comprised the cohort. Recurrence/progression was determined by follow-up survey and medical records review. Mortality and cause of death were obtained from the SEER registry. Outcomes were determined with Cox proportional hazards regression analysis.
Of 753 men with PCa, 65 PCa-specific deaths occurred during a median follow-up of 13.2 years. The 10-year PCa-specific survival rates for Gleason ≤6, 3+4, 4+3, and 8–10 were 98.4%, 92.1%, 76.5% and 69.9%, respectively. Compared to patients with Gleason 3+4 disease, those with Gleason 4+3 tumors had an increased risk of PCSM in both the unadjusted (HR 2.80, 95%CI 1.26 – 6.18) and multivariate models (HR 2.12, 95% CI 0.87–5.17, p=0.1). In men undergoing curative therapy with radical prostatectomy or radiation therapy, there was an increased risk of recurrence/progression (HR 2.1, 95% CI 1.1–4.0) and PCSM (HR 3.2, 95% CI 1.0–9.7) in those with Gleason 4+3 compared to 3+4 tumors in the multivariate models. No difference in PCSM was seen between Gleason 4+3 and 8 – 10 tumors.
Gleason 7 PCa tumors exhibit a heterogeneous behavior with Gleason 3+4 and 4+3 tumors conferring different PCSM. These data provide important information for counseling patients with Gleason 7 PCa on the natural history of their disease and may inform treatment decisions.
prostate cancer; Gleason score; survival; population-based; Gleason 4+3
Experimental studies suggest a role for aspirin in the chemoprevention of prostate cancer and epidemiological evidence supports a modest inverse association between regular aspirin use and prostate cancer risk, especially for advanced disease. In a prospective cohort study of 51,529 health professionals aged 40–75 years at baseline, we evaluated long-term aspirin use and the incidence of total, high-grade (Gleason 8–10, n=488), regionally advanced (T3b-T4 or N1, n=228) and lethal prostate cancer (M1, bony metastases or prostate cancer death, n=580) from 1988–2006. We used Cox proportional hazards regression to evaluate risk associated with frequency (days/week), quantity (tablets/week), recency and duration of aspirin use after multivariable adjustment for confounders and other predictors of prostate cancer risk. A total of 4,858 men were diagnosed with prostate cancer during the 18-year study period. Men taking ≥ 2 adult-strength aspirin tablets a week had a 10% lower risk of prostate cancer (p-for-trend=0.02). For regionally advanced cancer, we observed no significant associations with aspirin use. For high-grade and lethal disease, men taking ≥ 6 adult-strength tablets/week experienced similar reductions in risk (HR=0.72 (95% CI: 0.54, 0.96) and HR=0.71 (95% CI: 0.50, 1.00)). Analytical approaches to address bias from more frequent PSA screening among aspirin users did not yield different conclusions. We observed reductions in the risk of high-grade and lethal prostate cancer associated with higher doses of aspirin, but not with greater frequency or duration, in a large, prospective cohort of health professionals. Our data support earlier observations of modest inverse associations with advanced prostate cancer.
Recent genome-wide association studies have been successful in identifying common sequence variants associated with prostate cancer risk; however, their importance in prostate cancer prognosis remains unknown. To assess confirmed prostate cancer susceptibility variants with prostate cancer prognosis, we genotyped 16 established susceptibility variants in a Swedish cohort of 2,875 prostate cancer cases, ascertained between 2001 and 2003, with complete follow-up regarding vital status through January 2008. Cox regression models, adjusted for age, clinical stage, pathologic grade, nodal or distant metastases, and diagnostic serum levels of prostate-specific antigen level, were used to assess association between risk variants and prostate cancer–specific survival. During follow-up, 626 men died, and of those, 440 had prostate cancer classified as their underlying cause of death. We found no association between any of the explored sequence variants and prostate cancer–specific mortality, either in exploring individual variants or in assessing the cumulative effect of all variants. We conclude that hitherto established prostate cancer susceptibility variants are not associated with the lethal potential of prostate cancer.
The Prostate Cancer Prevention Trial has shown a protective effect of finasteride on prostate cancer in low-risk men. It is uncertain whether similar results can be expected when finasteride is used to treat benign prostatic hyperplasia.
We performed an observational cohort study within the Finnish Prostate Cancer Screening Trial. Using a comprehensive prescription database on medication reimbursements during 1995–2004 of men using finasteride or alpha-blockers for benign prostatic hyperplasia, we evaluated prostate cancer incidence among 23 320 men screened during 1996–2004.
Compared to medication non-users, overall prostate cancer incidence was not significantly affected in finasteride users (hazard ratio 0.87; 95% CI 0.63–1.19). Incidence of Gleason 2–6 tumours, however, was decreased among finasteride users (HR 0.59; 95% CI 0.38–0.91), whereas incidence of Gleason 7–10 tumours was unchanged (HR 1.33; 95% CI 0.77–2.30). The protective effect concerned mainly screen-detected tumours. Overall prostate cancer risk was not significantly reduced among alpha-blocker users relative to non-users, but decreased incidence of high-grade tumours was observed (0.55; 95% CI 0.31–0.96).
The detection of low-grade, early-stage tumours is decreased among men who use finasteride for symptomatic BPH. The protective effect of finasteride can also be expected in men with benign prostatic hyperplasia.
alpha-blockers; benign prostatic hyperplasia; finasteride; epidemiology; prostatic neoplasms; screening
Commonly used definitions for high-risk prostate cancer identify men at increased risk of PSA relapse after radical prostatectomy (RP). We assessed how accurately these definitions identify patients likely to receive secondary cancer therapy, experience metastatic progression, or die of prostate cancer.
Materials and methods
Among 5960 men with clinically localized or locally advanced prostate cancer who underwent RP, we identified eight different high-risk subsets, each comprising 4[en]40% of the study population. Estimates of freedom from radiation therapy, hormonal therapy, and metastatic progression after surgery were generated for each high-risk cohort with the Kaplan-Meier method, and hazard ratios (HR) were calculated with a Cox proportional hazards regression. The cumulative incidence and HR for prostate cancer[en]specific mortality (PCSM) were estimated with competing risk analysis.
Each of the studied high-risk criteria was associated with increased hazard of secondary cancer therapy (HR = 1.3[en]5.2, p < 0.05) and metastatic progression (HR = 2.1[en]6.9, p < 0.05). However, depending on the definition, the probability of freedom from additional therapy 10 yr after surgery ranged from 35% to 76%. The 10-yr cumulative incidence of PCSM in high-risk patients ranged from 3% to 11% (HR = 3.2[en]10.4, p < 0.0005).
Commonly used definitions for high-risk prostate cancer identify men at increased risk of secondary cancer therapy, metastatic progression, and PCSM following RP. However, a substantial proportion of high-risk patients remain free from additional therapy or metastatic disease many years after surgery. The risk of PCSM within 10 yr of treatment is remarkably low, even for patients at the highest risk of recurrent disease.
Radical prostatectomy; Risk assessment; Metastatic progression; Radiation therapy; Hormonal therapy; Prostate cancer[en]specific mortality
Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. In the United States, 90% of men with prostate cancer are more than age 60 years, diagnosed by early detection with the prostate-specific antigen (PSA) blood test, and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting (WW), surgery to remove the prostate gland (radical prostatectomy), external-beam radiation therapy and interstitial radiation therapy (brachytherapy), and androgen deprivation. Little is known about the relative effectiveness and harms of treatments because of the paucity of randomized controlled trials. The Department of Veterans Affairs/National Cancer Institute/Agency for Healthcare Research and Quality Cooperative Studies Program Study #407:Prostate Cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy with WW in men with clinically localized prostate cancer. We describe the study rationale, design, recruitment methods, and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy vs WW conducted in Scandinavia. We screened 13 022 men with prostate cancer at 52 US medical centers for potential enrollment. From these, 5023 met initial age, comorbidity, and disease eligibility criteria, and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African American. Approximately 85% reported that they were fully active. The median PSA was 7.8ng/mL (mean 10.2ng/mL). In three-fourths of men, the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade, and tumor stage, it was found that approximately 40% had low-risk, 34% had medium-risk, and 21% had high-risk prostate cancer based on local histopathology. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the United States and quite different from men in the Scandinavian trial. PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared with WW for men with predominately PSA-detected clinically localized prostate cancer.
Diabetes is associated with lower risk of prostate cancer. Most men with diabetes are obese, and obesity is associated with greater prostate cancer mortality. Whether diabetes influences outcomes after prostate cancer diagnosis is unknown.
Patients and Methods
We assessed the relationship between prevalent diabetes and mortality using data from Radiation Therapy Oncology Group Protocol 92-02, a large randomized trial of men (N = 1,554) treated with radiation therapy and short-term versus long-term adjuvant goserelin for locally advanced prostate cancer. Regression and proportional hazard models were performed to evaluate relationships between prevalent diabetes and all-cause mortality, prostate cancer mortality, and non–prostate cancer mortality. Covariates included age, race, tumor stage, Gleason score, prostate-specific antigen, weight, and treatment arm.
There were a total of 765 deaths; 210 (27%) were attributed to prostate cancer. In univariate analyses, prevalent diabetes was associated with greater all-cause mortality and non–prostate cancer mortality but not prostate cancer mortality. After controlling for other covariates, prevalent diabetes remained significantly associated with greater all-cause mortality and non–prostate cancer mortality (hazard ratio [HR] = 2.12; 95% CI, 1.69 to 2.66; P < .0001) but not prostate cancer mortality (HR = 0.80; 95% CI, 0.51 to 1.25; P = .34). In contrast, weight was associated with greater prostate cancer mortality (HR = 1.77; 95% CI, 1.22 to 2.55; P = .002) but not all-cause or non–prostate cancer mortality.
Weight but not prevalent diabetes is associated with greater prostate cancer mortality in men receiving combined modality treatment for locally advanced disease. These observations suggest that the association between obesity and greater prostate cancer mortality is mediated by mechanism(s) other than the characteristic metabolic alterations of diabetes.