Prostate Cancer Progression In Men Research Articles

The Impact of Physical Activity on the Outcomes of Active Surveillance in Prostate Cancer Patients: A Scoping Review

Introduction: Active surveillance has emerged as a valid therapeutic option in patients with low-risk prostate cancer, allowing for the deferral of definitive treatment until the time of possible disease progression. Although it is known that physical activity plays a protective role in the onset and progression of this tumor, its impact on patients with low-risk disease who are managed with active surveillance remains unclear. Our scoping review aims to summarize the existing evidence on this subject. Evidence Acquisition: On 9 April 2023, a systematic search was conducted using the PubMed and Scopus databases. The search employed the combination of the following terms: (“prostate cancer” OR “prostate tumor”) AND (“active surveillance”) AND (“physical activity” OR “physical exercise” OR “physical intensive activity” OR “intensive exercise”) AND (“lifestyle”). Out of the 506 identified articles, 9 were used for the present scoping review, and their results were reported according to the PRISMA-ScR statement. Evidence Synthesis: We discovered a lack of uniformity in the assessment of PA and its stratification by intensity. There was no consensus regarding what constitutes cancer progression in patients choosing expectant management. In terms of the impact of PA on AS outcomes, conflicting results were reported: some authors found no correlation, while others (six of total studies included) revealed that active men experience smaller increases in PSA levels compared to their sedentary counterparts. Additionally, higher levels of exercise were associated with a significantly reduced risk of PCa reclassification. Conclusion: Due to the heterogeneity of the methodologies used in the available studies and the conflicting results reported, it is not possible to draw definitive conclusions concerning the role physical activity may play in the risk of prostate cancer progression in men managed with active surveillance.

Abstract 5261: Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression

Abstract Prostate cancer is the most common cancer in men. Commensurate with risk, current approaches to localized prostate cancer include prostatectomy, prostate radiation with or without radiation therapy or active surveillance. Recent data suggest that systemic anti-androgen therapy with enzalutamide reduced the risk of prostate cancer progression in men on active surveillance but was associated with considerable side effects. We developed a novel polymer-based drug delivery method to provide sustained localized drug administration of anti-androgens selectively to the prostate. In vitro and in vivo mouse and canine studies show that this drug eluting implant delivers sustained high prostate to plasma therapeutic anti-androgen levels for an anticipated range of 2 years while preventing accumulation of anti-androgens in the liver, lungs, heart and brain. We performed a proof of concept study in a canine prostate model implanting an 15mm x 1mm bicalutamide eluting implant into each lobe of the prostate. Bicalutamide levels in the prostate measured near the implant at 6 months were 3250 ± 1622 ng/g, n = 3 compared to 3809 ± 638 ng/g, n = 3 to those achieved at steady-state oral administration. Plasma and other off target levels were over 1000-fold lower in the implant cohort compared to oral administration: Plasma: 5.9 ± 0.2 ng/ml, liver: 11.3 ±4.3 ng/g, and brain: 5.4 ±0.8 ng/g versus plasma: 18170 ± 3820 ng/ml, liver: 35407 ±8510 ng/g, and brain: 8870 ±1797 ng/g. The implants were well tolerated without local toxicity and imaged easily with ultrasound. The design characteristics of the implant facilitates minimally invasive surgical implantation under standard image guidance and withstands the concomitant use of prostate radiation. This novel technology warrants future clinical exploration of prostate specific anti-androgen therapy for (neo)adjuvant therapy or in active surveillance. Tissue Bicalutamide oral (2m)(ng/g) Bicalutamide implant (6m)(ng/g) Plasma 18,170 (3820) 5.9 (0.2) Prostate 3,809 (638) 3,250 (1622) Liver 35,407 (8510) 11.3 (4.3) Cerebrum 8,870 (1797) 5.4 (0.8) Cerebellum 8,737 (1550) 6.2 (1.3) Spleen 7,727 (1288) 4.2 (0.9) Lung 27,013 (2896) 11.3 (4.3) Heart 11,737 (3491) 10.0 (1.9) Kidneys 17,413 (6581) 8.5 (2.0) Citation Format: Pujan Desai, Maithili Rairkar, Nela Pawlowska, Scott Thomas, Pamela N. Munster. Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5261.

Evidence on Statins, Omega-3, and Prostate Cancer: A Narrative Review.

Dietary intake selections might play a crucial role in prostate cancer (PCa) occurrence and progression. Several studies have investigated whether statin use could reduce PCa risk but with conflicting results. Nevertheless, a significantly decreased incidence of advanced PCa has been consistently noted. Statins may also reduce the risk of biochemical recurrence (BCR) in men with PCa after receiving active treatment. However, the influence of statin usage on BCR and PCa progression in men with high prostate-specific antigen levels has been found to be insignificant. In contrast, the combined use of a statin and metformin was significantly related to the survival status of PCa patients. However, some studies have revealed that the intake of long-chain omega-3 fatty acid (ω-3) from fish or fish oil supplements may elevate PCa risk. Several meta-analyses on ω-3 consumption and PCa have shown controversial results for the relationship between PCa and ω-3 consumption. However, studies with positive results for various genotypes, fatty acid intake or levels, and PCA risk are emerging. This review highlights the association among statins, ω-3, and PCa. The findings summarized here may be helpful for clinicians counseling patients related to PCa.

Testosterone Therapy in Men with Biochemical Recurrence and Metastatic Prostate Cancer: Initial Observations

Introduction: Although prostate cancer (PCa) has long been considered an absolute contraindication for testosterone therapy (TTh), growing literature suggests TTh may be safely offered to men with localized PCa. We here present a single-center series of men treated with TTh for relief of symptoms, despite having more advanced disease, namely biochemical recurrence (BCR) or metastatic PCa (MET). Methods: We identified men treated with TTh with BCR, MET, or adjuvant androgen deprivation therapy (ADT). Consent included risks of rapid PCa progression and death. Laboratory and clinical results were analyzed. Results: Twenty-two men received TTh: 7 with BCR, 13 with MET, and 2 with adjuvant ADT. Median age was 70.5 years (range 58–94). Median TTh duration was 12 months (range 2–84) overall, including 20 months for BCR and 9.5 months for MET. Mean serum testosterone (T) increased from 210 to 1111 ng/dL. Median PSA (interquartile range) increased from 3.1 ng/mL (0.2–4.5) to 13.3 ng/mL (3.4–22) in the BCR group, 6.3 ng/mL (1.2–31) to 17.8 ng/mL (6.2–80.1) in the MET group, and <0.1 to 0.3 ng/mL in the ADT group. All patients reported symptom relief, especially improved vigor and well-being. Overall mortality was 13.6% and PCa-specific mortality was 4.5% during the period of TTh and 6 months after discontinuation. Seven of 10 with follow-up imaging within 12 months showed no progression. Five men have died: three during TTh and two succumbed at 2 years or longer after discontinuing TTh. One of the three deaths during TTh was PCa-specific. Three men developed significant bone pain at 7–41 months; two discontinued TTh and one continued, after focal radiation. There were no cases of rapid-onset complications, vertebral collapse, or pathological fracture. Conclusions: These initial observations indicate TTh was not associated with precipitous progression of PCa in men with BCR and MET, suggesting a possible role for TTh in selected men with advanced PCa whose desire for improved quality of life is paramount.

A phase II randomized controlled trial of exercise on biochemical progression in men with prostate cancer on active surveillance.

5080 Background: Men with prostate cancer (PCa) undergoing active surveillance (AS) are at increased risks of cardiovascular death and disease progression. Any intervention that can address these issues during AS would be highly beneficial. Clinical and preclinical studies have demonstrated the benefits of exercise to improve cardiovascular health in cancer patients and suggested the potential role of exercise in suppressing PCa progression in men with PCa undergoing AS. Therefore, the purpose of this study was to investigate the effects of exercise on cardiorespiratory fitness and biochemical progress of PCa in men with PCa on AS. Methods: The Exercise During Active Surveillance for Prostate Cancer (ERASE) Trial was a single-centre, two-armed, randomized controlled trial in Edmonton, Canada. 52 men with localized PCa who were undergoing AS were randomized to high-intensity interval training (HIIT; n = 26) or usual care (UC; n = 26). The HIIT group performed thrice-weekly, supervised, aerobic HIIT on a treadmill at 85-95% of peak cardiorespiratory fitness (VO2peak) for 12 weeks. The primary outcome was VO2peak, and the secondary and exploratory outcomes included biochemical progression of PCa (prostate-specific antigen [PSA]), PSA kinetics, and growth of prostate cancer cell line LNCaP. Results: 46/52 participants (88%) completed the postintervention VO2peak assessment and adherence to HIIT was 96%. Compared to UC, HIIT significantly improved VO2peak (adjusted between-group mean difference, 1.6 ml·kg-1·min-1; 95% confidence interval [CI], 0.3 to 2.9; p= 0.014). HIIT also significantly reduced PSA level (adjusted between-group mean difference, -1.1 ug/L; 95% CI, -2.1 to 0.0; p= 0.043) and PSA velocity ( p= 0.040), and suppressed LNCaP cell growth ( p =0.024). No significant differences were found in PSA doubling time ( p= 0.10) and testosterone ( p= 0.24). Conclusions: The ERASE Trial is the first randomized controlled trial to demonstrate the impact of HIIT exercise for improving physical fitness and inhibiting biochemical progression of PCa in men with localized PCa on AS. Our findings suggest that supervised aerobic HIIT may be a promising intervention in this clinical setting. Larger-scale randomized controlled trials are warranted to determine if improvements in physical fitness and PCa-related markers translate into improved long-term clinical outcomes in these men such as disease progression, receipt of radical treatments, posttreatment complications, and survival. Clinical trial information: NCT03203460.

Long-term use of 5-alpha-reductase inhibitors is safe and effective in men on active surveillance for prostate cancer.

Although 5-alpha-reductase inhibitors (5ARIs) have been shown to benefit men with prostate cancer (PCa) on active surveillance (AS), their long-term safety remains controversial. Our objective is to describe the long-term association of 5ARI use with PCa progression in men on AS. The cohort of men with low-risk PCa was derived from a prospectively maintained AS database at the Princess Margaret (1995-2016). Pathologic, grade, and volume progression were the primary end points. Kaplan-Meier time-to-event analysis was performed and Cox proportional hazards regression was used to determine predictors of progression where 5ARI exposure was analyzed as a time-dependent variable. Patients who came off AS prior to any progression events were censored at that time. The cohort included 288 men with median follow-up of 82 months (interquartile range: 37-120 months). Among non-5ARI users (n = 203); 114 men (56.2%) experienced pathologic progression compared with 24 men (28.2%) in the 5ARI group (n = 85), (p < 0.001). Grade and volume progression were higher in the non-5ARI group compared with the 5ARI group (n = 82; 40.4% vs. n = 19; 22.4% respectively, p = 0.003 for grade progression; n = 87; 43.1% and n = 15; 17.7%, respectively for volume progression p < 0.001). Lack of 5ARI use was independently positively associated with pathologic progression (HR: 2.65; CI: 1.65-4.24), grade progression (HR: 2.75; CI: 1.49-5.06), and volume progression (HR: 3.15; CI: 1.78-5.56). The frequency of progression to high-grade (Grade Group 4-5) tumors was not significantly different between the groups. Use of 5ARIs diminished both grade and volume progression without an increased risk of developing Grade Groups 4-5 disease.

Is BMI a risk factor for active surveillance progression in patients with prostate cancer diagnosed by MRI-Trus fusion biopsy?

124 Background: MRI−TRUS fusion biopsy (FBx) use in the diagnosis of prostate cancer (PCa) results in a more accurate assessment of disease burden and has increasingly been incorporated into urologic practice. In addition, with more men choosing active surveillance (AS) and the reports of increased PCa aggressiveness with obesity, we wanted to study the impact of obesity on the risk of PCa progression in men on AS diagnosed and followed by MRI and MRI−TRUS FBx. Methods: A retrospective review was performed on a prospectively maintained database of all men who underwent MRI−TRUS FBx at our institution from January 2007 to May 2015. Patient demographics, clinical data, imaging, pathology, treatment and outcomes were recorded. Patients who enrolled on AS were stratified by BMI into normal weight (BMI 18.5−24.9), overweight (BMI 25.0−29.9), and obese (BMI ≥ 30.0). Statistical analysis was performed using SPSS software. Results: 204 men were enrolled in AS. Within the AS cohort, 51 (25%) had a normal weight, 101 (49.5%) were overweight, and 52 (25.5%) were obese. Age, BMI, PSA and mean estimated progression free survival time are described for each of these groups in Table 1. The overall rate of progression was 32.8%. Of the patients who progressed, 18 (26.9%) were normal weight, 32 (15.7%) were overweight and 17 (25.4%) were obese. On multivariate analysis, BMI was not a risk factor for AS progression, HR = 1.00 (p = 0.99, 95% CI = 0.95−1.06). Conclusions: There is evidence of increased risk of aggressive PCa specific death in obese patients. However, we demonstrate that in patients diagnosed by FBx, obesity does not confer an additional risk of progression on AS. This may be due to the improved characterization of cancer volume and grade by MRI−TRUS fusion biopsy. Further study is required to determine risk factors for AS progression in patients undergoing FBx. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH, Medical Research Scholars Program.

Associations between statin use and progression in men with prostate cancer treated with primary androgen deprivation therapy

Introduction: In several observational studies, statin use has been associated with reduced risk of progression and mortality in men with prostate cancer (PCa). The study aim was to investigate the association between statin use at time of PCa diagnosis and time to PCa progression in men with advanced or metastatic PCa receiving androgen deprivation therapy (ADT) as primary treatment.Patients and methods: The study population consisted of all men receiving ADT as primary therapy at two Danish Urological Departments in 2007–2013. The primary outcome was time to progression defined as castration-resistant PCa (CRPC) or PCa death. Survival analyses were conducted with Kaplan-Meier analyses, cause specific Cox proportional hazards models, and competing risk analyses.Results: A total of 537 men were included, of whom 141 were statin users at time of diagnosis. The median follow-up time was 5.7 years (95% CI: 5.1–6.2). No significant difference in progression-free survival between statin users and non-statin users was observed at 5 years; 29% for statin users (95% CI: 19–40%) and 28% (95% CI: 23–34%) for non-statin users, p = 0.31. In multivariable Cox analyses, there was no significant association between statin use and risk of progression, HR 0.98 (95% CI: 0.72–1.32). In competing risk analyses the 5-year cumulative incidence of progression was 55% (95% CI: 46–64%) for statin users and 62% (95% CI: 57–67%) for non-statin users, p = 0.11.Conclusion: In the current study, statin use at time of PCa diagnosis was unrelated to time to progression in men primarily treated with ADT.

Comparison of multiparametric MRI to PSA kinetics as an indication of prostate cancer progression in men on active surveillance.

59 Background: Pathologic progression is identified in &gt; 25% of prostate cancer (CaP) patients on active surveillance (AS). Yet, identifying patients at risk for progression is limited to PSA based biomarkers with variable utility. Multiparametric MRI (mpMRI) with fusion-guided prostate biopsy (FBx) has shown utility in risk stratification for patients considering AS. We compared mpMRI characteristics with PSA kinetics for the prediction of pathologic progression in AS patients. Methods: A review of men on AS with serial mpMRI and 2 or more FBx sessions was performed. FBx sessions consisted of targeted biopsies and a 12 core systematic biopsy. Men who met NIH Expanded AS criteria included those with low and intermediate risk CaP, Gleason score ≤ 3+4 = 7 with no restriction on percent core involvement or number of cores positive. Progression was defined by patients with initial Gleason 3+3 = 6 to any Gleason 4, and Gleason 3+4 = 7 to a primary Gleason 4 or higher. MRI progression was defined as increase in suspicion score, size, or new lesion on follow-up. PSA velocity (PSAV) &gt; 0.75ng/ml/yr, PSA doubling time (PSAdt) &lt; 3 yrs, and imaging characteristics were examined for association with pathologic progression at surveillance biopsy. Results: A total of 164 men, median age of 63 yrs [58-67], were included. Median length of follow up was 19.4 months [IQR 14.3-30.0]. Median PSA, and prostate volume of our cohort were 4.9ng/ml [3.3-7.3] and 47.0ml [36.5-59.8]. The sensitivity and specificity of predicting pathologic progression by mpMRI, PSAV and PSAdt were 45% and 65%, 30% and 76%, and 17% and 86% respectively. A combination of MRI, and PSAV or PSAdt yielded a sensitivity and specificity of 61% and 49% or 54% and 56% respectively. Using a decision curve analysis, mpMRI offers minimal benefit for predicting pathologic progression of CaP. Conclusions: MpMRI alone marginally outperforms PSA kinetics for predicting pathologic progression in men on AS for CaP. The combination of mpMRI along with PSA parameters increase the sensitivity of prostate imaging in identifying progression in AS patients. Research in combinations of imaging with other biomarkers will be needed to more accurately risk stratify AS patients.

Moving ahead of prostate-specific antigen

Prostate gland is the second most leading site of cancer among males in Indian cities and it is the second most common site of cancer among US men. Prostate cancer (PCa) is the sixth leading cause of cancer death among men worldwide. The worldwide PCa burden is expected to grow to 1.7 million new cases and 499,000 new deaths by 2030. Prostate specific antigen (PSA) is a protein made by the prostate. Biochemically, it belongs to the protease family of kallikrein and is also known as human kallikrein 3. PSA test was originally approved by the Food and Drug Administration in 1986 to monitor the progression of PCa in men who had already been diagnosed with the disease. PSA test is a nonspecific test for PCa. It can be raised in a number of benign conditions of the prostate as well. The most frequent benign prostate conditions that cause an elevation in PSA level is prostatitis and benign prostatic hyperplasia. Moreover, PSA test may give false-positive or false-negative results. Scientists and researchers are experimenting new ways to improve the PSA test to give us the ability to distinguish cancerous from benign conditions. Some new methods/genetic studies such as PCa gene 3, TMPRSS2-ERG fusion gene, micro ribonucleic acid patterns, proteo-imaging, etc., are being developed to detect PCa in its earliest form. These new tests are much more sensitive and specific than the age old PSA test. It is only a matter of time when these new tests will be fully functional and will either augment or fully replace the age old PSA test.

Effect of Metformin, Rapamycin, and Their Combination on Growth and Progression of Prostate Tumors in HiMyc Mice.

In this study, we compared the effect of oral administration of metformin (MET) and rapamycin (RAPA) alone or in combination on prostate cancer development and progression in HiMyc mice. MET (250 mg/kg body weight in the drinking water), RAPA (2.24 mg/kg body weight microencapsulated in the diet), and the combination inhibited progression of prostatic intraepithelial neoplasia lesions to adenocarcinomas in the ventral prostate (VP). RAPA and the combination were more effective than MET at the doses used. Inhibition of prostate cancer progression in HiMyc mice by RAPA was associated with a significant reduction in mTORC1 signaling that was further potentiated by the combination of MET and RAPA. In contrast, treatment with MET alone enhanced AMPK activation, but had little or no effect on mTORC1 signaling pathways in the VP of HiMyc mice. Further analyses revealed a significant effect of all treatments on prostate tissue inflammation as assessed by analysis of the expression of cytokines, the presence of inflammatory cells and NFκB signaling. MET at the dose used appeared to reduce prostate cancer progression primarily by reducing tissue inflammation whereas RAPA and the combination appeared to inhibit prostate cancer progression in this mouse model via the combined effects on both mTORC1 signaling as well as on tissue inflammation. Overall, these data support the hypothesis that blocking mTORC1 signaling and/or tissue inflammation can effectively inhibit prostate cancer progression in a relevant mouse model of human prostate cancer. Furthermore, combinatorial approaches that target both pathways may be highly effective for prevention of prostate cancer progression in men.

Abstract 4056: Differential phosphorylation of focal adhesion kinase and activation of Yes kinase are associated with increased metastatic potential of prostate cancer

Abstract Metastatic Prostate Cancer (PCa) is the second leading cause of cancer related-deaths in men in the United States. Understanding the molecular events critical to PCa metastasis should lead to novel therapies for treatment of metastatic disease. To assess molecular alterations required for increased PCa cell migration, a critical step in metastasis, multiple rounds of selection of PC3 and DU145 PCa cells were performed using a modified Boyden chamber assay. Highly migratory cells (termed PC3-Mig-3 and DU145-Mig-3) were obtained, a phenotype that has remained stable. PC3-Mig-3 and DU145-Mig-3 cells were also increased in invasiveness, decreased in adhesion and proliferation; thus acquiring additional properties of metastatic cells. Following orthotopic injection into nude mice, migratory variants were significantly increased in number of lymph node metastases (P&amp;lt;0.05). In examining signaling pathways associated with migration and invasion, we determined both PC3-Mig-3 and DU145-Mig-3 were increased in phosphorylation of FAK at tyrosine 861, but not other sites of FAK phosphorylation, relative to their isogenic parental cells. Overexpression a FAK Y861F mutant in PC3-Mig-3 cells decreased migration, demonstrating the importance of pY861 in migratory and invasive potential. Further, expression of FAK pY861 in human PCa lymph node metastases correlated with decreased overall patient survival, suggesting phosphorylation of FAK Y861 may be a predictive biomarker of clinical outcome. To examine potential mechanisms of differential phosphorylation of FAK Y861, the expression and activity of Src family tyrosine kinases was determined. The expression and activity of the Src family kinase, Yes, but not other members of the Src family, were increased in both migratory variants. This increased Yes expression correlated with increased Yes mRNA expression throughout PCa progression as determined from Oncomine. To determine the role Yes kinase in FAK Y861 phosphorylation, Yes was silenced by shRNA expression in PC3-Mig-3 cells. Decreased Yes expression led to both decreased migration, and selectively decreased phosphorylation of FAK Y861. Overexpression of Yes kinase in PC3 parental cells led to specific increased phosphorylation of FAK Y861. These results suggest: the new models of migration we developed have similar alterations as those that occur during PCa progression in men with PCa; Yes activation may play a unique role in PCa progression by leading to differential phosphorylation of FAK Y861; FAK Y861 phosphorylation is important in metastatic potential of PCa cells; and that Yes and FAK may be important markers of metastatic potential of PCa cells. Further studies are designed to investigate specific signaling pathways affected by increased Yes expression and FAK Y861 phosphorylation. Citation Format: Tanushree Chatterji, Jian H. Song, Nila U. Parikh, Chien-Jui Cheng, Sue-Hwa Lin, Gary E. Gallick. Differential phosphorylation of focal adhesion kinase and activation of Yes kinase are associated with increased metastatic potential of prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4056. doi:10.1158/1538-7445.AM2014-4056

Prostatic and dietary omega-3 fatty acids and prostate cancer progression during active surveillance.

The association between omega-3 (ω-3) fatty acids and prostate cancer has been widely studied. However, little is known about the impact of prostate tissue fatty acid content on prostate cancer progression. We hypothesized that compared with the estimated dietary ω-3 fatty acids intake and the ω-3 fatty acids levels measured in red blood cells (RBC), the prostate tissue ω-3 fatty acid content is more strongly related to prostate cancer progression. We present the initial observations from baseline data of a phase II clinical trial conducted in a cohort of 48 untreated men affected with low-risk prostate cancer, managed under active surveillance. These men underwent a first repeat biopsy session within 6 months after the initial diagnosis of low-risk prostate cancer, at which time 29% of the men had progressed from a Gleason score of 6 to a Gleason score of 7. At the first repeat biopsy session, fatty acid levels were assessed with a food-frequency questionnaire, and determined in the RBC and in the prostate tissue biopsy. We found that eicosapentaenoic acid (EPA) was associated with a reduced risk of prostate cancer progression when measured directly in the prostate tissue. Thus, this initial interim study analysis suggests that prostate tissue ω-3 fatty acids, especially EPA, may be protective against prostate cancer progression in men with low-risk prostate cancer.

Targeting psychoemotional stress to treat prostate cancer

Targeting psychoemotional stress to treat prostate cancer

Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial

We aimed to investigate the safety and efficacy of dutasteride, a 5α-reductase inhibitor, on prostate cancer progression in men with low-risk disease who chose to be followed up with active surveillance. In our 3 year, randomised, double-blind, placebo-controlled study, undertaken at 65 academic medical centres or outpatient clinics in North America, we enrolled men aged 48-82 years who had low-volume, Gleason score 5-6 prostate cancer and had chosen to be followed up with active surveillance. We randomly allocated participants in a one-to-one ratio, stratified by site and in block sizes of four, to receive once-daily dutasteride 0·5 mg or matching placebo. Participants were followed up for 3 years, with 12-core prostate biopsy samples obtained after 18 months and 3 years. The primary endpoint was time to prostate cancer progression, defined as the number of days between the start of study treatment and the earlier of either pathological progression (in patients with ≥1 biopsy assessment after baseline) or therapeutic progression (start of medical therapy). This trial is registered with ClinicalTrials.gov, number NCT00363311. Between Aug 10, 2006, and March 26, 2007, we randomly allocated 302 participants, of whom 289 (96%) had at least one biopsy procedure after baseline and were included in the primary analysis. By 3 years, 54 (38%) of 144 men in the dutasteride group and 70 (48%) of 145 controls had prostate cancer progression (pathological or therapeutic; hazard ratio 0·62, 95% CI 0·43-0·89; p=0·009). Incidence of adverse events was much the same between treatment groups. 35 (24%) men in the dutasteride group and 23 (15%) controls had sexual adverse events or breast enlargement or tenderness. Eight (5%) men in the dutasteride group and seven (5%) controls had cardiovascular adverse events, but there were no prostate cancer-related deaths or instances of metastatic disease. Dutasteride could provide a beneficial adjunct to active surveillance for men with low-risk prostate cancer. GlaxoSmithKline.

How can food extracts consumed in the Mediterranean and East Asia suppress prostate cancer proliferation?

We have developed a blend of food extracts commonly consumed in the Mediterranean and East Asia, named blueberry punch (BBP), with the ultimate aim to formulate a chemoprevention strategy to inhibit prostate cancer progression in men on active surveillance protocol. We demonstrated previously that BBP inhibited prostate cancer cell proliferation in vitro and in vivo. The purpose of this study was to determine the molecular mechanism responsible for the suppression of prostate cancer cell proliferation by BBP. Treatment of lymph node-metastasised prostate cancer cells (LNCaP) and bone-metastasised prostate cancer cells (PC-3 and MDA-PCa-2b) with BBP (up to 0·8%) for 72h increased the percentage of cells at the G0/G1 phase and decreased those at the S and G2/M phases. The finding was supported by the reduction in the percentage of Ki-67-positive cells and of DNA synthesis measured by the incorporation of 5-ethynyl-2'-deoxyuridine. Concomitantly, BBP treatment decreased the protein levels of phosphorylated retinoblastoma, cyclin D1 and E, cyclin-dependent kinase (CDK) 4 and 2, and pre-replication complex (CDC6 and MCM7) in LNCaP and PC-3 cells, whereas CDK inhibitor p27 was elevated in these cell lines. In conclusion, BBP exerts its anti-proliferative effect on prostate cancer cells by modulating the expression and phosphorylation of multiple regulatory proteins essential for cell proliferation.

Associations of Folate, Vitamin B12, Homocysteine, and Folate-Pathway Polymorphisms with Prostate-Specific Antigen Velocity in Men with Localized Prostate Cancer

Vitamin B(12), holo-haptocorrin, and the folate-pathway single-nucleotide polymorphisms MTR 2756A>G and SHMT1 1420C>T have been associated with an increased risk of prostate cancer. We investigated whether these and other elements of folate metabolism were associated with prostate-specific antigen (PSA) velocity (PSAV) as a proxy measure of prostate cancer progression in men with localized prostate cancer. We measured plasma folate, B(12), holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine at diagnosis in 424 men (ages 45-70 years) with localized prostate cancer in a U.K.-wide population-based cohort. Thirteen folate-pathway single-nucleotide polymorphisms were genotyped for 311 of these men. Postdiagnosis PSAV (continuous measure and with a threshold set a priori at 2 ng/mL/y) was estimated from repeat PSA measurements. Median follow-up time was 2.5 (range, 0.8-5.6) years. Vitamin B(12), holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine were not associated with postdiagnosis PSAV. Folate was associated with an increased risk of PSAV >2 ng/mL/y [odds ratio (OR) per unit increase in log(e) concentration, 1.57; 95% confidence interval (95% CI), 0.98-2.51; P = 0.06]. MTRR 66A>G (rs1801394) was associated with a reduced risk (recessive model OR, 0.33; 95% CI, 0.11-0.97; P = 0.04), and SHMT1 1420C>T (rs1979277) with an increased risk (per-allele OR, 1.49; 95% CI, 0.93-2.37; P = 0.09) of PSAV >2 ng/mL/y. We found weak evidence that higher folate levels may be associated with faster progression of localized prostate cancer. Long-term follow-up is needed to test associations with metastases and mortality, and the observed genetic effects require replication.

Mass Spectrometry-based Expression Profiling of Clinical Prostate Cancer

The maturation of MS technologies has provided a rich opportunity to interrogate protein expression patterns in normal and disease states by applying expression protein profiling methods. Major goals of this research strategy include the identification of protein biomarkers that demarcate normal and disease populations, and the identification of therapeutic biomarkers for the treatment of diseases such as cancer (Celis, J. E., and Gromov, P. (2003) Proteomics in translational cancer research: Toward an integrated approach. Cancer Cell 3, 9-151). Prostate cancer is one disease that would greatly benefit from implementing MS-based expression profiling methods because of the need to stratify the disease based on molecular markers. In this review, we will summarize the current MS-based methods to identify and validate biomarkers in human prostate cancer. Lastly, we propose a reverse proteomic approach implementing a quantitative MS research strategy to identify and quantify biomarkers implicated in prostate cancer development. With this approach, the absolute levels of prostate cancer biomarkers will be identified and quantified in normal and diseased samples by measuring the levels of native peptide biomarkers in relation to a chemically identical but isotopically labeled reference peptide. Ultimately, a centralized prostate cancer peptide biomarker expression database could function as a repository for the identification, quantification, and validation of protein biomarker(s) during prostate cancer progression in men.