Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer.

Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgen-induced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.

Extensive metabolic consequences of human glycosyltransferase gene knockouts in prostate cancer.

BACKGROUND: Naturally occurring germline gene deletions (KO) represent a unique setting to interrogate gene functions. Complete deletions and differential expression of the human glycosyltransferase UGT2B17 and UGT2B28 genes are linked to prostate cancer (PCa) risk and progression, leukaemia, autoimmune and other diseases. METHODS: The systemic metabolic consequences of UGT deficiencies were examined using untargeted and targeted mass spectrometry-based metabolomics profiling of carefully matched, treatment-naive PCa cases. RESULTS: Each UGT KO differentially affected over 5% of the 1545 measured metabolites, with divergent metabolic perturbations influencing the same pathways. Several of the perturbed metabolites are known to promote PCa growth, invasion and metastasis, including steroids, ceramides and kynurenine. In UGT2B17 KO, reduced levels of inactive steroid-glucuronides were compensated by sulfated derivatives that constitute circulating steroid reservoirs. UGT2B28 KO presented remarkably lower levels of oxylipins paralleled by reduced inflammatory mediators, but higher ceramides unveiled as substrates of the enzyme in PCa cells. CONCLUSION: The distinctive and broad metabolic rewiring caused by UGT KO reinforces the need to examine their unique and divergent functions in PCa biology.

A DNA copy number alteration classifier as a prognostic tool for prostate cancer patients.

BACKGROUND: Distinguishing between true indolent and potentially life-threatening prostate cancer is challenging in tumours displaying clinicopathologic features associated with low or intermediate risk of relapse. Several somatic DNA copy number alterations (CNAs) have been identified as potential prognostic biomarkers, but the standard cytogenetic method to assess them has a limited multiplexing capability. METHODS: Multiplex ligation-dependent probe amplification (MLPA) targeting 14 genes was optimised to survey 448 tumours of patients with low or intermediate risk (Grade Group 1-3, Gleason score ≤7) who underwent radical prostatectomy. A 6-gene CNA classifier was developed using random survival forest and Cox proportional hazard modelling to predict biochemical recurrence. RESULTS: The classifier score was significantly associated with biochemical recurrence after adjusting for standard clinicopathologic variables and the known prognostic index CAPRA-S score with a hazard ratio of 2.17 and 1.80, respectively (n = 406, P < 0.01). The prognostic value of this classifier was externally validated in published CNA data from three radical prostatectomy cohorts and one radiation therapy pre-treatment biopsy cohort. CONCLUSION: The 6-gene CNA classifier generated by a single MLPA assay compatible with the small quantities of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue specimens has the potential to improve the clinical management of patients with low or intermediate risk disease.

Preoperative Circulating 11-Oxygenated Androgens Are Associated With Metastasis-free Survival in Localized Prostate Cancer.

PURPOSE: Adrenal 11-oxygenated androgens may support cancer progression in men with prostate cancer owing to their abundance and androgenic potential. We hypothesized that preoperative circulating levels of 11-oxygenated androgens influence clinical outcomes in men with newly diagnosed localized prostate cancer. MATERIALS AND METHODS: We studied 1,793 treatment-naïve patients and 155 patients who received preoperative treatment with 5α-reductase inhibitors in the prospective PROCURE cohort, for which preoperative plasma samples were obtained prior to radical prostatectomy. Adrenal 11-oxygenated precursors, potent 11-oxygenated androgens and their metabolites (n=7), were quantified using liquid chromatography-tandem mass spectrometry. Circulating levels were evaluated in relation to prognostic factors, disease-free survival, and metastasis-free survival using multivariable Cox proportional hazards models. RESULTS: At a median follow-up of 93.8 months after surgery, 583 patients experienced biochemical recurrence, 104 developed metastatic disease, and 168 deceased. Higher levels of 11-hydroxytestosterone and 11-ketotestosterone were observed in men with PSA >20 ng/mL and positive nodal status (P < .05). In multivariable analyses, no significant association between 11-oxygenated androgens and disease-free survival was observed. Adrenal 11ß-hydroxyandrostenedione, the predominant androgenic 11-ketotestosterone, and its metabolite 11-ketoandrosterone, modeled as quartiles, were associated with metastasis-free survival (P = .06, P = .03, and P = .008, respectively). Significant accumulation of 11-oxygenated androgen precursors and bioactive androgens, but reduced metabolite levels, was observed in patients on 5α-reductase inhibitors (P < .001). CONCLUSIONS: Preoperative circulating 11-oxygenated androgen levels are associated with metastasis-free survival in men with localized prostate cancer undergoing radical prostatectomy and are affected by 5α-reductase inhibitor treatment.

Urinary oestrogen steroidome as an indicator of the risk of localised prostate cancer progression.

BACKGROUND: Prostate cancer (PCa) is the most common cancer in North American men. Beyond the established contribution of androgens to disease progression, growing evidence suggest that oestrogen-related pathways might also be of clinical importance. The aim of this study was to explore the association of urinary oestrogen levels with clinical outcomes. METHODS: Urine samples from the prospective multi-institutional PROCURE cohort were collected before RP for discovery (n = 259) and validation (n = 253). Urinary total oestrogens (unconjugated + conjugated), including oestrone and oestradiol, their bioactive and inactive catechol and methyl derivatives (n = 15), were measured using mass spectrometry (MS). RESULTS: The median follow-up time for the discovery and replication cohorts was 7.6 and 6.5 years, respectively. Highly significant correlations between urinary oestrogens were observed; however, correlations with circulating oestrogens were modest. Our findings indicate that higher levels of urinary oestriol and 16-ketoestradiol were associated with lower risk of BCR. In contrast, higher levels of 2-methoxyestrone were associated with an increased risk of development of metastasis/deaths. CONCLUSIONS: Our data suggest that urinary levels of oestriol and 16-ketoestradiol metabolites are associated with a more favourable outcome, whereas those of 2-methoxyestrone are associated with an elevated risk of metastasis after RP. Further studies are required to better understand the impact of oestrogens on disease biology and as easily accessible urine-based risk-stratification markers.

Validation of the prognostic value of NF-κB p65 in prostate cancer: A retrospective study using a large multi-institutional cohort of the Canadian Prostate Cancer Biomarker Network.

BACKGROUND: The identification of patients with high-risk prostate cancer (PC) is a major challenge for clinicians, and the improvement of current prognostic parameters is an unmet clinical need. We and others have identified an association between the nuclear localization of NF-κB p65 and biochemical recurrence (BCR) in PC in small and/or single-centre cohorts of patients. METHODS AND FINDINGS: In this study, we accessed 2 different multi-centre tissue microarrays (TMAs) representing cohorts of patients (Test-TMA and Validation-TMA series) of the Canadian Prostate Cancer Biomarker Network (CPCBN) to validate the association between p65 nuclear frequency and PC outcomes. Immunohistochemical staining of p65 was performed on the Test-TMA and Validation-TMA series, which include PC tissues from patients treated by first-line radical prostatectomy (n = 250 and n = 1,262, respectively). Two independent observers evaluated the p65 nuclear frequency in digital images of cancer tissue and benign adjacent gland tissue. Kaplan-Meier curves coupled with a log-rank test and univariate and multivariate Cox regression models were used for statistical analyses of continuous values and dichotomized data (cutoff of 3%). Multivariate analysis of the Validation-TMA cohort showed that p65 nuclear frequency in cancer cells was an independent predictor of BCR using continuous (hazard ratio [HR] 1.02 [95% CI 1.00-1.03], p = 0.004) and dichotomized data (HR 1.33 [95% CI 1.09-1.62], p = 0.005). Using a cutoff of 3%, we found that this biomarker was also associated with the development of bone metastases (HR 1.82 [95% CI 1.05-3.16], p = 0.033) and PC-specific mortality (HR 2.63 [95% CI 1.30-5.31], p = 0.004), independent of clinical parameters. BCR-free survival, bone-metastasis-free survival, and PC-specific survival were shorter for patients with higher p65 nuclear frequency (p < 0.005). As the small cores on TMAs are a limitation of the study, a backward validation of whole PC tissue section will be necessary for the implementation of p65 nuclear frequency as a PC biomarker in the clinical workflow. CONCLUSIONS: We report the first study using the pan-Canadian multi-centre cohorts of CPCBN and validate the association between increased frequency of nuclear p65 frequency and a risk of disease progression.

A three-gene DNA methylation biomarker accurately classifies early stage prostate cancer.

BACKGROUND: We identify and validate accurate diagnostic biomarkers for prostate cancer through a systematic evaluation of DNA methylation alterations. MATERIALS AND METHODS: We assembled three early prostate cancer cohorts (total patients = 699) from which we collected and processed over 1300 prostatectomy tissue samples for DNA extraction. Using real-time methylation-specific PCR, we measured normalized methylation levels at 15 frequently methylated loci. After partitioning sample sets into independent training and validation cohorts, classifiers were developed using logistic regression, analyzed, and validated. RESULTS: In the training dataset, DNA methylation levels at 7 of 15 genomic loci (glutathione S-transferase Pi 1 [GSTP1], CCDC181, hyaluronan, and proteoglycan link protein 3 [HAPLN3], GSTM2, growth arrest-specific 6 [GAS6], RASSF1, and APC) showed large differences between cancer and benign samples. The best binary classifier was the GAS6/GSTP1/HAPLN3 logistic regression model, with an area under these curves of 0.97, which showed a sensitivity of 94%, and a specificity of 93% after external validation. CONCLUSION: We created and validated a multigene model for the classification of benign and malignant prostate tissue. With false positive and negative rates below 7%, this three-gene biomarker represents a promising basis for more accurate prostate cancer diagnosis.

The combination of PTEN deletion and 16p13.3 gain in prostate cancer provides additional prognostic information in patients treated with radical prostatectomy.

Prostate cancer is a clinically heterogeneous disease and accurately risk-stratifying patients is a key clinical challenge. We hypothesized that the concurrent identification of the DNA copy number alterations 10q23.3 (PTEN) deletion and 16p13.3 (PDPK1) gain, related to the PI3K/AKT survival pathway, would improve prognostication. We assessed PTEN deletion status using fluorescence in situ hybridization (FISH) and evaluated its clinical significance in combination with the 16p13.3 gain in a set of 332 primary radical prostatectomy cases on a tissue microarray with clinical follow-up. The PTEN deletion was detected in 34% (97/287) of the evaluable tumors and was significantly associated with high Gleason grade group (P < 0.0001) and advanced pathological tumor stage (pT-stage, P < 0.001). The PTEN deletion emerged as a significant predictor of biochemical recurrence independent of the standard clinicopathologic parameters (hazard ratio: 3.00, 95% confidence interval: 1.81-4.98; P < 0.0001) and further stratified patients with low and intermediate risk of biochemical recurrence [Gleason grade group 1-2 (≤3 + 4), Gleason grade group 2 (3 + 4), pT2, prostate-specific antigen ≤ 10, low and intermediate CAPRA-S score; log-rank P ≤ 0.007]. A PTEN deletion also increased the risk of distant metastasis (log-rank, P = 0.001), further supporting its role in prostate cancer progression. Combining both 16p13.3 gain and PTEN deletion improved biochemical recurrence risk stratification and provided prognostic information beyond the established CAPRA-S score (co-alteration: hazard ratio: 4.70, 95% confidence interval: 2.12-10.42; P < 0.0001). Our study demonstrates the potential clinical utility of PTEN genomic deletion in low-intermediate risk patients and highlights the enhanced prognostication achieved when assessed in combination with another genomic biomarker related to the PI3K/AKT pathway, thereby supporting their promising usefulness in clinical management of prostate cancer.

Optimization of the 2014 Gleason grade grouping in a Canadian cohort of patients with localized prostate cancer.

OBJECTIVES: To evaluate the five-tier Gleason grade group (GG) scoring of prostate cancers adopted by the International Society of Urology Pathology (ISUP) in 2014, and to propose modifications to optimize its performance. PATIENTS AND METHODS: Data were obtained from PROCURE, a prospective cohort of patients with localized prostate cancer undergoing radical prostatectomy in Québec, 2006-2013. Surgical specimens were evaluated by genitourinary pathologists using 2014 ISUP criteria. Treatment failure was defined as biochemical recurrence and/or initiation of secondary, non-adjuvant therapy. Analyses were conducted using Kaplan-Meier methods, log-rank tests, Cox proportional hazards models and Harrell's concordance indices. RESULTS: A total of 1 917 patients were included, with a median follow-up of 69 months. The 5-year treatment failure rates were 9.6%, 23.5%, 43.1%, 52.6% and 84.3% in GG1-5, respectively (P < 0.001 when comparing GG2 with GG3). Treatment failure rates for patients in GG2 and GG3 with tertiary Gleason 5 pattern were higher than patients in the same group without a tertiary pattern (P < 0.001), but were similar to rates for patients in GGs 3 or 4 without a tertiary pattern (P > 0.3). Primary Gleason pattern (4/5) predicted treatment failure in GG5 (5-year failure rates 82.3% vs 97.1%, respectively; P = 0.001). The five-tier GG system had greater accuracy as a prognostic indicator compared with the four-tier system (Harrell's concordance index 0.716 vs 0.676). When upgrading patients in GG2/3 with tertiary Gleason 5 pattern to patients in GG3/4, and separating patients in GG5 by primary Gleason pattern, the Harrell's concordance index increased to 0.730. CONCLUSION: The five-tier GG system increased accuracy for predicting treatment failure compared with the previous grading systems, but can be further improved.

The relationship between body-mass index, physical activity, and pathologic and clinical outcomes after radical prostatectomy for prostate cancer.

PURPOSE: We evaluated whether an increased body-mass index (BMI) and decreased physical activity increase the risk of locally advanced or high-risk prostate cancer (PCa) at radical prostatectomy (RP), and treatment failure after surgery. METHODS: Data were collected from the PROCURE Biobank, a prospective cohort of patients with localized PCa undergoing RP in four academic centers in Québec between 2006 and 2013. Treatment failure was defined as biochemical recurrence and/or initiation of secondary, non-adjuvant therapy, and analyzed using the Kaplan-Meier method, log-rank tests, and Cox proportional-hazards models. Uni- and multivariate (ordered) logistic regression was used for time-independent variables. RESULTS: 1813 patients were included. Median follow-up time was 69 months. Patients who reported a lower BMI were generally older, of Asian descent, and physically more active (p < 0.05). Younger, black, and overweight/obese patients reported less physical activity (p < 0.05). In multivariate analyses, a higher BMI increased the risk for locally advanced, high-risk PCa (defined as a pT3, N1 and/or Gleason 8-10 tumor; odds ratio 1.33, p < 0.001), but increased physical activity did not predict high-risk disease (odds ratio 0.84, p = 0.39). Patients with a higher BMI also had a larger prostate at surgery (odds ratio 1.13, p = 0.03). BMI and physical activity were not associated with positive surgical margins or time to treatment failure (p > 0.05). CONCLUSIONS: BMI was an independent predictor for locally advanced, high-risk disease in this cohort of PCa patients undergoing RP, but was unrelated to treatment failure. Physical activity was not related to locally advanced, high-risk PCa or treatment failure.

Psychosocial adjustment to a prostate cancer diagnosis in a cohort of radical prostatectomy patients in Quebec, Canada.

OBJECTIVE: The psychosocial impact of a prostate cancer diagnosis significantly affects a patient's quality of life. We studied patient communication at the time of diagnosis and its impact on psychosocial adjustment of patients. METHODS: This is a cross-sectional data analysis from self-administered questionnaires in the PROCURE biobank study, consisting of a cohort of patients with localized prostate cancer undergoing radical prostatectomy in Québec (Canada), 2006 to 2013. Odds ratios (OR) and their respective 95% confidence intervals (95% CI) were calculated using binary or ordered logistic regression models. RESULTS: Data from 1841 patients were analyzed. The median age of patients was 62 years (range 41-80 years), the majority was French-Canadian (68.3%) and married (79.6%). Most patients (90.1%) considered conversations with their treating physician a useful information source. Patients were dissatisfied on the communication when receiving their diagnosis by telephone (OR = 0.19, 95% CI, 0.11-0.33). Younger patients were also more dissatisfied. Most patients preferred to receive information on prostate cancer (89.5%) and radical prostatectomy (88.0%) at the time of diagnosis, while only 58.8% and 52.4% of patients received this information at this stage. Patients who were dissatisfied with the communication of the diagnosis had more negative responses, such as increased worries and fear (P < 0.05). The five most useful coping mechanisms were physical activity (62.3%), breathing exercises (44.5%), music (32.8%), faith (30.3%), and muscle relaxation (30.1%), but varied by demographics. CONCLUSIONS: This study highlights the importance of physicians communicating a prostate cancer diagnosis well to their patients. Patients may benefit from individually tailored interventions to facilitate their overall coping.

Improving ultrasound-based prostate volume estimation.

BACKGROUND: To define a new coefficient to be used in the formula (Volume = L x H x W x Coefficient) that better estimates prostate volume using dimensions of fresh prostates from patients who had transrectal ultrasound (TRUS) imaging prior to prostatectomy. METHODS: The prostate was obtained from 153 patients, weighed and measured to obtain length (L), height (H), and width (W). The density was determined by water displacement to calculate volume. TRUS data were retrieved from patient charts. Linear regression analyses were performed to compare various prostate volume formulas, including the commonly used ellipsoid formula and newly introduced bullet-shaped formula. RESULTS: By relating measured prostate volumes from fresh prostates to TRUS-estimated prostate volumes, 0.66 was the best fitting coefficient in the (L x H x W x Coefficient) equation. This newfound coefficient combined with outlier removal yielded a linear equation with an R2 of 0.64, compared to 0.55 and 0.60, for the ellipsoid and bullet, respectively. By comparing each of the measured vs. estimated dimensions, we observed that the mean prostate height and length were overestimated by 11.1 and 10.8% using ultrasound (p < 0.05), respectively, while the mean width was similar (p > 0.05). Overall, the ellipsoid formula underestimates prostate volumes by 18%, compared to an overestimation of 4.6 and 5.7% for the bullet formula and the formula using our coefficient, respectively. CONCLUSIONS: This study defines, for the first time, a coefficient based on freshly resected prostates as a reference to estimate volumes by imaging. Our findings support a bullet rather than an ellipsoid prostate shape. Moreover, substituting the coefficient commonly used in the ellipsoid formula by our calculated coefficient in the equation estimating prostate volume by TRUS, provides a more accurate value of the true prostate volume.

The Terry Fox Research Institute Canadian Prostate Cancer Biomarker Network: an analysis of a pan-Canadian multi-center cohort for biomarker validation.

BACKGROUND: Refinement of parameters defining prostate cancer (PC) prognosis are urgently needed to identify patients with indolent versus aggressive disease. The Canadian Prostate Cancer Biomaker Network (CPCBN) consists of researchers from four Canadian provinces to create a validation cohort to address issues dealing with PC diagnosis and management. METHODS: A total of 1512 radical prostatectomy (RP) specimens from five different biorepositories affiliated with teaching hospitals were selected to constitute the cohort. Tumoral and adjacent benign tissues were arrayed on tissue microarrays (TMAs). A patient clinical database was developed and includes data on diagnosis, treatment and clinical outcome. RESULTS: Mean age at diagnosis of patients in the cohort was 61 years. Of these patients, 31% had a low grade (≤6) Gleason score (GS), 55% had GS 7 (40% of 3 + 4 and 15% of 4 + 3) and 14% had high GS (≥8) PC. The median follow-up of the cohort was 113 months. A total of 34% had a biochemical relapse, 4% developed bone metastasis and 3% of patients died from PC while 9% died of other causes. Pathological review of the TMAs confirmed the presence of tumor and benign tissue cores for > 94% of patients. Immunohistochemistry and FISH analyses, performed on a small set of specimens, showed high quality results and no biorepository-specific bias. CONCLUSIONS: The CPCBN RP cohort is representative of real world PC disease observed in the Canadian population. The frequency of biochemical relapse and bone metastasis as events allows for a precise assessment of the prognostic value of biomarkers. This resource is available, in a step-wise manner, for researchers who intend to validate prognostic biomarkers in PC. Combining multiple biomarkers with clinical and pathologic parameters that are predictive of outcome will aid in clinical decision-making for patients treated for PC.

Describing perspectives of health care professionals on active surveillance for the management of prostate cancer.

BACKGROUND: Over the last decade, active surveillance has proven to be a safe approach for patients with low-risk prostate cancer. Although active surveillance presents several advantages for both patients and the health care system, all eligible patients do not adopt this approach. Our goal was to evaluate the factors that influence physicians to recommend active surveillance and the barriers that impact adherence to this approach. METHODS: Focus groups (n = 5) were held with physicians who provided care for men with low-risk prostate cancer and had engaged in conversations with men and their families about active surveillance. The experience of health care professionals (HCPs) was captured to understand their decisions in proposing active surveillance and to reveal the barriers and facilitators that affect the adherence to this approach. A content analysis was performed on the verbatim transcripts from the sessions. RESULTS: Although physicians agreed that active surveillance is a suitable approach for low-risk prostate cancer patients, they were concerned about the rapidly evolving and non-standardized guidelines for patient follow-up. They pointed out the need for additional tools to appropriately identify proper patients for whom active surveillance is the best option. Urologists and radiation-oncologists were keen to collaborate with each other, but the role of general practitioner remained controversial once patients were referred to a specialist. CONCLUSIONS: Integration of more reliable tools and/or markers in addition to more specific guidelines for patient follow-up would increase the confidence of both patients and physicians in the choice of active surveillance.

Asporin is a stromally expressed marker associated with prostate cancer progression.

BACKGROUND: Prostate cancer shows considerable heterogeneity in disease progression and we propose that markers expressed in tumour stroma may be reliable predictors of aggressive tumour subtypes. METHODS: We have used Kaplan-Meier, univariate and multivariate analysis to correlate the expression of Asporin (ASPN) mRNA and protein with prostate cancer progression in independent cohorts. We used immunohistochemistry and H scoring to document stromal localisation of ASPN in a tissue microarray and mouse prostate cancer model, and correlated expression with reactive stroma, defined using Masson Trichrome staining. We used cell cultures of primary prostate cancer fibroblasts treated with serum-free conditioned media from prostate cancer cell lines to examine regulation of ASPN mRNA in tumour stromal cells. RESULTS: We observed increased expression of ASPN mRNA in a data set derived from benign vs tumour microdissected tissue, and a correlation with biochemical recurrence using Kaplan-Meier and Cox proportional hazard analysis. ASPN protein localised to tumour stroma and elevated expression of ASPN was correlated with decreased time to biochemical recurrence, in a cohort of 326 patients with a median follow up of 9.6 years. Univariate and multivariate analysis demonstrated that ASPN was correlated with progression, as were Gleason score, and clinical stage. Additionally, ASPN expression correlated with the presence of reactive stroma, suggesting that it may be a stromal marker expressed in response to the presence of tumour cells and particularly with aggressive tumour subtypes. We observed expression of ASPN in the stroma of tumours induced by p53 inhibition in a mouse model of prostate cancer, and correlation with neuroendocrine marker expression. Finally, we demonstrated that ASPN transcript expression in normal and cancer fibroblasts was regulated by conditioned media derived from the PC3, but not LNCaP, prostate cancer cell lines. CONCLUSIONS: Our results suggest that ASPN is a stromally expressed biomarker that correlates with disease progression, and is observed in reactive stroma. ASPN expression in stroma may be part of a stromal response to aggressive tumour subtypes.

Canadian Men's perspectives about active surveillance in prostate cancer: need for guidance and resources.

BACKGROUND: In prostate cancer, men diagnosed with low risk disease may be monitored through an active surveillance. This research explored the perspectives of men with prostate cancer regarding their decision-making process for active surveillance to identify factors that influence their decision and assist health professionals in having conversations about this option. METHODS: Focus group interviews (n = 7) were held in several Canadian cities with men (N = 52) diagnosed with prostate cancer and eligible for active surveillance. The men's viewpoints were captured regarding their understanding of active surveillance, the factors that influenced their decision, and their experience with the approach. A content and theme analysis was performed on the verbatim transcripts from the sessions. RESULTS: Patients described their concerns of living with their disease without intervention, but were reassured by the close monitoring under AS while avoiding harmful side effects associated with treatments. Conversations with their doctor and how AS was described were cited as key influences in their decision, in addition to availability of information on treatment options, distrust in the health system, personality, experiences and opinions of others, and personal perspectives on quality of life. CONCLUSIONS: Men require a thorough explanation on AS as a safe and valid option, as well as guidance towards supportive resources in their decision-making.

Management of localized and advanced prostate cancer in Canada: A lifetime cost and quality-adjusted life-year analysis.

BACKGROUND: To the authors' knowledge, the literature to date lacks studies examining lifetime costs and quality-adjusted life-years (QALYs) of prostate cancer (PCa) management strategies that integrate localized and advanced disease. The objective of the current study was to assess lifetime costs and QALYs associated with contemporary PCa management strategies across risk groups by integrating localized and advanced disease. METHODS: The authors' validated Markov chain Monte Carlo model was used to predict lifetime direct costs and QALYs. The health states modeled were active surveillance, initial treatments (radical prostatectomy or radiotherapy), PCa recurrence, PCa recurrence free, metastatic castration-resistant prostate cancer, and death (cause specific/other causes). Data regarding treatment distribution, state transition probabilities, adverse effects of management options, costs, utilities, and disutilities were derived from the published literature. RESULTS: The total cost per patient for the overall cohort increased from $18,503 at 5 years to $28,032 and $39,143, respectively, at 10 years and 15 years. Furthermore, the results indicated the influence of risk group on total cost, with the high-risk group accruing the maximum per patient cost followed by the intermediate-risk and low-risk groups. Active surveillance was found to confer the most QALYs (12.5 years) and was the least costly strategy ($18,452) for individuals at low risk. For all risk groups, radical prostatectomy was less costly and conferred modestly more QALYs compared with intensity-modulated radiotherapy modalities. CONCLUSIONS: Public health care systems in Canada and elsewhere are operating under budget constraints to allocate finite resources. The findings of the current study might inform discussions concerning budget planning to provide health care services.

Long term evaluation of optimized Gleason grading in a large cohort of men with prostate cancer in Canada.

OBJECTIVES: To evaluate the International Society of Urological Pathology (ISUP) 5-tier grade grouping (GG) system of prostate cancers as well as previously proposed optimizations. PATIENTS AND METHODS: The PROCURE biobank is a prospective cohort study of patients with localized prostate cancer who underwent radical prostatectomy in Quebec province between 2005 and 2013. Surgical specimens were graded by experienced genitourinary pathologists using 2019 ISUP criteria. Follow-up was conducted until November 2021. The current 5-tier and a proposed 6-tier GG system were evaluated, the latter having two changes: 1) Gleason 3 + 4 and 4 + 3 tumors with minor/tertiary Gleason 5 patterns were upgraded to GG 3 and 4, respectively; and 2) patients in GG5 were separated based on primary Gleason pattern (4 or 5). Cox proportional hazards models and Harrell's concordance (C) indices were used for statistical analyses. RESULTS: 2003 patients were included (median follow-up: 8.7 years). The current 5-tier GG system predicted time to recurrence (hazard ratio [HR] 2.12, 95% confidence interval [95%CI] 1.99-2.25, C 0.717), androgen-deprivation therapy (HR 2.58, 95%CI 2.38-2.80, C 0.790), metastasis (HR 2.48, 95%CI 2.17-2.83, C 0.806), castration-resistant prostate cancer (HR 2.67, 95%CI 2.28-3.13, C 0.829), and cancer-specific mortality (HR 2.80, 95%CI 2.27-3.44, C 0.835). Goodness-of-fit further improved with the proposed 6-tier GG system, with Harrell's C of 0.733, 0.807, 0.827, 0.853, and 0.853, respectively. CONCLUSIONS: The 5-tier GG system predicted short- and long-term outcomes for patients with localized prostate cancer, and the proposed 6-tier GG system further improved its accuracy.

Endoscopic vascular targeted photodynamic therapy with the photosensitizer WST11 for benign prostatic hyperplasia in the preclinical dog model.

PURPOSE: Vascular targeted photodynamic therapy with WST11 (TOOKAD® Soluble) is in phase III clinical trials of an interstitial transperineal approach for focal therapy of prostate cancer. We investigated the safety and efficacy of the endourethral route in the context of benign prostatic hyperplasia in the dog model. MATERIALS AND METHODS: An optical laser fiber was positioned in the prostatic urethra of 34 dogs, including 4 controls. It was connected to a 753 nm diode laser at 200 mW/cm fluence, delivering 200 to 300 J. WST11 (5 to 15 mg/kg) was infused intravenously in 2 modes, including continuous, starting 5 to 15 minutes before and during illumination, or a bolus 5 to 10 minutes before illumination. Prostate ultrasound, cystourethrogram, urodynamics and histopathology were performed. Followup was 1 week to 1 year. RESULTS: Endourethral WST11 vascular targeted photodynamic therapy was uneventful in all except 1 dog, which experienced urinary retention but reached the 1-week end point. All prostates except those in controls showed hemorrhagic lesions. They consisted of 2 levels of concentric alterations, including periurethral necrosis with endothelial layer destruction and adjacent inflammation/atrophy with normal blood vessels. Prostatic urethral width increased as early as 6 weeks after treatment, while prostatic volume decreased, reaching 25% by 18 to 26 weeks. A parallel decrease in urethral pressure at 6 weeks lasted up to 1 year. CONCLUSIONS: We confirmed the vascular effect of endourethral WST11 vascular targeted photodynamic therapy. To our knowledge we report for the first time that the resulting periurethral necrosis led to significant, sustained widening of the prostatic urethra, accompanied by long-term improvement in urodynamic parameters. These findings support future clinical applications of this minimally invasive approach to benign prostatic hyperplasia.

Cell-by-cell quantification of the androgen receptor in benign and malignant prostate leads to a better understanding of changes linked to cancer initiation and progression.

The androgen receptor (AR) plays a crucial role in the development and homeostasis of the prostate and is a key therapeutic target in prostate cancer (PCa). The gold standard therapy for advanced PCa is androgen deprivation therapy (ADT), which targets androgen production and AR signaling. However, resistance to ADT develops via AR-dependent and AR-independent mechanisms. As reports on AR expression patterns in PCa have been conflicting, we performed cell-by-cell AR quantification by immunohistochemistry in the benign and malignant prostate to monitor changes with disease development, progression, and hormonal treatment. Prostates from radical prostatectomy (RP) cases, both hormone-naïve and hormone-treated, prostate tissues from patients on palliative ADT, and bone metastases were included. In the normal prostate, AR is expressed in >99% of luminal cells, 51% of basal cells, and 61% of fibroblasts. An increase in the percentage of AR negative (%AR-) cancer cells along with a gradual loss of fibroblastic AR were observed with increasing Gleason grade and hormonal treatment. This was accompanied by a parallel increase in staining intensity of AR positive (AR+) cells under ADT. Staining AR with N- and C-terminal antibodies yielded similar results. The combination of %AR- cancer cells, %AR- fibroblasts, and AR intensity score led to the definition of an AR index, which was predictive of biochemical recurrence in the RP cohort and further stratified patients of intermediate risk. Lastly, androgen receptor variant 7 (ARV7)+ cells and AR- cells expressing neuroendocrine and stem markers were interspersed among a majority of AR+ cells in ADT cases. Altogether, the comprehensive quantification of AR expression in the prostate reveals concomitant changes in tumor cell subtypes and fibroblasts, emphasizing the significance of AR- cells with disease progression and palliative ADT.