Dataset Information

SPINK1 Defines a Molecular Subtype of Prostate Cancer in Men with More Rapid Progression in an at Risk, Natural History Radical Prostatectomy Cohort.

ABSTRACT: PURPOSE:Prostate cancer is clinically and molecularly heterogeneous. We determined the prognosis of men with ERG-ETS fusions and SPINK1 over expression. MATERIALS AND METHODS:Men were identified with intermediate or high risk localized prostate cancer treated with radical prostatectomy and no therapy before metastasis. A case-cohort design sampled a cohort (262) enriched with metastasis from the entire cohort and a cohort (213) enriched with metastasis from patients with biochemical recurrence. We analyzed transcriptomic profiles and subtyped tumors as m-ERG+, m-ETS+, m-SPINK1+ or Triple Negative (m-ERG?/m-ETS?/m-SPINK1?), and multivariable logistic regression analyses, Kaplan-Meier and multivariable Cox models were used to evaluate subtypes as predictors of clinical outcomes. RESULTS:Overall 36%, 13%, 11% and 40% of prostate cancer was classified as m-ERG+, m-ETS+, m-SPINK1+ and Triple Negative, respectively. Univariable analysis demonstrated that m-SPINK1+ tumors were more common in African-American men (OR 5, 95% CI 1.6-16) but less commonly associated with positive surgical margins (OR 0.16, 95% CI 0.03-0.69) compared to the m-ERG+ group. Compared to the Triple Negative group, m-SPINK1+ showed similar associations with race and surgical margins in univariable and multivariable analyses across the entire cohort. Survival analyses did not show significant differences among m-ERG+, m-ETS+ and Triple Negative cases. m-SPINK1+ independently predicted prostate cancer specific mortality after metastasis (HR 2.48, 95% CI 0.96-6.4) and biochemical recurrence (HR 3, 95% CI 1.1-8). CONCLUSIONS:SPINK1 over expression is associated with prostate cancer specific mortality in at risk men with biochemical and clinical recurrence after prostatectomy. ERG-ETS alterations are not prognostic for outcome.

SUBMITTER: Johnson MH

PROVIDER: S-EPMC6615051 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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SPINK1 Defines a Molecular Subtype of Prostate Cancer in Men with More Rapid Progression in an at Risk, Natural History Radical Prostatectomy Cohort.

Johnson Michael H MH Ross Ashley E AE Alshalalfa Mohammed M Erho Nicholas N Yousefi Kasra K Glavaris Stephanie S Fedor Helen H Han Misop M Faraj Sheila F SF Bezerra Stephania M SM Netto George G Partin Alan W AW Trock Bruce J BJ Davicioni Elai E Schaeffer Edward M EM

The Journal of urology 20160527 5

<h4>Purpose</h4>Prostate cancer is clinically and molecularly heterogeneous. We determined the prognosis of men with ERG-ETS fusions and SPINK1 over expression.<h4>Materials and methods</h4>Men were identified with intermediate or high risk localized prostate cancer treated with radical prostatectomy and no therapy before metastasis. A case-cohort design sampled a cohort (262) enriched with metastasis from the entire cohort and a cohort (213) enriched with metastasis from patients with biochemic ...[more]

PMID: 27238617

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Project description:BackgroundArousal incontinence (AI) occurs during physical or psychological sexual stimulation in men and has been described after radical prostatectomy (RP).AimThe goals of this study are to describe the characteristics of men experiencing AI, outline the nature of their symptoms, and assess for predictors of this condition.MethodsA survey with questions on AI, stress urinary incontinence (SUI), the International Index of Erectile Function and International Prostate Symptom Score were sent out to men who had undergone an RP within the past 24 months at a single institution. The data were deidentified and analyzed using descriptive statistics. Comparisons between men with and without AI were made using t-tests and χ2 and Fisher exact tests. Logistic regression in univariable and multivariable analyses were used to define predictors of AI.Main outcome measuresThe outcomes of this study included prevalence of AI, symptom severity and timing, patient and patient-perceived partner bother, management strategies used by the patients, and concurrent SUI.Results226 (32%) men completed the survey. Of these men, almost half (49%) experienced AI at some point during their recovery. Improvement over time was endorsed by 62% of men. 57% of men reported AI in less than half of the sexual encounters, with the amount of urine leakage being equivalent to a tablespoon or less in 88% of men. On univariate analysis, increasing degree of SUI, as measured by pads per day, was associated with AI (P = .01). A lower International Prostate Symptom Score was also associated (P = .05). On multivariate analysis, the absence of hypertension and pads per day were associated with AI (P = .01 for both).Clinical implicationsAI occurred in almost half of the respondents in our series. Thus, AI should be discussed with patients before surgery to allow for realistic expectations.Strengths & limitationsStrengths of this study include the largest patient population analyzed to date regarding AI and that it is the only one to address timing and patient experiences with the use of validated instruments for erectile and urinary function. Limitations include single-center data, non-validated AI patient-reported outcomes, and poor survey response rate.ConclusionBased on the available data, AI is reported by almost half of men after RP and is associated with SUI. Bach PV, Salter CA, Katz D, et al. Arousal Incontinence in Men Following Radical Prostatectomy: Prevalence, Impact and Predictors. J Sex Med 2020;16:1947-1952.

Project description:Distinguishing between patients with early stage, screen detected prostate cancer who must be treated from those that can be safely watched has become a major issue in prostate cancer care. Identification of molecular subtypes of prostate cancer has opened the opportunity for testing whether biomarkers that characterize these subtypes can be used as biomarkers of prognosis. Two established molecular subtypes are identified by high expression of the ERG oncoprotein, due to structural DNA alterations that encode for fusion transcripts in approximately ½ of prostate cancers, and over-expression of SPINK1, which is purportedly found only in ERG-negative tumors. We used a multi-institutional prostate cancer tissue microarray constructed from radical prostatectomy samples with associated detailed clinical data and with rigorous selection of recurrent and non-recurrent cases to test the prognostic value of immunohistochemistry staining results for the ERG and SPINK1 proteins. In univariate analysis, ERG positive cases (419/1067; 39%) were associated with lower patient age, pre-operative serum PSA levels, lower Gleason scores (? 3+4=7) and improved recurrence free survival (RFS). On multivariate analysis, ERG status was not correlated with RFS, disease specific survival (DSS) or overall survival (OS). High-level SPINK1 protein expression (33/1067 cases; 3%) was associated with improved RFS on univariate and multivariate Cox regression analysis. Over-expression of either protein was not associated with clinical outcome. While expression of ERG and SPINK1 proteins was inversely correlated, it was not mutually exclusive since 3 (0.28%) cases showed high expression of both. While ERG and SPINK1 appear to identify discrete molecular subtypes of prostate cancer, only high expression of SPINK1 was associated with improved clinical outcome. However, by themselves, neither ERG nor SPINK1 appear to be useful biomarkers for prognostication of early stage prostate cancer.

Project description:An emerging field of research describes the role of preoperative health behaviours, known as prehabilitation. The preoperative period may be a more physically and emotionally salient time to introduce and foster chronic adherence to health behaviours, such as exercise, in patients compared to post-treatment during recovery. Moreover, physical and psychosocial improvements during the preoperative period may translate into an enhanced recovery trajectory with reduced operative complications and postoperative adverse effects. No studies have assessed prehabilitation for men with prostate cancer undergoing radical prostatectomy.This is a multi-centre, pilot randomized control trial conducted at two Canadian urban teaching hospitals. 100 men undergoing radical prostatectomy for prostate cancer with no contraindications to exercise will be recruited and randomized to the prehabiliation program or usual care. Prehabilitation participants will engage in a preoperative, individualized exercise program including pelvic floor muscle strengthening instructions and a healthy lifestyle guide for men with prostate cancer. These participants will be asked to engage in 60 minutes of home-based, unsupervised, moderate-intensity exercise on 3-4 days per week. Usual care participants will receive the same pelvic floor muscle strengthening instructions and healthy lifestyle guide only. We will assess the feasibility of conducting an adequately powered trial of the same design via recruitment rate, programmatic adherence/contamination, attrition, and safety. Estimates of intervention efficacy will be captured through measurements at baseline (4-8 weeks preoperatively), within 1 week prior to surgery, and postoperatively at 4, 12, and 26 weeks. Efficacy outcomes include: fatigue, quality of life, urinary incontinence, physical fitness, body composition, aerobic fitness, pain, and physical activity volume.The primary outcome of this study is to determine the feasibility of conducting a full-scale, randomized controlled trial of prehabilitation versus usual care and to estimate effect sizes that will inform sample size determinations for subsequent trials in this field. To our knowledge, this is the first study to examine a structured presurgical exercise program for men undergoing radical prostatectomy for prostate cancer. This trial will advance our understanding of strategies to efficiently and effectively use the preoperative period to optimize postoperative recovery.Clinicaltrials.gov Identifier: NCT02036684.

Project description:BackgroundThe link between diabetes and prostate cancer progression is poorly understood and complicated by obesity. We investigated associations between diabetes and prostate cancer-specific mortality (PCSM), castrate-resistant prostate cancer (CRPC), and metastases in obese and nonobese men undergoing radical prostatectomy (RP).MethodsWe included 4688 men from the Shared Equal Access Regional Cancer Hospital cohort of men undergoing RP from 1988 to 2017. Diabetes prior to RP, anthropometric, and clinical data were abstracted from 6 Veterans Affairs Medical Centers electronic medical records. Primary and secondary outcomes were PCSM and metastases and CRPC, respectively. Multivariable-adjusted hazard ratios (adj-HRs) and 95% confidence intervals (CIs) were estimated for diabetes and PCSM, CRPC, and metastases. Adjusted hazard ratios were also estimated in analyses stratified by obesity (body mass index: nonobese <30 kg/m2; obese ≥30 kg/m2). All statistical tests were 2-sided.ResultsDiabetes was not associated with PCSM (adj-HR = 1.38, 95% CI = 0.86 to 2.24), CRPC (adj-HR = 1.05, 95% CI = 0.67 to 1.64), or metastases (adj-HR = 1.01, 95% CI = 0.70 to 1.46), among all men. Interaction terms for diabetes and obesity were statistically significant in multivariable models for PCSM, CRPC, and metastases (P ≤ .04). In stratified analyses, in obese men, diabetes was associated with PCSM (adj-HR = 3.06, 95% CI = 1.40 to 6.69), CRPC (adj-HR = 2.14, 95% CI = 1.11 to 4.15), and metastases (adj-HR = 1.57, 95% CI = 0.88 to 2.78), though not statistically significant for metastases. In nonobese men, inverse associations were suggested for diabetes and prostate cancer outcomes without reaching statistical significance.ConclusionsDiabetes was associated with increased risks of prostate cancer progression and mortality among obese men but not among nonobese men, highlighting the importance of aggressively curtailing the increasing prevalence of obesity in prostate cancer survivors.

Project description:BackgroundSeveral biologic mechanisms, including inflammation and immune changes, have been proposed to explain the role of obesity in prostate cancer (CaP) progression. Compared to men of a healthy weight, overweight and obese men are more likely to have CaP recurrence post-prostatectomy. Obesity is related to inflammation and immune dysregulation; thus, weight loss may be an avenue to reduce inflammation and reverse these immune processes.ObjectivesThis study explores the reversibility of the biological mechanisms through intentional weight loss using a comprehensive weight management program in men undergoing prostatectomy. Outcomes include blood and tissue biomarkers, microtumor environment gene expression, inflammation markers and Dietary Inflammatory Index (DII) scores.MethodsTwenty overweight men undergoing prostatectomy participated in this study. Fifteen men chose the intervention and 5 men chose the nonintervention group. The intervention consisted of a comprehensive weight loss program prior to prostatectomy and a weight maintenance program following surgery. Prostate tissue samples were obtained from diagnostic biopsies before the intervention and prostatectomy samples after weight loss. Blood samples and diet records were collected at baseline, pre-surgery after weight loss and at study end after weight maintenance. Immunohistochemistry and NanoString analysis were used to analyze the tissue samples. Flow cytometry was used to assess circulating immune markers. Inflammation markers were measured using Luminex panels.ResultsThe intervention group lost >5% body weight prior to surgery. DII scores improved during the weight loss intervention from baseline to pre-surgery (P = 0.002); and between group differences were significant (P = 0.02). DII scores were not associated with IL-6 nor hsCRP. In the intervention, CXCL12, CXCR7, and CXCR4 (C-X-C motif chemokine ligand/receptor) and Ki67 expression decreased in the prostate tissue from biopsy to surgery (P = 0.06), yet plasma CXCL12 increased during the same timeframe (P = 0.009). The downregulation of several genes (FDR<0.001) was observed in the intervention compared to the non-intervention. Changes in immune cells were not significant in either group.ConclusionThis feasibility study demonstrates that in overweight men with localized CaP, weight loss alters blood, and tissue biomarkers, as well as tumor gene expression. More research is needed to determine the biological and clinical significance of these findings.

Dataset Information

SPINK1 Defines a Molecular Subtype of Prostate Cancer in Men with More Rapid Progression in an at Risk, Natural History Radical Prostatectomy Cohort.

Publications

SPINK1 Defines a Molecular Subtype of Prostate Cancer in Men with More Rapid Progression in an at Risk, Natural History Radical Prostatectomy Cohort.

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