METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.

RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.

METHODS: Tissues were collected from 80 patients with clinically detected prostate cancer and treated with radical prostatectomy. Cases were tested for ERG by immunohistochemistry using the mouse monoclonal antibody EP111. All blocks on 48 cases were tested in order to determine the extent of heterogeneity of ERG expression within individual cases. ERG expression was analysed in relation to patient age, ethnicity and tumour stage and grade.

RESULTS: Forty-six percent of cases were ERG positive. There was no significant association between ERG and tumour grade or stage. Sixty-nine percent of Indian patients had ERG positive tumours; this was significantly higher (p=0.031) than for Chinese (40%) and Malay (44%) patients. Heterogeneity of ERG expression, in which both positive and negative clones were present, was seen in 35% of evaluated cases. Evaluation by tumour foci showed younger patients had more ERG positive tumour foci than older patients (p=0.01). Indian patients were more likely to have the majority of tumour foci with ERG staining positively, compared to either Chinese or Malay patients (P <0.01).

MATERIALS AND METHODS: From a PSA screening initiative, 161 men were shown to have elevated PSA levels in their blood and underwent prostatic tissue biopsy. DNA was extracted from the blood, and exon 1 of the AR gene amplified by PCR and sequenced. The number of CAG repeat sequences were counted and compared to the immunohistochemical expression of ERG and AR in the matched tumour biopsies.

RESULTS: Of men with elevated PSA, 89 were diagnosed with prostate cancer, and 72 with benign prostatic hyperplasia (BPH). There was no significant difference in the length of the CAG repeat in men with prostate cancer and BPH. The CAG repeat length was not associated with; age, PSA or tumour grade, though a longer CAG repeat was associated with tumour stage. ERG and AR were expressed in 36% and 86% of the cancers, respectively. There was no significant association between CAG repeat length and ERG or AR expression. However, there was a significant inverse relationship between ERG and AR expression. In addition, a significantly great proportion of Indian men had ERG positive tumours, compared to men of Malay or Chinese descent.

METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.

RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.

CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.

MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

METHODS: Six key sections were chosen: (1) high-risk localized and locally advanced prostate cancer, (2) oligometastatic prostate cancer, (3) castration-naïve prostate cancer, (4) castrate resistant prostate cancer, (5) use of osteoclast-targeted therapy and (6) global access to prostate cancer drugs. There were 101 consensus questions, consisting of 91 questions from APCCC 2017 and 10 new questions from MyAPCCC 2018, selected and modified by the steering committee; of which, 23 questions were assessed in both ideal world and real-world settings. A panel of 22 experts, comprising of 11 urologists and 11 oncologists, voted on 101 predefined questions anonymously. Final voting results were compared with the APCCC 2017 outcomes.

RESULTS: Most voting results from the MyAPCCC 2018 were consistent with the APCCC 2017 outcomes. No consensus was achieved for controversial topics with little level I evidence, such as management of oligometastatic disease. No consensus was reached on using high-cost drugs in castration-naïve or castration-resistant metastatic prostate cancer in real-world settings. All panellists recommended using generic drugs when available.

PATIENTS AND METHODS: Validity and reliability were assessed in patients with lower urinary tract symptoms (LUTS) and in patients with no LUTS. Reliability was evaluated using the test-retest method and internal consistency using Cronbach's alpha. Sensitivity to change was expressed as the effect size in the score before and after intervention in additional patients with LUTS who underwent transurethral resection of the prostate (TURP).

RESULTS: Internal consistency was excellent; there was a high degree of internal consistency for each of the seven domains and for the total score (Cronbach's alpha > or = 0.60 and > or = 0.79, respectively) in the populations studied. The test-retest correlation coefficient for the seven domain scores was highly significant. The intra-class correlation coefficient was high (> or = 0.59). There was a high level of sensitivity and specificity for the effects of treatment, with a very significant change between the seven scores domains in the treated group but not in the control group.