Faculty Bibliography

OBJECTIVE:To assess the frequency of a novel prostate cancer-associated single nucleotide polymorphism (SNP), rs188140481, in a North American population and to evaluate the clinical significance of this variant including annotated prostatectomy pathology. PATIENTS/SUBJECTS AND METHODS/UNASSIGNED:We examined the frequency of the minor allele at rs188140481 in 4299 North American men including 1979 men with prostate cancer and 2320 healthy volunteers. We compared the clinicopathological features of prostate cancer between carriers and non-carriers of the SNP. RESULTS:The rs188140481[A] SNP was present in 1.6% of the cohort; it was significantly more likely to be carried by men with prostate cancer than healthy controls (odds ratio 3.14; 95% confidence interval [CI] 1.85-5.35). After adjusting for age and PSA levels, carriers were found to be 6.73-fold (95% CI 1.69-26.76) more likely to develop prostate cancer than non-carriers. Age at diagnosis, frequency of a positive family history of prostate cancer, and biochemical recurrence rates were similar between SNP carriers and non-carriers. Patients with the SNP had a proportionately higher frequency of stage ≥T2c disease (29.5% vs 20.1%; P = 0.13), Gleason ≥8 tumours (13.3% vs 6.5%; P = 0.10), and extracapsular extension (28.9% vs 18.8%; P = 0.12) compared with non-carriers. CONCLUSIONS:rs188140481[A] is a rare SNP that confers greater risk of prostate cancer compared with SNPs identified by genome-wide association studies. Because of its low frequency, larger studies are needed to validate the prognostic significance of this locus, and associations with adverse pathology.

PURPOSE/OBJECTIVE:The Prostate Health Index (phi) is a new test combining total, free and [-2]proPSA into a single score. It was recently approved by the FDA and is now commercially available in the U.S., Europe and Australia. We investigate whether phi improves specificity for detecting clinically significant prostate cancer and can help reduce prostate cancer over diagnosis. MATERIALS AND METHODS/METHODS:From a multicenter prospective trial we identified 658 men age 50 years or older with prostate specific antigen 4 to 10 ng/ml and normal digital rectal examination who underwent prostate biopsy. In this population we compared the performance of prostate specific antigen, % free prostate specific antigen, [-2]proPSA and phi to predict biopsy results and, specifically, the presence of clinically significant prostate cancer using multiple criteria. RESULTS:The Prostate Health Index was significantly higher in men with Gleason 7 or greater and "Epstein significant" cancer. On receiver operating characteristic analysis phi had the highest AUC for overall prostate cancer (AUCs phi 0.708, percent free prostate specific antigen 0.648, [-2]proPSA 0.550 and prostate specific antigen 0.516), Gleason 7 or greater (AUCs phi 0.707, percent free prostate specific antigen 0.661, [-2]proPSA 0.558, prostate specific antigen 0.551) and significant prostate cancer (AUCs phi 0.698, percent free prostate specific antigen 0.654, [-2]proPSA 0.550, prostate specific antigen 0.549). At the 90% sensitivity cut point for phi (a score less than 28.6) 30.1% of patients could have been spared an unnecessary biopsy for benign disease or insignificant prostate cancer compared to 21.7% using percent free prostate specific antigen. CONCLUSIONS:The new phi test outperforms its individual components of total, free and [-2]proPSA for the identification of clinically significant prostate cancer. Phi may be useful as part of a multivariable approach to reduce prostate biopsies and over diagnosis.

BACKGROUND:Many SNPs influence prostate cancer risk. To what extent genetic risk can be reduced by environmental factors is unknown. METHODS:We evaluated effect modification by environmental factors of the association between susceptibility SNPs and prostate cancer in 1,230 incident prostate cancer cases and 1,361 controls, all white and similar ages, nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Trial. Genetic risk scores were calculated as number of risk alleles for 20 validated SNPs. We estimated the association between higher genetic risk (≥12 SNPs) and prostate cancer within environmental factor strata and tested for interaction. RESULTS:Men with ≥12 risk alleles had 1.98, 2.04, and 1.91 times the odds of total, advanced, and nonadvanced prostate cancer, respectively. These associations were attenuated with the use of selenium supplements, aspirin, ibuprofen, and higher vegetable intake. For selenium, the attenuation was most striking for advanced prostate cancer: compared with <12 alleles and no selenium, the OR for ≥12 alleles was 2.06 [95% confidence interval (CI), 1.67-2.55] in nonusers and 0.99 (0.38-2.58) in users (Pinteraction = 0.031). Aspirin had the most marked attenuation for nonadvanced prostate cancer: compared with <12 alleles and nonusers, the OR for ≥12 alleles was 2.25 (1.69-3.00) in nonusers and 1.70 (1.25-2.32) in users (Pinteraction = 0.009). This pattern was similar for ibuprofen (Pinteraction = 0.023) and vegetables (Pinteraction = 0.010). CONCLUSIONS:This study suggests that selenium supplements may reduce genetic risk of advanced prostate cancer, whereas aspirin, ibuprofen, and vegetables may reduce genetic risk of nonadvanced prostate cancer. IMPACT/CONCLUSIONS:The effect of genetic factors on prostate cancer risk may vary by lifestyle interventions.

CONTEXT/BACKGROUND:The relationship between early detection of prostate cancer (PCa) and disease-specific mortality is still the subject of much debate. OBJECTIVE:This review describes developments in PCa mortality rates and disease-stage shift on a population level. The main findings from the randomised screening trials are also discussed. Finally, we consider the expected consequences for the individual man interested in screening. EVIDENCE ACQUISITION/METHODS:The PubMed database was searched for trials of screening for PCa from inception through October 11, 2014. Supplementary information was collected by cross-referencing the reference lists. EVIDENCE SYNTHESIS/RESULTS:Since the introduction of prostate-specific antigen testing, PCa incidence has risen, and a stage shift towards more favourable disease at diagnosis has been observed. PCa mortality rates are gradually decreasing. Although screening trials show conflicting results, the largest randomised trial of screening for PCa shows a 21% decrease in PCa-specific mortality. After correction for noncompliance and contamination, a risk reduction in PCa-specific mortality of up to 49% has been reported. The main side effect of screening is that some studies have estimated that approximately 50% of detected cases may represent overdiagnosis, which may be reduced by stopping screening in older men and using an individual risk-based approach. CONCLUSIONS:To maximise the benefits while minimising the risk of overdiagnosis, future screening should follow an individual risk-based approach. PATIENT SUMMARY/UNASSIGNED:On a population level, the introduction of screening for prostate cancer (PCa) is associated with more men diagnosed but with more favourable disease. The largest screening study confirmed the reduction in death due to PCa. Individual risk estimation is important to best balance the benefits and potential harms of early detection.

At the 2014 International Society of Urological Pathology meeting, changes to prostate cancer grading were discussed including new prognostic Gleason grade groups 1-5 representing Gleason scores of 3+3, 3+4, 4+3, 8, and 9-10, respectively.