Faculty Bibliography

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.

IMPORTANCE/OBJECTIVE:The target for the oral erectile dysfunction drugs, phosphodiesterase type 5 (PDE5) inhibitors, is part of a pathway implicated in the development of malignant melanoma. An increased risk of melanoma in sildenafil users was recently reported. OBJECTIVE:To examine the association between use of PDE5 inhibitors and melanoma risk, including data on specific PDE5 inhibitors, number of prescriptions, and melanoma stage. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Nationwide, population-based, nested case-control study in the Swedish Prescribed Drug Register, the Swedish Melanoma Register, and other health care registers and demographic databases in Sweden, including 4065 melanoma cases diagnosed from 2006 through 2012 and 5 randomly selected controls per case with matching year of birth. EXPOSURES/METHODS:Number of filled prescriptions for the PDE5 inhibitors sildenafil and vardenafil or tadalafil. MAIN OUTCOMES AND MEASURES/METHODS:Risk of melanoma; overall and by stage and risk of basal cell carcinoma in multivariable logistic regression analyses. RESULTS:Of 4065 melanoma cases, 435 men (11%) had filled prescriptions for PDE5 inhibitors, as did 1713 men of 20,325 controls (8%). In multivariable analysis, there was an increased risk of melanoma in men taking PDE5 inhibitors (OR, 1.21 [95% CI, 1.08-1.36]). The most pronounced increase in risk was observed in men who had filled a single prescription (OR, 1.32 [95% CI, 1.10-1.59]; exposure rate, 4% for cases vs 3% for controls), but was not significant among men with multiple filled prescriptions (for 2-5 prescriptions: OR, 1.14 [95% CI, 0.95-1.37], 4% for cases and 3% for controls; for ≥6 prescriptions: OR, 1.17 [95% CI, 0.95-1.44], 3% for cases vs 2% for controls). PDE5 inhibitors were significantly associated with melanoma stage 0 (OR, 1.49 [95% CI, 1.22-1.83], 13% for cases vs 8% for controls) and stage I (OR, 1.21 [95% CI, 1.02-1.43], 12% for cases vs 10% for controls), but not stage II through IV (OR, 0.83 [95% CI, 0.63-1.09], 6% for cases vs 7% for controls). The risk estimates were similar for sildenafil and vardenafil or tadalafil. PDE5 inhibitor use was also associated with an increased risk of basal cell carcinoma (OR, 1.19 [95% CI, 1.14-1.25], 9% for cases vs 8% for controls). Men taking PDE5 inhibitors had a higher educational level and annual income, factors that were also significantly associated with melanoma risk. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:In a Swedish cohort of men, the use of PDE5 inhibitors was associated with a modest but statistically significant increased risk of malignant melanoma. However, the pattern of association (eg, the lack of association with multiple filled prescriptions) raises questions about whether this association is causal.

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.