Toward a rational strategy for prostate cancer screening based on long-term risk of prostate cancer metastases and death: Data from a large, unscreened, population-based cohort followed for up to 30 years.

4512 Background: Prostate-specific antigen (PSA) testing remains controversial due to high number of men need to be screened to prevent one death. Current screening recommendations are based on few data. We analyzed PSA in archived blood plasma collected in 1974-92 as part of the Malmö Preventive Project. This is a large, representative cohort of Swedish men not subject to screening, chiefly accruing at age 44-50 (i.e. shortly before PSA is recommended to begin in US) and followed for up to 30 years. The study is a unique "natural experiment" to understand the association between early PSA and long-term risk of prostate cancer morbidity and mortality. METHODS: We conducted a case control study nested within a cohort of 12090 men providing blood in 1974-86 and 4999 providing a repeat sample 6 years later and an independent cohort of 1,167 men with blood provided at age 60. 252 men with carefully ascertained evidence of prostate cancer metastasis or death were matched 3:1 with controls. Anti-coagulated plasma was analyzed using methods shown to give highly accurate PSA values. RESULTS: PSA was strongly associated with risk of prostate cancer death or metastasis up to 30 years later (AUC 0.70, 0.76 and 0.90 at age 44-50, 51-55 and 60 respectively, p<0.005). At age 44-50, 44% of cancer deaths occurred in men with PSA >1.6 ng/ml (top 10%) at a median follow up of 27 years. PSA at median at age 44-50 did not rule out risk of metastases or death but did so in older men: 28%, 18% and 0.5% of metastases occurred in men with PSA at median (<0.7, <0.8 and <1.1 ng/ml at age 44-50, 51-55 and, 60 respectively). The risk of prostate cancer metastasis by 15 years for men with PSA at median was never greater than 0.3% at any age. CONCLUSIONS: PSA is highly predictive of long-term risk of prostate cancer morbidity and mortality. Close to half of all deaths could be prevented by intense surveillance of a small proportion of men with the highest PSA levels at age 44-50. For men with lower PSA, testing at age 51-55 and age 60 is sufficient to capture risk of prostate cancer metastases or death 10+ years in advance. This strategy would allow 50% of men to have only three lifetime PSA tests.