Table 1 shows characteristics of the entire cohort at 31 December 2006. A total of 126 men were diagnosed with prostate cancer, of whom 43 either had metastatic disease at diagnosis (n=13), subsequently developed metastases (n=18), or died from prostate cancer without clinical documentation of metastases (n=12). Thirty five men died from prostate cancer. We excluded one case (a man who died from prostate cancer) from the analysis because blood samples were insufficient to measure prostate specific antigen. We also excluded 11 controls (two matched for prostate cancer, five matched for metastases, and four matched for death) with insufficient blood samples. Median times to diagnosis, metastasis, and cancer specific death were 15.3, 15.7, and 15.9 years, respectively. The similarity of these estimates is because only a subset of men diagnosed with cancer went on to develop metastases and these tended to be diagnosed earlier. The imputed median prostate specific antigen concentration for the entire cohort was 1.06 ng/ml (interquartile range 0.65-1.92), similar to that reported for US men.21
Table 1 Characteristics of entire study cohort (n=1162) at 31 December 2006. Figures are numbers (percentages) unless stated otherwise
Table 2 gives details of the diagnosis in the 126 affected men. Most commonly, prostate cancer was detected during investigation for urinary symptoms (79%). No man had cancer detected by screening. Curative treatment was rare, with only one man undergoing radical prostatectomy. Bone scans were not routine for much of the period of the study, and many patients are therefore not classified for metastasis at diagnosis.
Table 2 Characteristics of 126 (11%) men from study cohort with diagnosis of prostate cancer. Figures are numbers (percentages) unless stated otherwise
Prostate specific antigen at age 60 was associated with risk of prostate cancer diagnosed clinically by age 85 (area under the curve 0.76, 95% confidence interval 0.71 to 0.81; P<0.001). This association remained for cancers detected more than 20 years after the blood sample (33 cases, 0.69, P=0.005). Prostate specific antigen was also associated with prostate cancer metastases (0.86, 0.79 to 0.92; P<0.001), and death from prostate cancer (0.90, 0.84 to 0.96; P<0.001). Again, these associations remained for events occurring after 20 years (0.83, P=0.046, in 12 patients with metastasis; 0.84, P=0.051, in 10 patients who died).
Table 3 gives an initial descriptive analysis of the association between prostate specific antigen and subsequent prostate cancer events after we categorised the data by population quarters of prostate specific antigen concentration. As an example, men with a prostate specific antigen concentration ≥2 ng/ml at age 60, have, on average, 26 times the odds of dying from prostate cancer than men with a concentration <2 ng/ml. Table 4 gives predicted risks of a diagnosis of prostate cancer, metastasis, and death by age 85 for population centiles of prostate specific antigen; the association is shown graphically in figure 1, showing strong trends with increasing concentration. If adjustment is made for overdiagnosis,10
the relation between prostate specific antigen and subsequent clinically detected cancer is comparable with that reported between prostate specific antigen and biopsy detectable cancer in the US population,4
indicating broad applicability of our findings. The risk of a clinically detected prostate cancer rises smoothly with increasing concentration of prostate specific antigen; in contrast, metastases and death from prostate cancer were rare in men with a concentration less than 1 ng/ml at age 60, but then rose rapidly as the concentrations increased. As a result, prostate specific antigen concentration at age 60 can predict the probability that a man will die from prostate cancer after a subsequent diagnosis. For example, of 25 men with baseline concentrations of 1-2 ng/ml who were later diagnosed with prostate cancer, only two (8%) died from prostate cancer by the end of the study. In comparison, of 18 men with baseline concentrations of 5-10 ng/ml who were later diagnosed with prostate cancer, six (33%) died from prostate cancer.
Table 3 Conditional logistic regression based on prostate specific antigen (PSA) concentrations at age 60. Categories of PSA are close to quarters of distribution
Table 4 Risk of clinically diagnosed prostate cancer and death from prostate cancer before age 85 by prostate specific antigen (PSA) concentration at age 60. Figures are predicted risk (95% confidence interval)
Fig 1 Lifetime risk of clinically diagnosed prostate cancer or prostate cancer metastasis. Shaded region represents population based distribution of prostate specific antigen. Curves for risk of death from prostate cancer nearly overlap with curves for (more ...)
Figures 2-4 show Lorenz curves for each event, with cumulative probabilities by population centile shown in table 5. These results can be used to evaluate risk stratification strategies for screening and early detection. It can be seen, for example, that 90% of metastases and 95% of deaths occur in men with prostate specific antigen concentrations above the median at age 60, equivalent to a concentration of about 1 ng/ml. Men with concentrations ≤1 ng/ml had a 0.5% probability of metastasis by age 85 and a 0.2% probability of death from prostate cancer. Two men in our cohort had concentrations close to or less than 1 ng/ml at age 60 and subsequently died from prostate cancer. These deaths occurred at age 84 (1.04 ng/ml at baseline) and 85 (0.86 ng/ml at baseline).
Fig 2 Lorenz curve for clinically detected prostate cancer: x axis shows percentage of population with prostate specific antigen (PSA) above indicated concentrations, hence percentages run from 100 down to 0; y axis shows number of events that would be (more ...)
Fig 3 Lorenz curve for prostate cancer metastasis: x axis shows percentage of population with prostate specific antigen (PSA) above indicated concentrations, hence percentages run from 100 down to 0; y axis shows number of events that would be included (more ...)
Fig 4 Lorenz curve for death from prostate cancer: x axis shows percentage of population with prostate specific antigen (PSA) above indicated concentrations, hence percentages run from 100 down to 0; y axis shows number of events that would be included (more ...)
Table 5 Cumulative proportion (%) of cases (95% confidence intervals) above centiles of prostate specific antigen (PSA) concentration
Six men in our dataset had prostate specific antigen concentrations of 20 ng/ml or more, and four of these men died of prostate cancer. These men might have had incurable disease at the time of the blood sample and therefore prostate specific antigen based screening at this age would possibly have made little difference to their survival. In a sensitivity analysis, we excluded these six cases but saw no important influence on our findings: the proportion of deaths from cancer in men in the top quarter of prostate specific antigen remained at 90%. The proportion of deaths occurring in the top quarter was also unaffected if we excluded men dying of prostate cancer within five (91%) or 10 (89%) years.
Baseline free prostate specific antigen, free:total prostate specific antigen ratio, and hK2 predicted all three end points. Total prostate specific antigen, however, was the best single marker, and its predictive accuracy was enhanced only by the other kallikrein markers for men with concentrations above the median (table 6).
Table 6 Association between prostate cancer outcomes and total prostate specific antigen (PSA), free PSA, % free PSA, and kallikrein related peptidase 2 (hK2) at age 60, overall and for men with total PSA above median. Figures are areas under curve (95% (more ...)