The Malmö Preventive Medicine cohort was enrolled before the PSA era, and there was no subsequent recommendation for prostate cancer screening in this region. The rate of PSA testing has accordingly remained very low up to our current study endpoint [2]. Furthermore, the participation rate (74%) was high and case ascertainment was complete owing to the excellent coverage of the Swedish National Cancer Registry [13]. Our study is therefore not subject to the sort of verification and selection biases commonly associated with prostate cancer studies and provides a 'natural experiment' to test hypotheses concerning the long-term prediction of prostate cancer.
Our results describe the relationship between prostate kallikreins in blood plasma obtained at a single occasion at age 50 or below and the diagnosis of advanced prostate cancer up to 25 years later. We found that prostate-specific kallikreins were significantly increased decades before the clinical manifestation of advanced disease. The predictive accuracy of total PSA was very high (AUC 0.791). Modestly increased levels of total PSA in the ranges of 1.01–2 ng/ml and 2.01–3 ng/ml were associated with 7- and 22-fold elevated odds of advanced prostate cancer, respectively. The majority of advanced cancers (66%) occurred in the 20% of the population with the highest PSA levels. It is also noteworthy that our study of archived blood samples is taken from a highly representative, population-based sample. There was no selection based on test results (indeed, this would not have been possible, as the PSA test was not available during the period when bloods were drawn). As such, we can be confident that our reported test characteristics reflect those of the population to which we would like to apply our results.
These results confirm our previous finding of an association between PSA levels and subsequent prostate cancer, and suggest that this association is not restricted to cancers unlikely to affect a man's survival or quality of life. Indeed, we found total PSA to be more strongly predictive of subsequent advanced prostate cancer (AUC 0.791) than of any prostate cancer (AUC 0.762). This illustrates the rule of thumb that it is easier to predict more extreme medical events. Free-to-total PSA ratio and hK2, two markers associated more specifically with malignancy, were far less predictive than total PSA, a marker associated with both benign and malignant prostate conditions. This suggests that PSA elevations in cases below or at age 50 may be related to a premalignant state, or to a carcinogenic process, rather than the presence of malignant cells in the prostate.
A possible limitation of our study is that any definition of clinically significant prostate cancer is open to question. However, we repeated our analysis altering our definition of advanced cancer to be more restrictive (only patients with skeletal metastases at diagnosis) or more inclusive (skeletal metastases or clinical stage al least T3 or positive lymph nodes or grade III at time of diagnosis) and found no important differences in our results. It might also be argued that death from prostate cancer would be the most appropriate endpoint, but owing to a small number of events in our current study cohort, statistical analysis would have been underpowered. Future studies will address the relationship between kallikreins and death from prostate cancer as the cohort matures.
Previously, both our group and other investigators have studied the association between PSA level in the blood and the long-term risk of being diagnosed with any stage of prostate cancer, but did not specifically address whether these findings were applicable to diagnosis of advanced tumors [1, 14–16]. Our findings reconfirm previous analyses suggesting that prostate cancer can be predicted many years before it is diagnosed and that we might therefore reduce prostate cancer mortality by intervening at an early stage when curative treatment is still possible.
Current US prostate screening guidelines recommend that all men over age 50 who have a life expectancy of at least 10 years should have an annual digital examination and PSA test. Results from ongoing screening trials show that these recommendations result in over-diagnosis and over-treatment. For example, the Rotterdam section of the European Randomized Screening Study for Prostate Cancer have shown that almost 50% of screen-detected cancers are indolent (organ-confined, Gleason 6 or less, and 0.5 cc or less in volume) and thus unlikely to affect a man's survival or quality of life [17]. Over-treatment is associated not only with high morbidity, such as poor erectile, bowel and urinary function resulting from surgery or radiotherapy, but also high healthcare costs. A screening program that focused on those at highest risk of prostate cancer morbidity or mortality might well have a superior benefit-to-harm ratio compared with the current approach of screening all men. One scenario might be to make exceptional efforts to ensure that all men obtain a PSA test in their mid to late forties. Although a man with a PSA elevated above the threshold for biopsy (e.g. 3 ng/ml) could be referred for immediate biopsy, this would be very rare (~1–2% in the current data set); the primary purpose of the early PSA test would be to determine which men should be invited back for regular screening at age 50 and which men advised that PSA screening is unlikely to benefit them.
This study is based on a previously published case-control study in which we attempted to predict the occurrence of prostate cancer at any stage. We did not re-match for this study and hence patients with a prostate cancer diagnosis were not included in the sample from which controls were selected. We note that kallikrein levels of these 301 participants are likely to be higher than those of Malmö Preventive Medicine participants not diagnosed with prostate cancer, thus inflating differences between cases and controls in our current analysis. However, the original Malmö Preventive Medicine cohort contains approximately 21,270 participants who could act as controls, from whom 436 controls were randomly chosen to be included in our current analysis. As there were 462 prostate cancer cases, we would expect prostate cancer patients to comprise approximately 2% of the control group. Therefore, we conclude that our failure to sample from non-advanced prostate cancer cases is unlikely to have any major effect on the current results.