We have replicated our finding that PSA measured at age 44–50 is a very strong predictor of prostate cancer clinically diagnosed many years later. Our observations now extend to cancers diagnosed more than 25 years later, and to PSA measured in men before age 40. We confirmed that our findings are not restricted to cancers of questionable clinical significance, but apply to cancers that are palpable and to those locally advanced or metastatic at diagnosis. With the greater number of cases in this update, we have the statistical power to provide more precise estimates for the association between early PSA and advanced cancers, such that even the lower bound of the confidence interval is of clear clinical relevance.
As in a prior study (7), early measurements of the additional kallikreins (free PSA, free-to-total PSA ratio, and hK2) did not importantly aid prediction beyond that of PSA alone. We noted, however, that among men with elevated PSA (≥0.95 ng/ml), the additional kallikreins moderately enhanced prediction of clinically diagnosed prostate cancers, albeit the utility of these markers may be greater if measured closer to the time of diagnosis.12
Further, several studies provided evidence that they can aid in prostate cancer screening as indication for biopsy, particularly in men with moderately elevated PSA.20, 21
Our conclusions on the long-term predictive value of PSA are consistent with several earlier studies.4–6, 8, 9
. The current study is distinguished by its inclusion of a highly representative population-based sample of unscreened men, rather than those subject to PSA screening. Therefore, our study has little or no verification bias.
A limited number of studies have been conducted on the long-term association between PSA and subsequent prostate cancer diagnosis in unscreened men. In a study of 21,172 Finnish men, baseline PSA was ≥2.5 ng/ml in 95% of men diagnosed with cancer within the first 5 years and 52% diagnosed within 6–10 years. Gann et al., analyzing 366 Physicians’ Health Study participants diagnosed with prostate cancer, reported that serum PSA was elevated 5–6 years before the identification of a palpable tumor. Similar results have been reported for participants in the prospective Baltimore Longitudinal Study of Aging. However, this report includes far more cases at much longer follow-up.
A limitation of our study is that we examined cancer diagnosis, rather than morbidity or mortality from cancer. Nevertheless, the advanced cancers in our analysis represent an important endpoint, because they are highly likely to affect quality or length of life if left untreated. Another possible limitation is that, although the national guidelines continue to recommend against screening, PSA testing has become more common in Sweden in recent years,22
and some of the more recent cases may have been detected due to PSA testing. Nevertheless, differences from our previous results7, 10, 12
were slight and, perhaps most importantly, findings were highly robust for advanced cancers.
Interestingly, the participants with advanced cancer diagnosed more than 25 years after baseline were a heterogeneous subset. Most were men in their 40’s at baseline with cancer diagnosed late—after age 75. A substantial fraction, however, were men younger than 40 years at baseline, with advanced cancer diagnosed before age 60; these cancers are therefore presumably highly aggressive. That early PSA was predictive many years before diagnosis for this heterogeneous group underscores the strength of its association with cancer risk.
The predictive accuracy of PSA at age 44–50 compares favorably to that of other means of assessing prostate cancer risk: race, family history of prostate cancer, and genetic markers associated with the disease. For example, in this study early PSA had AUC 0.72 for predicting any prostate cancer, whereas 5 SNPs had an AUC of 0.57.23
A SNP near the gene encoding PSA (KLK3
) has been reported to associate with prostate cancer risk, as well as with serum PSA level.24, 25
Its influence on cancer risk has, however, been disputed,26
and in any case its predictive value appears to be far less than that of an early PSA measurement.
The finding that PSA levels can indicate future prostate cancer risk for men below age 40 has intriguing biological implications. Cancer-related PSA elevations are generally held to result from the cancer disrupting the tissue architecture, thereby allowing PSA to leak into extracellular space. Under this view, a relatively high PSA level before age 40 in a man later diagnosed with cancer would be explained by the prostate already harboring prostate cancer, or possibly a premalignant condition. Addressing such issues will provide important directions for research on prostate cancer chemoprevention. We are, however, cautious about any clinical implications of PSA before age 40; for example, we see no rationale for starting PSA screening at this age.
The major clinical implication of this study is that an early PSA value could be used to individualize later screening for prostate cancer, generally recommended to begin around age 50. Based on our study results, we propose that the frequency of screening be determined by a risk appraisal based on early PSA level before age 50. Consistent with our data, a PSA at 45 would be appropriate, although there may be cases, such as men with a strong family history, in which an earlier PSA, such as at age 40, would be indicated. Men with PSA levels below the median (~0.6 ng/mL) might be expected to benefit little from subsequent annual or even biennial PSA checkups. As yet, we do not have sufficient data to suggest that these men need no further screening, but it appears reasonable to suggest that they be asked to return for a screening around age 55–60. Men with high early PSA levels - those in the top 10–25% (~ 1 ng/ml) - could be advised that they are at high risk for advanced prostate cancer and that it is critical that they return for frequent (e.g. annual or biennial) screening. Those at intermediate risk, above the median but below the top 10–25%, could be advised to return for screening at intervals of no more than 4 years, which has been found to allow detection of most prostate cancers while they are still confined to the prostate and therefore curable.1, 27
Compared to screening all men, this stratified screening strategy would also likely reduce the incidence of unnecessary prostate biopsy. Consider, for example, a man with an early PSA below median, who sometime after age 50 has a temporary elevation of PSA because of asymptomatic prostatitis. A strategy of annual screening for all men would likely lead to an unnecessary biopsy for such a man.
In conclusion, an early PSA, taken at or before age 50, is a strong predictor of advanced prostate cancer diagnosed 25 or more years later. Given that we have replicated our prior results on an independent set of cases, and that our findings are derived from a large, highly representative study that was subject to little or no verification bias, we consider our findings to be highly robust. Based on these findings, we advocate a change in the clinical paradigm for prostate cancer screening. Whereas currently the use and frequency of PSA-based screening are determined largely by national practice patterns, we propose that screening frequency be determined by individual risk as assessed from an early PSA test. Early PSA testing could also serve as the foundation for a more comprehensive risk assessment that also includes genetic markers, family history, race, and risk factors defined in the future.