Prostate-Specific Antigen–Based Risk Assessment in Younger Men

Loeb and colleagues present an interesting and timely review of prostate-specific antigen (PSA) testing in younger men, titled ‘‘Baseline Prostate-Specific Antigen Testing at a Young Age’’ [1]. In the article, younger is defined as 60 yr. Intuitively, it makes sense that PSA may be a better tumor marker in younger men. Serum levels are less likely to be confounded by coexistent benign prostatic hyperplasia, and as has been described in many autopsy series, many such men already harbor small tumors. These features underlie the presumption that younger men with the highest serum PSA values are at highest risk for a later diagnosis of important prostate cancer (PCa). Moreover, compared with older men, younger men have more risk of death from a diagnosis of PCa and the most to gain from treatment. The Scandinavian Prostate Cancer Group-4 study showed an overall benefit for treatment of PCa, but in stratified analysis this benefit was limited to men 75 yr [3]; Drazer et al showed that 45% of men in their 70s, were tested [4]. Moreover, few organizations have advocated PSA testing in younger men. While the American Urological Association and the National Comprehensive Cancer Network in the United States now recommend starting discussions about PSA testing in men at the age of 40 yr [5], the European Association of Urology guidelines and others from a variety of primary care organizations do not specify 40 yr as the age at which to start PCa early detection efforts in average-risk men [6]. Such caution stems from concerns about both overdiagnosis of cancers that might not be harmful to patients and the lack of randomized data on which to base recommendations. The three large randomized trials in the literature—the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial [7]; the Prostate, Lung, Colorectal and Ovary (PLCO) trial [8]; and the Goteborg trial [9]—did not address PSA testing among younger men. In the ERSPC study, the core age range of men was 55–69 yr, with the mean and median age of participants just >60 yr. In the PLCO trial, the age range was 55–74 yr, with nearly 70% of patients >60 yr. In the Goteborg study, the age range of participants was lower than in the ERSPC and PLCO studies, 50–64 yr. The median age at first invitation to screening was 56 yr. None of the studies addressed PSA testing among men <50 yr. Thus, all recommendations about PSA testing in younger age groups rely on observational data. As Loeb and colleagues explain, these observational data are of mixed quality for answering the question of when to offer men PSA testing. Prospective cohort studies in which PCa cases and mortality were ascertained independently of PSA testing provide substantial support for the concept of measuring PSA at younger ages. In these studies, serum from participants was stored, this serum was later checked for PSA levels, and the PCa status of the participants was ascertained based on clinically diagnosed PCa. This prospective cohort design eliminates the selection bias that occurs when clinical screening data are analyzed. In contrast, studies in which the serum PSA level has been used to justify the need for, and intensity of, further PSA screening introduce a significant selection bias. Men with higher PSA levels are more likely to continue PSA testing and ultimately are more likely to have a prostate biopsy