Baseline Prostate-Specific Antigen Levels in Midlife Predict Lethal Prostate Cancer

Abstract

Purpose Prostate-specific antigen (PSA) level in midlife predicted future prostate cancer (PCa) mortality in an unscreened Swedish population. Our purpose was to determine if a baseline PSA level during midlife predicts lethal PCa in a US population with opportunistic screening. Materials and Methods We conducted a nested case-control study among men age 40 to 59 years who gave blood before random assignment in the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and β-carotene among 22,071 US male physicians initiated in 1982 and then transitioned into a prospective cohort with 30 years of follow-up. Baseline PSA levels were available for 234 patients with PCa and 711 age-matched controls. Seventy-one participants who developed lethal PCa were rematched to 213 controls. Conditional logistic regression was used to estimate odds ratios and the area under the receiver operating characteristic curve, with 95% CIs, of the association between baseline PSA and risk of lethal PCa. Results Median PSA among controls was 0.68, 0.88, and 0.96 ng/mL for men age 40 to 49, 50 to 54, and 55 to 59 years, respectively. Risk of lethal PCa was strongly associated with baseline PSA in midlife: odds ratios (95% CIs) comparing PSA in the > 90th percentile versus less than or equal to median were 8.7 (1.0 to 78.2) at 40 to 49 years, 12.6 (1.4 to 110.4) at 50 to 54 years, and 6.9 (2.5 to 19.1) at 55 to 59 years. A total of 82%, 71%, and 86% of lethal cases occurred in men with PSA above the median at ages 40 to 49, 50 to 54, and 55 to 59 years, respectively. Conclusion PSA levels in midlife strongly predict future lethal PCa in a US cohort subject to opportunistic screening. Risk-stratified screening on the basis of midlife PSA should be considered in men age 45 to 59 years.

Canadian Urological Association recommendations on prostate cancer screening and early diagnosis

“…Justification: Although the optimal age for starting PSA screening has not been vigorously studied, our recommendation for starting PSA screening at age 50 comes from the Goteborg trial, which provides randomized data on the benefits of screening in men starting at this age; 11 however, evidence from observational studies suggests that certain men may benefit from PSA screening at an earlier age, with a nearly 5% risk of developing lethal prostate cancer within 15 years for men aged 45-49 with a PSA >4 ng/ml. 38,39 Although it remains unclear which men will benefit from early PSA screening, family history imparts a substantially increased risk of prostate cancer diagnosis at a younger age. Particularly, men aged <50 with a family history of prostate cancer in a first-or second-degree relative have an approximately five-fold and two-fold increased risk of receiving a prostate cancer diagnosis, respectively.…”

“…40 Furthermore, the nested case-control study referenced above identified that the risk of developing metastatic disease within 15 years for a man of any age with PSA <1 ng/ml is very low. 39 As such, allowing a longer interval between PSA testing for these men is unlikely to result in an increase in prostate cancer morbidity or mortality and will potentially reduce the risk of over-detection as a result of leadtime bias or natural fluctuations in PSA levels.…”

“…[39][40][41] As such, we recommend that these men, if electing PSA screening, should undergo testing every two years. The ERSPC trial considered a positive test to be a PSA level of 3 ng/ml, while the Goteborg trial considered a positive test to be between 2.5 and 3.4 ng/ml (depending on the year of study).…”

The New US Preventive Services Task Force “C” Draft Recommendation for Prostate Cancer Screening

“…In fact, a growing body of evidence from nonrandomized but very wellcharacterized-and, in one case, completely uncontaminated-cohorts indicates that the use of PSA at earlier ages, when benign prostatic hyperplasia and related processes are less likely to drive false-positive PSA elevation, could effectively stratify men to early detection, repeat PSA testing, or extended deferral of further testing. Under such a strategy, the majority of men tested once at 45 or 50 yr could defer any further consideration of prostate cancer risk for a decade or more [14,15].…”

“…For a 55-yr-old man, the question is outcomes at 30 yr and more. While the guideline reflects the latest follow-up reported to date for the ERSPC trial, the evidence is abundantly clear that mortality risk increases sharply with longer follow-up, and that, by extension, the number of lives saved rises and the numbers needed to screen and treat fall accordingly [14][15][16][17]. Randomized trials yield valuable insights, but a new trial randomizing men younger than 50 yr is extremely unlikely at this stage, and avoiding contamination in a control arm in any developed country would be pragmatically impossible.…”