The Role of Baseline Prostate-specific Antigen Value Prior to Age 60 in Predicting Lethal Prostate Cancer: Analysis of a Contemporary North American Cohort

Background and objective: Studies evaluating the role of baseline midlife prostate-specific antigen (PSA) as a predictor of development and progression of prostate cancer relied predominately on cohorts from the pre-PSA screening introduction era. The aim of our study was to examine the role of baseline PSA prior to the age of 60 yr as a predictor of developing lethal prostate cancer using a contemporary North American cohort.

Methods: Our cohort included all men aged 40-59 yr who received their first PSA through our health system between the years 1995 and 2019. Patients were divided into four categories based on age: 40-44, 45-49, 50-54, and 55-59 yr. Baseline PSA was the predictor of interest. Lethal disease was defined as death from prostate cancer or development of metastatic disease either at diagnosis or during follow-up. Cancer-specific mortality and overall mortality were obtained by linking our database to the Michigan Vital Records registry. Competing-risk regression was used to evaluate the association between PSA and lethal prostate cancer.

Key findings and limitations: A total of 129067 men met the inclusion criteria during the study period. The median follow-up for patients free from cancer was 7.4 yr. For men aged 40-44, 45-49, 50-54, and 55-59 yr, the estimated rates of lethal prostate cancer at 20 yr were 0.02%, 0.14%, 0.33%, and 0.51% in men with PSA <median, and 0.79%, 0.16%, 2.5%, and 5.4% in men with PSA ≥90th percentile, respectively. For the same age category, the estimated rates of any prostate cancer at 20 yr were, respectively, 1.6%, 2.9%, 3.9%, and 5.8% in men with PSA <median, and 25%, 28%, 38%, and 39% in men with PSA ≥90th percentile. On a multivariable analysis, men with PSA ≥90th percentile had a hazard ratio of 7.48 (95% confidence interval [CI]: 6.20-9.03) for lethal disease, when compared with those with PSA <median. On the multivariable analysis, men with PSA ≥90th percentile had a hazard ratio of 20.47-fold (95% CI: 18.58-22.55) for prostate cancer incidence, when compared with those with PSA <median at first. Limitations included shorter median follow-up than prior literature.

Conclusions and clinical implications: Baseline PSA is a very strong predictor of the subsequent risk of developing lethal prostate cancer in a large contemporary diverse North American cohort, which was exposed to opportunistic PSA screening. The association was far larger than that found for polygenic risk scores, confirming that baseline PSA prior to the age of 60 yr is the most effective tool for adjusting subsequent screening. Compared with studies of unscreened cohorts, there was a smaller difference in discrimination between incident and lethal disease, reflecting the influence of screening.

Patient summary: In this study, we found that a single baseline prostate-specific antigen (PSA) value is strongly predictive of the subsequent risk of developing metastatic prostate cancer, as well as the risk of dying from prostate cancer. The initial PSA level can therefore be used to adjust the frequency of subsequent PSA testing.