Assessment of fluctuations in PSA levels relative to frequency of testing
Prostate-specific antigen testing is widely used for the early detection, staging, and monitoring of prostate cancer and is known to reduce morbidity and mortality. However, prostate-specific antigen (PSA) testing has significant limitations, including low specificity, as elevated PSA levels can also be found in benign prostatic hyperplasia and inflammation. A false-positive PSA can cause unnecessary follow-up testing and patient anxiety. Additional diagnostic workups, such as a prostate biopsy, have their own risks, such as infection, bleeding, and pain, and can lead to increased health care costs. Intra-individual variability in PSA levels may fluctuate by an average of 15 percent from one week to the next, which can impact medical decision-making. Even technical factors in the testing itself may cause PSA levels to fluctuate. Therefore, it may be unsound to rely on a single PSA test when considering further patient testing and workups. It is not clear which patients may benefit most from repeat testing. The authors conducted a study to determine annual PSA variability using samples from men who participated in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In this randomized trial, patients were examined annually during a six-year period for PSA variation. The intent was to evaluate the clinical utility of repeating a PSA test after an elevated value by identifying different predictors of a subsequent measurement below a certain threshold. The retrospective multicenter cohort study used data from men aged 54 to 75 years. All participants were enrolled in the screening arm of the randomized PLCO trial and received PSA testing annually over a six-year time frame between 1995 and 2006. Participants did not have a prostate cancer diagnosis. The investigators analyzed data from February 2023 to May 2025 and measured the proportion of PSA values above one of the three biopsy thresholds of interest (2.5, 3.0, and 4.0 ng/mL) that decreased below the threshold at the following annual PSA test. Of 11,000 men with complete PSA measurements across all six years of the study period, 2,700 had a PSA threshold of 2.5 ng/mL, 1,928 had a threshold of 3.0 ng/mL, and 952 had a threshold of 4.0 ng/mL for at least one test. Of interest, among all PSA values of 2.5 ng/mL or greater, 22 percent decreased to below 2.5 ng/mL by the following year’s measurement. The probability of a PSA measurement decreasing below the threshold increased with the higher thresholds and was similar for the 3.0 ng/mL threshold (25 percent) and 4.0 ng/mL threshold (30 percent). In addition, 54 percent of men with at least one PSA of 2.5 ng/mL or greater had a follow-up level below this threshold the following year. Slightly greater rates were observed for the higher PSA thresholds. Of importance, the study also found that a predictive scoring system that included prior and current PSA levels showed that patients with PSA levels persistently above thresholds had a probability of less than 10 percent of a PSA value decreasing below the threshold. The authors concluded that this study supports the utility of guideline recommendations to confirm elevated PSA results in most patients before performing further diagnostic evaluation. It also demonstrated that patients with a prior PSA score above a given threshold but no recent PSA score below that threshold should proceed to further diagnostic evaluation without repeat testing. The authors noted that further research is needed to determine the optimal time for repeat testing.
Pickersgill NA, Peré MM, Vertoscik EA, et al. Prostate-specific antigen levels among participants receiving annual testing. JAMA Oncol. 2025. doi.org/10.1001/jamaoncol.2025.3386
Correspondence: Dr. Sigrid V. Carlsson at carlssos@mskcc.org