Risk-stratified multi-round PSA screening for prostate cancer integrating the screening reference level and subgroup-specific progression indicators

BACKGROUND: Although prostate-specific antigen (PSA) is widely used in prostate cancer (PCa) screening, nearly half of PCa cases are missed and less than one-third of cases are non-lethal. Adopting diagnostic criteria in population-based screening and ignoring PSA progression are presumed leading causes. METHODS: A total of 31,942 participants with multi-round PSA tests from the PLCO trial were included. Time-dependent receiver-operating-characteristic curves and area under curves (tdAUCs) were performed to determine the screening reference level and the optimal subgroup-specific progression indicator. Effects of risk-stratified multi-round PSA screening were evaluated with multivariable Cox regression and measured with hazard ratio [HR (95%CIs)]. RESULTS: After a median follow-up of 11.6 years, a total of 3484 PCa cases and 216 PCa deaths were documented. The tdAUC of 10-year incidence PCa with PSA was 0.816, and the cut-off value was 1.61 ng/ml. Compared to subgroup with stable negative PSA in both first-round (FR) and last-round (LR) tests [FR(−)/LR(−)], HRs (95%CI) of PCa incidence were 1.66 (1.20–2.29), 8.29 (7.25–9.48), and 14.52 (12.95–16.28) for subgroups with loss of positive PSA[FR(+)/LR(−)], gain of positive PSA[FR(−)/LR(+)], and stable positive PSA[FR(+)/LR(+)]; while HRs(95%CI) of PCa mortality were 1.47 (0.52–4.15), 5.71 (3.68–8.86), and 5.01 (3.41–7.37). After excluding regressive PSA [(namely FR(+)/LR(−)], absolute velocity was the shared optimal progression indicator for subgroups with FR(−)/LR(−), FR(−)/LR(+), and FR(+)/LR(+), with tdAUCs of 0.665, 0.681 and 0.741, and cut-off values of 0.07, 0.21, and 0.33 ng/ml/year. After reclassifying participants into groups with positive and negative progression based on subgroup-specific progression indicators, incidence HR (95%CI) were 2.41 (1.87–3.10), 2.91 (2.43–3.48), and 3.16 (2.88–3.46) for positive progression compared to negative progression within subgroups of FR(−)/LR(−), FR(−)/LR(+), and FR(+)/LR(+), while mortality HR (95%CI) were 2.22 (0.91–5.38), 2.37 (1.28–4.38), and 2.98 (1.94–4.59). To improve screening performances by excluding regressive PSA and low-risk positive progression in FR(−)/LR(−), optimized screening strategy not only significantly reduce 32.4% of missed PCa (54.0% [1881/3484] vs. 21.6% [754/3484], P < 0.001), but also detected additional 8.0% of high-grade PCa (Gleason score 7–10: 36.0% [665/1849] vs. 28.0% [206/736], P < 0.001) than traditional screening strategy. CONCLUSIONS: Risk-stratified multi-round PSA screening strategy integrating the screening reference level and the optimal subgroup-specific progression indicator of PSA could be recommended as a fundamental strategy to reduce missed diagnosis and improve the detection of high-grade PCa cases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40001-023-01228-x.