Overdiagnosis and Lives Saved by Reflex Testing Men With Intermediate Prostate-Specific Antigen Levels

Abstract

Background: Several prostate cancer (PCa) early-detection biomarkers are available for reflex testing in men with intermediate prostate-specific antigen (PSA) levels. Studies of these biomarkers typically provide information about diagnostic performance but not about overdiagnosis and lives saved, the primary drivers of associated harm and benefit.

Methods: We projected overdiagnoses and lives saved using an established microsimulation model of PCa incidence and mortality with screening and treatment efficacy based on randomized trials. We used this framework to evaluate four urinary reflex biomarkers (measured in 1112 men presenting for prostate biopsy at 10 US academic or community clinics) and two hypothetical ideal biomarkers (with 100% sensitivity or specificity for any or for high-grade PCa) at one-time screening tests at ages 55 and 65 years.

Results: Compared with biopsying all men with elevated PSA, reflex testing reduced overdiagnoses (range across ages and biomarkers = 8.8-60.6%) but also reduced lives saved (by 7.3-64.9%), producing similar overdiagnoses per life saved. The ideal biomarker for high-grade disease improved this ratio (by 35.2% at age 55 years and 42.0% at age 65 years). Results were similar under continued screening for men not diagnosed at age 55 years, but the ideal biomarker for high-grade disease produced smaller incremental improvement.

Conclusions: Modeling is a useful tool for projecting the implications of using reflex biomarkers for long-term PCa outcomes. Under simplified conditions, reflex testing with urinary biomarkers is expected to reduce overdiagnoses but also produce commensurate reductions in lives saved. Reflex testing that accurately identifies high-grade PCa could improve the net benefit of screening.

Figure 1.

Two definitions of “nonthreatening” disease for a prostate cancer (PCa) diagnosed by prostate-specific antigen (PSA) screening. A) D’Amico classification of clinically localized PCa into low- (white), intermediate- (light gray), and high- (dark gray) risk groups. B) An overdiagnosed PCa (white) is any PCa that would not have been diagnosed during the patient’s remaining lifetime in the absence of screening.

Figure 2.

A microsimulation model of linked prostate-specific antigen (PSA) levels and prostate cancer (PCa) natural history and survival.

Figure 3.

A model of the relationship between prostate cancer early detection and the probability of cure associated with definitive treatment.

Figure 4.

Predicted 20-year cumulative incidence of prostate cancer death for men with prostate-specific antigen between 4.0 and 10.0 ng/mL at screening age 55 or 65 years by biopsy strategy. *IDEAL = ideal biomarker with 100% sensitivity or specificity for any PCa; IDEALhg = ideal biomarker with 100% sensitivity or specificity for high-grade PCa; MiPS = Michigan Prostate Score for any PCa; MiPShg = Michigan Prostate Score for high-grade PCa; PCa = prostate cancer; PCA3 = prostate cancer antigen 3; T2:ERG = TMPRSS2:ERG gene fusion.