Commentary

PSA screening: Back to the future

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ACTIVE SURVEILLANCE CAN REDUCE OVERTREATMENT

In parallel with the design and completion of these trials, there was a significant effort to better identify and manage patients initially overdiagnosed with nonlethal cancers by developing active surveillance regimens.

This management strategy recognizes that most low-grade cancers pose no short-term risk to the patient’s health or longevity, that definitive therapy can be deferred, and that with regular monitoring by digital rectal examination, PSA measurement, and repeat biopsy, cancers that progress can still be cured. The result of this strategy is a marked reduction in the harms caused by overtreatment (ie, the aforementioned adverse effects), as well as the avoidance of unnecessary treatment in many patients.

A randomized trial and 2 large prospective cohort studies have confirmed the long-term safety of this approach,7–9 and the development of commercially available, biopsy-based gene expression profiling tools promises to further improve risk stratification at diagnosis and during follow-up for individual patients.10

NEW USPSTF RECOMMENDATIONS: AN INDIVIDUAL, INFORMED DECISION

Based on the results of the ERSPC and the widespread adoption and safety of active surveillance, which together show benefit to screening and fewer harms in overdetection and overtreatment, in 2018 the USPSTF recast its recommendations. In upgrading the recommendation from “D” to “C,” the recommendation now states that for men ages 55 to 69, PSA screening should be an individual decision after a discussion with an informed provider, although men over 70 are still advised not to undergo screening at all.11

Some may think that this recommendation has arrived just in time, or that it should be made even stronger to actually recommend screening, as recent data from 2 national registries—the Surveillance, Epidemiology, and End Results program and the National Cancer Database—show that the fall in screening after the 2012 USPSTF guidelines has resulted in an increase in men presenting with advanced stage disease.12,13 (All of you Back to the Future fans, please return to the mid to late 1980s to see how that plays out.)

So the pendulum has now swung back in favor of screening, largely supported by solid data showing meaningful clinical benefit, better understanding of PSA and prostate cancer biology, and adoption of active surveillance.

AN IDEAL SCREENING PROGRAM

An ideal screening program would detect only biologically significant cancers, thus eliminating overdetection and overtreatment. There is reason for optimism on this front.

Second-generation PSA tests have better diagnostic accuracy for high-grade disease than earlier tests. Two such tests, the Prostate Health Index (Beckman Coulter) and the 4K-score (Opko Health), are commercially available though not usually covered by commercial insurers.14 A third test, IsoPSA (Cleveland Diagnostics), is under development. Most hospital laboratories will be able to be run this test with no need for a central laboratory.15 All 3 tests have been shown to reduce unnecessary biopsies (because of a low probability of finding a biologically significant cancer) by 30% to 45% and will help reduce overdetection.

Moreover, multiparametric magnetic resonance imaging of the prostate has been shown to improve detection of high-grade cancers,16 and a randomized trial has suggested that its incorporation into a screening strategy is cost-effective and could be better than PSA testing plus transrectal ultrasonography alone (the current standard of care).17

Several risk scores based on germline genomics also hold promise for better identifying those at risk and for helping to de-intensify screening for those unlikely to have high-grade cancer.18

Screening for prostate cancer reduces mortality rates and the burden of metastatic disease, and the paradigm continues to evolve. Men at risk by virtue of age (55 to 69, and healthy men > 70), family history, race, and newly identified factors (germline genetics) all deserve an informed discussion on the benefits and risks of screening

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