Improving Prostate Cancer Screening and Diagnosis: Health Policy and Biomarkers Beyond PSA

The initial goal of prostate cancer screening with prostatespecific antigen (PSA) was to identify men with early-stage disease according to the general oncologic principle of secondary prevention that early diagnosis and treatment would prevent disease progressionand improve survival. However, 2 randomized clinical trials evaluating PSA screening and a large body of literature have identified unintended harms of overdiagnosis and overtreatment of potentially indolentprostatecancer.1,2TherevisedUSPreventiveServices Task Force grade D recommendation for PSA screening in 2012, stating that there is a lack of evidence that its benefits outweigh itsharms, further thrustprostate cancer screening into the spotlight of health policy in the United States.3 Recently, one of the intended consequences of the US Preventive ServicesTaskForce recommendationwas realized in that fewer men are being screened for and diagnosed with prostate cancer,withanestimated33000fewer incident cases in 2012 than in 2011.4 Although a uniform recommendation against screeningcan reduceoverdiagnosis andovertreatment of low-riskdisease, it also reduces theopportunity todiagnose higher-riskdisease, inwhich treatmenthas beenproven to reduce deaths from prostate cancer. Amore nuanced approach toPSAscreeningbasedona systematic reviewof the literature was proposed in 2013 by theAmericanUrological Association guideline for the earlydetectionof prostate cancer.5Although the review also investigated other serum and urine biomarkersofprostatecancer, suchasPSAisoforms, theProstateHealth Index, prostate cancer antigen 3 assay, and TMPRSS2-ERG fusion,6 the quality of the reviewed data was insufficient for determining their role in screening. In the current prospective cohort study reported in JAMA Oncology,McKiernanand colleagues7 demonstrate thepotential utility of a urine-based 3-gene exosome expression assay utilizing SAM pointed domain containing ETS transcription factor, ERG, and PCA3 (ExoDx Prostate IntelliScore, Exosome Diagnostics) to discriminate prostate cancer with a Gleason score of 7 ormore from that with a Gleason score of 6 and benign disease at initial biopsy. The population forwhich use of the assaywas intended includedmenolder than50yearswith no prior biopsy and a PSA value between 2 and 10 ng/mL (to convert tomicrograms per liter,multiply by 1.0). Similar estimates of the area under the curve were seen in the training (0.74) and validation (0.71) cohorts for the assay, with statistically significant improvements inmodel areaunder thecurve when the test was added to standard-of-care variables alone. Inapracticalapplication,applyingacutoffvalue fromthetraining cohort to serve as a threshold for biopsy in the validation cohort showed that 27% (138 of 519) of initial biopsies could havebeenavoidedat the cost ofmissing8%(12of 148) of prostate cancers of a Gleason score of 7 or more. A cutoff adjustment avoided 37% (192 of 519) of biopsies at a cost ofmissing 13% (19 of 148) of prostate cancers of a Gleason score of 7 or more (only 4 of the 19 patients had prostate cancer with a Gleason score including dominant pattern 4 disease). McKiernan and colleagues7 suggest that this 3-gene expression signature assay and similar tests could provide a route to reducing thediagnosis of low-riskprostate cancer and decreasing the number of unnecessary prostate biopsies. Instead of uniformly halting efforts to screen for early-stage prostate cancer, the focus shifts to detecting clinically significant disease.Notably, thepopulation included23% (55of 237) of menwith digital rectal examinations that raised the suspicionof prostate cancer and25% (64of 255) ofmenwith a familyhistoryofprostatecancer.These factors, combinedwithPSA values, led to the decision to perform a biopsy of the prostate, which resulted in a diagnosis of prostate cancer in almost half of the men in the study population and the finding that more than one-fourth of the study population had a Gleason score of 7 or more. The performance of the 3-gene expressionassay ina randomsampleofmennot scheduled for biopsy is unknown, making it uncertain whether the assay holds promise as an independent screening modality. Longitudinal assessment of the assay in a screening cohort will provide more data. Therefore, the current role of the 3-gene expression signature assay, if validated in external cohorts, would be as a secondary or reflex test for risk stratification in the setting of exercising stewardship with PSA screening, as suggested in theAmericanUrological Association guidelines, rather than as ameans of completely stopping PSA screening. The introduction of an effective reflex test for risk stratification adds an additional procedure to health policy efforts to combat overdiagnosis and overtreatment of prostate cancer. Health policy considerations in these efforts can be listed in downstream order from population-based screening to individualizedmanagementdecisions. The first step in this process includes guideline statements by the American Urological Association advocating shared decision making for men aged 55 to 69 years and PSA screening intervals of 2 years or more,5 resembling the2009USPreventiveServicesTaskForce recommendation for screeningmammography.A second step is effective risk stratification before conducting a diagnostic biopsy by using a validated gene-expression signature, such Related article page 882 Opinion