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Original Investigation
May 18, 2017

Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer

Author Affiliations
  • 1Department of Urology, Emory University School of Medicine, Atlanta, Georgia
  • 2Department of Biostatistics, The University of Texas, MD Anderson Cancer Center, Houston, Texas
  • 3Department of Biostatistics, Rollins School of Public Health, Emory University, Atlanta, Georgia
  • 4Department of Urology, University of Michigan, Ann Arbor, Michigan
  • 5Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan
  • 6Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
  • 7Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
  • 8Hologic Inc, San Diego, California
  • 9Hofstra North Shore–LIJ School of Medicine, The Arthur Smith Institute for Urology, New Hyde Park, New York
  • 10Department of Urology, Weill-Cornell Medical Center, New York, New York
  • 11Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
  • 12University of Texas Health Sciences Center – San Antonio, Texas
  • 13Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, California
  • 14Department of Pathology, Weill-Cornell Medical Center, New York, New York
JAMA Oncol. Published online May 18, 2017. doi:10.1001/jamaoncol.2017.0177
Key Points

Questions  Can urinary testing of prostate cancer–associated RNA (PCA3 and TMPRSS2:ERG) improve detection of aggressive prostate cancer (Gleason score, ≥7), and how would such testing affect health care costs?

Findings  In this prospective diagnostic study of 1077 men, urinary RNA parameters that significantly improved specificity for predicting prostate cancer were identified in the developmental cohort and improvement of specificity for predicting aggressive cancer (33% vs 17%) was confirmed in a validation cohort. Potential health care cost savings were shown by modeling the effect of urinary PCA3 and TMPRSS22:ERG testing.

Meaning  Urinary testing for TMPRSS2:ERG and PCA3 can avert unnecessary biopsy with consequent potential health care cost savings.


Importance  Potential survival benefits from treating aggressive (Gleason score, ≥7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease.

Objective  To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs.

Design, Setting, and Participants  Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort.

Interventions/Exposures  Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy.

Main Outcomes and Measures  Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes.

Results  Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men.

Conclusions and Relevance  Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings.