Low PCA3 expression is a marker of poor differentiation in localized prostate tumors: exploratory analysis from 12,076 patients
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Mohammed Alshalalfa1, Gerald W. Verhaegh2,3, Ewan A. Gibb1, Maria Santiago-Jiménez1, Nicholas Erho1, Jennifer Jordan1, Kasra Yousefi1, Lucia L.C. Lam1, Tyler Kolisnik1, Jijumon Chelissery1, Roland Seiler1,4, Ashley E. Ross5, R. Jeffrey Karnes6, Edward M. Schaeffer7, Tamara T. Lotan8, Robert B. Den9, Stephen J. Freedland10, Elai Davicioni1, Eric A. Klein11 and Jack A. Schalken2,3
1GenomeDx Biosciences Inc., Vancouver, BC, Canada
2Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands
3Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
4Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
5James Buchanan Brady Urological Institute, Johns Hopkins Hospital, Baltimore, MD, USA
6Department of Urology, Mayo Clinic, Rochester, MN, USA
7Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
8Department of Pathology and Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
9Sidney Kimmel Cancer Centre, Thomas Jefferson University, Philadelphia, PA, USA
10Department of Surgery, Division of Urology, Center of Integrated Research on Cancer and Lifestyle, Samuel Oschin Comprehensive Cancer Center, Cedars Sinai Medical Center, Los Angeles, CA, USA
11Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
Mohammed Alshalalfa, email: firstname.lastname@example.org
Keywords: prostate cancer, PCA3, initial biopsy, prognosis, under-diagnosis
Received: November 16, 2016 Accepted: January 10, 2017 Published: February 07, 2017
Background: Prostate cancer antigen 3 (PCA3) is a prostate cancer diagnostic biomarker that has been clinically validated. The limitations of the diagnostic role of PCA3 in initial biopsy and the prognostic role are not well established. Here, we elucidate the limitations of tissue PCA3 to predict high grade tumors in initial biopsy.
Results: PCA3 has a bimodal distribution in both biopsy and radical prostatectomy (RP) tissues, where low PCA3 expression was significantly associated with high grade disease (p<0.001). PCA3 had a poor performance of predicting high grade disease in initial biopsy (GS≥8) with 55% sensitivity and high false negative rates; 42% of high Gleason (≥8) samples had low PCA3. In RP, low PCA3 is associated with adverse pathological features, clinical recurrence outcome and greater probability of metastatic progression (p<0.001).
Materials and Methods: A total of 1,694 expression profiles from biopsy and 10,382 from RP patients with high risk tumors were obtained from the Decipher Genomic Resource Information Database (GRIDTM)prostate cancer database. The primary clinical endpoint was distant metastasis-free survival for RP and high Gleason grade for biopsy. Logistic regression analyses and Cox proportional hazards models were used to evaluate the association of PCA3 with clinical variables and risk of metastasis.
Conclusions: There is high prevalence of high grade tumors with low PCA3 expression in the biopsy setting. Therefore, urologists should be warned that using PCA3 as stand-alone test may lead to high rate of under-diagnosis of high grade disease in initial biopsy setting.
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