Low PCA3 expression is a marker of poor differentiation in localized prostate tumors: Exploratory analysis from 12,076 patients

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.