Faculty Bibliography

CONTEXT: Technical improvements in prostate magnetic resonance imaging (MRI) have resulted in the use of MRI to target prostate biopsies. OBJECTIVE: To systematically review the literature to compare the accuracy of MRI-targeted biopsy with standard transrectal biopsy in the detection of clinically significant prostate cancer. EVIDENCE ACQUISITION: The PubMed, Embase, and Cochrane databases were searched from inception until December 3, 2011, using the search criteria 'prostate OR prostate cancer'AND 'magnetic resonance imaging OR MRI'AND 'biopsy OR target'. Four reviewers independently assessed 4222 records; 222 records required full review. Fifty unique records (corresponding to 16 discrete patient populations) directly compared an MRI-targeted with a standard transrectal approach. EVIDENCE SYNTHESIS: Evidence synthesis was used to address specific questions. Where MRI was applied to all biopsy-naive men, 62% (374 of 599) had MRI abnormalities. When subjected to a targeted biopsy, 66% (248 of 374) had prostate cancer detected. Both targeted and standard biopsy detected clinically significant cancer in 43% (236 or 237 of 555, respectively). Missed clinically significant cancers occurred in 13 men using targeted biopsy and 12 using a standard approach. Targeted biopsy was more efficient. A third fewer men were biopsied overall. Those who had biopsy required a mean of 3.8 targeted cores compared with 12 standard cores. A targeted approach avoided the diagnosis of clinically insignificant cancer in 53 of 555 (10%) of the presenting population. CONCLUSIONS: MRI-guided biopsy detects clinically significant prostate cancer in an equivalent number of men versus standard biopsy. This is achieved using fewer biopsies in fewer men, with a reduction in the diagnosis of clinically insignificant cancer. Variability in study methodology limits the strength of recommendation that can be made. There is a need for a robust multicentre trial of targeted biopsies.

Integration of cellular signaling pathways with androgen receptor (AR) signaling can be achieved through phosphorylation of AR by cellular kinases. However, the kinases responsible for phosphorylating the AR at numerous sites and the functional consequences of AR phosphorylation are only partially understood. Bioinformatic analysis revealed AR serine 213 (S213) as a putative substrate for PIM1, a kinase overexpressed in prostate cancer. Therefore, phosphorylation of AR serine 213 by PIM1 was examined using a phosphorylation site-specific antibody. Wild-type PIM1, but not catalytically inactive PIM1, specifically phosphorylated AR but not an AR serine-to-alanine mutant (S213A). In vitro kinase assays confirmed that PIM1 can phosphorylate AR S213 in a ligand-independent manner and cell type-specific phosphorylation was observed in prostate cancer cell lines. Upon PIM1 overexpression, AR phosphorylation was observed in the absence of hormone and was further increased in the presence of hormone in LNCaP, LNCaP-abl and VCaP cells. Moreover, phosphorylation of AR was reduced in the presence of PIM kinase inhibitors. An examination of AR-mediated transcription showed that reporter gene activity was reduced in the presence of PIM1 and wild-type AR, but not S213A mutant AR. Androgen-mediated transcription of endogenous PSA, Nkx3.1 and IGFBP5 was also decreased in the presence of PIM1, whereas IL6, cyclin A1 and caveolin 2 were increased. Immunohistochemical analysis of prostate cancer tissue microarrays showed significant P-AR S213 expression that was associated with hormone refractory prostate cancers, likely identifying cells with catalytically active PIM1. In addition, prostate cancers expressing a high level of P-AR S213 were twice as likely to be from biochemically recurrent cancers. Thus, AR phosphorylation by PIM1 at S213 impacts gene transcription and is highly prevalent in aggressive prostate cancer.Oncogene advance online publication, 17 September 2012; doi:10.1038/onc.2012.412.