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Context: Biomarker-driven cancer therapy, also referred to as precision oncology, has received increasing attention for its promise of improving patient outcomes by defining subsets of patients more likely to respond to various therapies., Objective: In this collaborative review article, we examine recent literature regarding biomarker-driven therapeutics in urologic oncology, to better define the state of the field, explore the current evidence supporting utility of this approach, and gauge potential for the future., Evidence Acquisition: We reviewed relevant literature, with a particular focus on recent studies about targeted therapy, predictors of response, and biomarker development., Evidence Synthesis: The recent advances in molecular profiling have led to a rapid expansion of potential biomarkers and predictive information for patients with urologic malignancies. Across disease states, distinct molecular subtypes of cancers have been identified, with the potential to inform choices of management strategy. Biomarkers predicting response to standard therapies (such as platinum-based chemotherapy) are emerging. In several malignancies (particularly renal cell carcinoma and castration-resistant prostate cancer), targeted therapy against commonly altered signaling pathways has emerged as standard of care. Finally, targeted therapy against alterations present in rare patients (less than 2%) across diseases has the potential to drastically alter patterns of care and choices of therapeutic options., Conclusions: Precision medicine has the highest potential to impact the care of patients. Prospective studies in the setting of clinical trials and standard of care therapy will help define reliable predictive biomarkers and new therapeutic targets leading to real improvement in patient outcomes., Patient Summary: Precision oncology uses molecular information (DNA and RNA) from the individual and the tumor to match the right patient with the right treatment. Tremendous strides have been made in defining the molecular underpinnings of urologic malignancies and understanding how these predict response to treatment-this represents the future of urologic oncology., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Prostate cancer screening by digital rectal examination and prostate specific antigen testing has been routine clinical practice in the United States for the last 25 years. Recent studies have shown a national decline in prostate specific antigen testing following the USPSTF (United States Preventive Services Task Force) recommendation against routine prostate specific antigen screening. However, to our knowledge the effect of this recommendation on digital rectal examination utilization remains unknown., Materials and Methods: We used NAMCS (National Ambulatory Medical Care Survey) to characterize trends in the rate of digital rectal examination and prostate specific antigen testing by primary care physicians in men older than 40 years presenting for preventive care. From 2005 to 2012 NAMCS contained 3,368 such visits (unweighted) for the study of digital rectal examination trends and 4,035 unweighted visits from 2002 to 2012 for the study of prostate specific antigen trends., Results: Following the USPSTF recommendation the proportion of visits where digital rectal examination was performed decreased from 16.0% (95% CI 13.1-19.5) to 5.8% (95% CI 4.0-8.3, p <0.001). Similarly, the proportion of visits where prostate specific antigen testing was performed decreased from 27.3% (95% CI 24.5-30.3) to 16.7% (95% CI 12.9-21.2, p <0.001). This represents a relative 64% decrease in digital rectal examination and a 39% decrease in prostate specific antigen testing. Among men 55 to 69 years old the number of visits where digital rectal examination and prostate specific antigen testing were performed decreased 65% and 39%, respectively (p <0.001)., Conclusions: Utilization of digital rectal examination and prostate specific antigen has declined significantly following the release of the USPSTF recommendation against prostate specific antigen screening. This suggests that prostate cancer screening is rapidly disappearing from primary care practice., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Prostate cancer is a clinically heterogeneous disease, with some men having indolent disease that can safely be observed, while others have aggressive, lethal disease. Over the past decade, researchers have begun to unravel some of the genomic heterogeneity that contributes to these varying clinical phenotypes. Distinct molecular sub-classes of prostate cancer have been identified, and the uniqueness of these sub-classes has been leveraged to predict clinical outcomes, design novel biomarkers for prostate cancer diagnosis, and develop novel therapeutics. Recent work has also elucidated the temporal and spatial heterogeneity of prostate cancer, helping us understand disease pathogenesis, response to therapy, and progression. New genomic techniques have provided us with a window into the remarkable clinical and genomic heterogeneity of prostate cancer, and this new perspective will increasingly impact patient care.

Objectives: Prostate cancer has a variable clinical course, and molecular characterization has revealed striking mutational heterogeneity that may underlie the unpredictable clinical behavior of the disease. Advances in technology have resulted in a rapid expansion of our understanding of the genomic events responsible for the development and progression of prostate cancer. In this review, we discuss the genomic alterations underlying prostate cancer, and potential to utilize this knowledge for diagnostic and prognostic benefit., Methods and Materials: We reviewed the relevant literature, with a focus on recent studies on somatic alterations in prostate cancer., Results: Pathways known to affect tumorigenesis across a wide spectrum of tissues are dysregulated, such as the PI3K pathway, cell cycle control, and chromatin regulation. Lesions more specific to prostate cancer include alterations in androgen signaling, gene fusions of ETS transcription factors, and mutations in SPOP. Accumulating data suggests that prostate cancer can be subdivided based on a molecular profile of these genetic alterations., Conclusions: These findings raise the possibility that prostate cancer could transition from a poorly understood, heterogeneous disease with a variable clinical course to a collection of homogenous subtypes, identifiable by molecular criteria, associated with distinct risk profiles, and perhaps amenable to specific management strategies or targeted therapies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Recurrent mutations in the Speckle-Type POZ Protein (SPOP) gene occur in up to 15% of prostate cancers. However, the frequency and features of cancers with these mutations across different populations is unknown., Objective: To investigate SPOP mutations across diverse cohorts and validate a series of assays employing high-resolution melting (HRM) analysis and Sanger sequencing for mutational analysis of formalin-fixed paraffin-embedded material., Design Setting and Participants: 720 prostate cancer samples from six international cohorts spanning Caucasian, African American, and Asian patients, including both prostate-specific antigen-screened and unscreened populations, were screened for their SPOP mutation status. Status of SPOP was correlated to molecular features (ERG rearrangement, PTEN deletion, and CHD1 deletion) as well as clinical and pathologic features., Results and Limitations: Overall frequency of SPOP mutations was 8.1% (4.6% to 14.4%), SPOP mutation was inversely associated with ERG rearrangement (P<.01), and SPOP mutant (SPOPmut) cancers had higher rates of CHD1 deletions (P<.01). There were no significant differences in biochemical recurrence in SPOPmut cancers. Limitations of this study include missing mutational data due to sample quality and lack of power to identify a difference in clinical outcomes., Conclusion: SPOP is mutated in 4.6% to 14.4% of patients with prostate cancer across different ethnic and demographic backgrounds. There was no significant association between SPOP mutations with ethnicity, clinical, or pathologic parameters. Mutual exclusivity of SPOP mutation with ERG rearrangement as well as a high association with CHD1 deletion reinforces SPOP mutation as defining a distinct molecular subclass of prostate cancer.

DeltaNp63alpha is a nuclear transcription factor that maintains epithelial progenitor cell populations, is overexpressed in several epithelial cancers, and can negatively regulate apoptosis. However, the mechanisms by which DeltaNp63alpha promotes cell survival are unclear. DeltaNp63alpha has been reported to act as a transcriptional repressor, but specific target genes directly repressed by DeltaNp63alpha remain unidentified. Here, we present evidence that DeltaNp63alpha functions to negatively regulate the proapoptotic protein IGFBP-3. Disruption of p63 expression in squamous epithelial cells increases IGFBP-3 expression, whereas ectopic expression of DeltaNp63alpha down-regulates IGFBP-3. DeltaNp63alpha binds to sites in the IGFBP-3 gene in vivo and can modulate transcription through these sites. Furthermore, DeltaNp63alpha and IGFBP-3 expression patterns are inversely correlated in normal squamous epithelium and squamous cell carcinomas. These data suggest that IGFBP-3 is a target of transcriptional repression by DeltaNp63alpha and that this repression represents a mechanism by which tumors that overexpress p63 may be protected from apoptosis.