Michael Cook

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NCI

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PLCO (Learn more about this study)

2012-0312

Oct 22, 2012

Expression levels and prostate cancer recurrence in PLCO

Identifying biomarkers that differentiate men who experience prostate cancer recurrence from those who experience a more indolent course after initial treatment is essential to reduce overtreatment. This study aims to identify, validate, and characterize candidate gene expression signatures associated with prostate cancer recurrence among men with clinically localized prostate cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Focused efforts have identified a multitude of expression differences in prostate cancer compared to benign prostate tissues, although few expression signatures have replicated across studies due to small validation sets. A collaborative team from OEEB, OD, BB, and LTG has just completed a pilot study to identify novel expression candidate markers using RNA-sequencing, an extremely sensitive state-of-the-art technology, resulting in the most comprehensive and systematic genome-wide evaluation of expression biomarkers with prostate cancer recurrence status to date. We propose a large follow-up study to validate and characterize the most prominent expression differences unique to recurrent status in the PLCO Cancer Screening Trial comparing 1003 PLCO prostatectomy tumor and benign paired tissue samples from men with clinically localized prostate cancer using immunohistochemistry performed on tissue microarrays. We will fit Cox Proportional Hazards models with biochemical recurrence, metastasis, or prostate cancer death as the outcome and the protein score as the independent variable, adjusting for relevant confounders and stratifying by clinicopathologic features. If these candidate markers prove to be useful biomarkers of prostate cancer recurrence, they may aid patients and clinicians when making initial treatment decisions, and thus, reduce overtreatment. In addition, these biomarkers may illuminate additional pathways that expand our understanding of the biological mechanisms most important to prostate cancer progression, which could provide the foundation for improved therapeutic interventions.

Hypothesis: Key molecular changes unique to prostate cancer recurrence occur prior to initial treatment increasing the likelihood of micrometastatic cells escaping and growing outside the primary tumor site elevating risk for recurrence and metastasis.

Primary Aim: To validate and characterize candidate gene expression signatures associated with subsequent prostate cancer recurrence among men with clinically localized prostate cancer. Candidates for staining will be selected based on pilot data generated by RNA-sequencing and a thorough review of the existing literature. Differences in gene expression patterns by recurrence status will be validated by comparing 1003 PLCO prostatectomy tumor and benign paired tissue samples from men with clinically localized prostate cancer using immunohistochemistry performed on tissue microarrays.

Secondary Aim: To evaluate the clinical utility of the candidate gene expression signature. We will use the ROC curve to test the predictive value of the expression marker signature beyond the standard clinicopathologic features typically used in risk prediction.