The long-term goal of this project is to further reduce the biological uncertainty associated with surveillance for favorable-risk prostate cancer. Although most men with favorable-risk disease are candidates for surveillance, its use varies widely and ranges from 20 to 90% across individual providers. A major barrier to implementation by providers, and acceptance by patients, relates to uncertainty around the biology of Grade Group 1 (GG1; Gleason 6) prostate cancer. Key unresolved questions include: Does GG1 prostate cancer progress over time? Does GG1 cancer share molecular origins with higher-grade disease and lymph node metastases? Are there molecular features of GG1 tumors that predict the presence of synchronous, but undetected, higher-grade disease elsewhere in the prostate? Is GG1 cancer more aggressive in African Americans? To be sure, the biological trajectory of GG1 prostate cancer represents a critical knowledge gap. We hypothesize that GG1 prostate cancer rarely undergoes clonal grade progression, and that molecular changes in GG1 cancer do not predict the presence of synchronous higher-grade disease. To test these hypotheses, we propose the following aims: 1) to determine if high-grade prostate cancer arises clonally from GG1 prostate cancer in men on surveillance over time, 2) to molecularly dissect GG1 prostate cancer both within and without the context of synchronous grade discordant multifocality, and 3) to interrogate primary multifocal prostate cancer for shared clonality between GG1 and higher-grade disease/lymph node or distant metastases. The successful completion of the aims of this project will alter the way men with GG1 prostate cancer are clinically managed by further reducing uncertainty about the clinical and molecular arc of favorable-risk disease. Practically, these findings have the potential to provide confidence to providers and patients when selecting surveillance for GG1 prostate cancer by reducing concerns over clonal disease progression and by shedding light on the likelihood of co-existing higher-risk cancer that has yet to be detected—factors that play key roles in the selection and effective implementation of surveillance. Our research team composed of experts in prostate cancer management, molecular profiling, and bioinformatics, coupled with our distinctive and extensive access to relevant tissue resources, is uniquely poised to complete our research plan. PHS 398/2590 (Rev. 6/09) Page Continuation Format Page

The goal of this project is to define the biological fate of low risk (Grade Group 1) prostate cancer in both African and European Americans. This project will allay patient concerns related to disease progression and the presence of co-existing higher-grade cancer—factors that play central roles in the safe and effective implementation of surveillance. Ultimately, findings from this research will enhance patient selection for surveillance and inform how to improve the quality of its implementation.