Abdulkadir, Sarki Clinical, Environmental, Genetic and Genomic profile of Men with Early Onset Lethal Prostate Cancer

Despite recent progress in the treatment of metastatic hormone sensitive and castration-resistant prostate cancer metastatic prostate cancer continues to be the terminal phase in the natural history of the disease with a median survival of about 4 years. This short median survival is a major medical concern and unmet need for all patients and especially younger men at diagnosis of metastatic disease. Of major concern are 2 recent trends: 1. The observation that a significant percentage of men with potentially deadly disease are diagnosed at a young age (< 60 years); Hoffman et al. have shown an increased incidence of prostate cancer presenting with distant disease in younger men ages 50 to 69 years from 2004 to 2012 (annual percentage change, 1.7; 95% CI, 0.2 to 3.2). Two randomized clinical trials data indicate that a significant % of men with metastasis are < 60 years old. In S9346; a randomized intergroup/international trial in new M1 patients 18% of men (all-comers Step 1, N=3000 + were 60 years or younger. A significant percentage of younger men with new metastatic disease have De Novo mets at diagnosis as reflected by data from CHAARTED where among 575 patients without prior local therapy (median age is 62) and among patients who are <60 years old at randomization (n=274), 80.3% (n=220) did not have prior local therapy. Similarly in another intergroup trial S9921 (N= XX) that was designed to evaluate the role of adjuvant therapy in high risk prostate cancer post radical prostatectomy 15% of men 60 years or younger had pathologic N1 disease. 2. Another concerning trend is the observation that some men with metastatic hormone sensitive disease progress during or shortly after initiation of ADT + docetaxel or ADT alone. These 2 groups of patients provide a significant clinical challenge given the frequently aggressive clinical course, very terminal nature of the disease, and limited understanding of clinical/molecular pathogenesis. Here, we propose an ambitious, first-in-field approach to better characterize the biological profile of unquestionably deadly prostate cancer. Critical understanding of the latter will lead to better clinical interventions at the detection and treatment levels. The studies described will systematically explore untouched territory in prostate cancer and will provide the first assessment of this deadly subtype of the disease. Aims: 1. Characterize the clinical, environmental and genomic profiles of men presenting with early-onset (age < 60) potentially lethal prostate cancer (N1 or M1) a. Define the clinical profile (race, family history, testosterone level, metastatic disease extent and distribution). b. Identify driver mutations, tumor clonality and mutation signature of young men with lethal prostate cancer and compare tumors from young men based on clinical (race, hormonal level), exposure (veterans based on deployment) c. Determine the germline risk variants of young men with lethal prostate cancer, utilizing the million veterans program stratifying men by race and deployment exposure. 2. Characteristics the clinical/genomic predictors and mechanisms of early progression on ADT +/- docetaxel (< 1 year). Secondary Objectives 1. To assess molecular features of primary tumors and metastatic sites using multiple genomic platforms (i.e., next generation sequencing of primary tumor, genetic analysis of circulating tumor DNA, fresh frozen sample for RNA sequencing). 2. To prospectively correlate clinical and molecular characteristics with treatment outcomes.