Clinical, environmental, genetic, and genomic profile of men with early-onset aggressive prostate cancer: A final report.
Authors: Fenton Sarah Elizabeth , Santana-Santos Lucas , Kocherginsky Masha , VanderWeele David James , Morgans Alicia K. , Palmbos Phillip Lee , Meeks Joshua J , Hussain Maha H. A. 
Published: June 2024

e17078 Background: Patients (pts) diagnosed with advanced prostate cancer (PCa) at a young age frequently have inferior outcomes compared to pts diagnosed later in life and rates of PCa diagnosis in this population have been increasing. However, the clinical, environmental, and genetic drivers of disease in this population have not been well characterized. Methods: This multisite study evaluated pts with early-onset (age ≤ 60 years) PCa with de novo metastasis (N+ or M+) or who relapsed within 5 years of definitive local therapy. Data were collected to define clinical, environmental, and genetic profiles, including whole genome and transcriptome sequencing using Tempus xE. Standard descriptive statistics were used. Results: 46 pts with metastatic hormone sensitive PCa were enrolled, the median age at diagnosis was 55 (range 41-60 years). Median PSA at diagnosis was 19 (range 1-534 ng/mL), 56% had a Gleason score 9-10, and 56% had de novo metastatic PCa. The most frequent sites of metastasis were to lymph nodes (67%) and bone (65%). Clinical data including biochemical exposures were recorded but rates of these factors were similar to prior studies evaluating pts of all ages. 4% of pts served in the U.S. Armed Forces, they denied Agent Orange exposure. 85% of pts reported a family history of cancer in a first degree relative (ex. breast and colon cancer), 46% had family history of PCa. Genetic data is available for 40 pts. Germline mutations associated with PCa were found in 15%, all were in the DNA damage repair pathway (BRCA2 5%, CHEK2 5%, PALB2 2.5%, ATM 2.5%). 19 mutations associated with non-PCa hereditary illnesses were identified, the clinical significance of these is unknown. The most common somatic mutations were TP53 (55%), TMPRSS2-ERG (37.5%), SPOP (15%) and PTEN (12.5%). Clinically significant somatic mutations were identified in 46 genes. Over 1,700 variants of unknown significance were identified. Transcriptomic data was collected for 25 pts and RNA levels were compared to expression levels in older pts through the TCGA database. Differential expression was detected in 10 genes. Conclusions: This cohort study focused on the clinical and genetic factors associated with aggressive PCa at a young age. An unusually high rate of PCa was identified in first degree relatives of enrolled pts. However, rates of clinically relevant germline mutations were similar to published data. Gene expression was also similar to what has been detected in older pts diagnosed with metastatic PCa. Previous studies evaluating young PCa pts suggest that this is a distinct clinical entity with poor outcomes. However no clear signal was identified in this analysis of the clinical, environmental and genetic contributors of disease in this pt population, suggesting further work is necessary to identify novel risk factors. Funding: This study was funded by Prostate Cancer FoundationChallenge Award (2017Chal2044).