Clinical, environmental, genetic, and genomic profile of men with early-onset aggressive prostate cancer.
Authors: Fenton Sarah Elizabeth , Kocherginsky Masha , VanderWeele David James , Morgans Alicia K. , Palmbos Phillip Lee , Meeks Joshua J. , Benning James , Martone Brenda K. , Szymaniak Brittany , Hussain Maha H. A. 
Published: June 2022

e17049

Background: Although prostate cancer (PC) is heterogeneous, the rate of patients diagnosed with aggressive metastatic disease at a young age has been increasing. Prior studies defining genetic abnormalities in high-risk PC have not focused on this unique population of patients, thus the clinical and molecular features of these lethal PC phenotypes are not well described. Methods: This multi-institutional study evaluated two cohorts. Cohort 1, reported here, included early-onset (age ≤ 60) PC that was metastatic (N+ or M+) at diagnosis or PC that metastasized within 5 years post curative intent/local therapy. Cohort 2 included men with metastatic hormone sensitive PC who rapidly progressed (≤ 14 months) after systemic therapy. Data was collected to define clinical and genomic profiles, including sequencing of somatic & germline DNA, circulating tumor DNA and tumor RNA. Standard descriptive statistics were used. Results: 44 patients were enrolled. Median age at diagnosis was 55 years (range 41-60); 84% were White and 14% were Black. Median prostate specific antigen at diagnosis was 20 (range 1-534 ng/mL). 54% reported a family history of PC, while breast and colorectal cancer were reported in 35% and 14%, respectively. 4.5% reported a history of biochemical agent exposure. 58.5% of patients had De Novo distant metastatic disease (56% of these were low-volume) and 59.5% had a Gleason score of 9-10. 59% had received prior local therapy. Germline and somatic genetic data are available for 36 patients (4 are pending). The most common somatic mutation was in TP53 (n=15), followed by BRAF (n=14), AR (n=7), ERBB3 & MYC (n=5 each), CDKN2B, HRAS, MUC4, OBSCN & SPOP (n=4 each). Additional unique mutations in over 1,000 genes were also identified. Germline mutations were detected in BRCA2, ATM, ATP7B & FBN1 (n=3 each), RB1, CDH1, MYBPC3, MYH11 & MYH7 (n=2 each). 11 other unique germline mutations were also identified. Germline mutations were identified in genes previously implicated in hereditary PC ( BRCA2, ATM, PALB2, BRIP1 & CHEK2), with an overall germline incidence of 25%. There were also incidental germline mutations in genes related to hereditary cardiac conditions ( MYBPC, MYH11, MYH7), as well as other hereditary cancers ( RB1 and CDH1). Conclusions: This study evaluated specific criteria to define risk factors associated with the development of aggressive PC at a young age. Nearly 90% of these patients had a family history of cancer, with over 50% reporting a family history of PC. Somatic mutations were identified in genes such as TP53 that are frequently associated with aggressive disease. Additionally, there was enrichment for germline mutations associated with PC that exceeded what has previously been reported and enrichment of mutations not commonly included in PC genetic risk panels. Thus, more work is needed to define characteristics of this high-risk population and optimize management.