Background: Although PCa incidence has stabilized/decreased in most age groups, the incidence of metastatic disease has increased among men 50-69 years-old. The incidence of fatal PCa has decreased for most age groups, it has remained unchanged in men under 55 years-old. Studies have described genetic abnormalities in aggressive localized or end-stage PCa, but early-onset cases are not included or are under-represented. The primary objective of this study is to characterize the clinical, environmental, genetic and genomic features of high-risk advanced PCa.

Methods: Study cohort includes men with PCa ≤ 60 years old with N1 or M1 stage at diagnosis or who develop metastases in 5-years after local therapy. Clinical (race, family history (Hx), environmental exposure), laboratory,/pathology, cell-free DNA germline analysis were collected. Primary/metastatic tumor tissue tested via the Tempus-Xe platform (DNA sequencing, whole transcriptome expression profiling, copy number analysis, comprehensive fusion gene analysis and calculation of tumor mutational burden). We report interim analysis.

Results: Study completed accrual with 30 pts. Median age 55 years (41-60), 87% are white, 13% are black, 77% had a family Hx of malignancy in 1-6 family members, including 40% with family hx of PCa. Only 33% had Hx of smoking. Median Gleason score 9. Only 27% had nodal disease, and 73% had metastatic disease at diagnosis. Molecular data are available in 25 pts. Most common germline mutations: BRCA2 (12%), ATM (12%), RB1 (8%), MSH3 (8%) and MYBPC3 (8%). Most common somatic mutations:TP53 (40%), TMPRSS2-ERG fusion (32%), MUC4 (16%), PTEN (12%), C2CD4D (12%), SPOP (12%), OBSCN (12%), MXRA5 (12%), and MYO15A (12%). Microsatellite stability status was available in 15 pts and all were stable. Tumor mutational burden was low in all pts, ranging between 0.7 to 2.7 mutations/megabase.

Conclusions: Our preliminary data suggest high rates of germline mutations in early onset lethal PCa. This aggressive subset of disease requires further studying to better characterize the underlying clinical/genomic factors driving this disease.

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