Prospective comprehensive genomic profiling (CGP) of 3,343 primary and metastatic site prostate tumors

Background: Sequencing of prostate cancer has identified genomic alterations (GAs) with therapeutic implications (PMID: 29694820). To more fully inform targeted treatment strategies, we performed prospective CGP on 3,343 prostate tumors to better define the spectrum of GAs and assess signatures of genomic instability in primary and metastatic site tumors. Methods: Prostate cancer samples (1,525 primary site, 1,818 metastatic site) were assessed by hybrid capture-based CGP for all exons of 395 genes and select introns for 31 genes. Results were analyzed for base substitutions, short insertions/deletions (indels), rearrangements, and copy number alterations, as well as genomic signatures including genome-wide loss of heterozygosity (LOH), microsatellite instability (MSI) status and tumor mutational burden (TMB). Results: There was an average of 4.6 GAs per tumor. Frequently altered genes were TP53 (45%), PTEN (33%), TMPRSS2-ERG (31%) and AR (23%). Targetable BRAF/RAF1 fusions were mutually exclusive with ETS fusions. The PI3K (41%), G1/S cell cycle (24%) and WNT (16%) pathways were frequently altered. DNA repair GAs were frequent and included homologous recombination repair (HRR) (22%), Fanconi Anemia (4%), and mismatch repair (MMR) (4%) pathway GAs; 39% of DNA repair mutations were predicted to be germline. BRCA1/2, ATR and FANCA GAs were associated with high genome-wide LOH. Overall median TMB was low (2.6 mutations/Mb), although a subset (3%) were TMB-High; 71% of TMB-High cases were MSI-High. Metastatic tumors were enriched in AR, LYN, 11q13 amplicon (CCND1/FGF19/FGF4/FGF3), MYC, NCOR1, CDKN2A, RB1, and CTNNB1 GAs. AR GAs associated with anti-androgen resistance were frequent in metastatic site samples including amplification (28%), mutations (12%), and rearrangements (2%). Conclusions: Routine CGP frequently identified GAs that may inform targeted therapy or trial selection for metastatic prostate cancer: PI3K pathway GAs, HRR pathway GAs, and MSI-High/TMB-High genomic signatures may inform PI3K/AKT inhibitor targeted therapy, PARP inhibitors, and immunotherapy, respectively. DNA repair mutations were frequently germline, and patients with such mutations may require further testing and genetic counselling. Legal entity responsible for the study: Foundation Medicine. Funding: Has not received any funding. Disclosure: S.M. Ali, J. Chung, N. Dewal, L.M. Gay, Y. He, E.S. Sokol, S.Z. Millis, J.K. Killian, A.B. Schrock, V.A. Miller, J.S. Ross: Employee: Foundation Medicine. All other authors have declared no conflicts of interest.