Circulating tumor (ct) DNA-based genomic profile of prostate cancer (PCa) patients with elevated carcinoembryonic antigen (CEA).

Abstract

218 Background: Neuroendocrine (aggressive variant) PCa patients often have elevated CEA (40-85%), which is associated with poor outcomes. We used ctDNA analysis to identify a genomic pattern for PCa patients with elevated CEA (CEA+ PCa). Methods: We analyzed ctDNA-based genomic profiles (Guardant 360) from 32 patients with CEA+ PCa. Profiles were compared with genomic profiles from the TCGA database, ctDNA profiles for 50 consecutive PCa patients with normal CEA levels (CEAnl PCa), and ctDNA profiles for GI tumors associated with elevated CEA. Results: CEA+ PCa patient profiles showed concordance with TCGA database genomic profiles for neuroendocrine PCa. There was high similarity in genes amplified; however many more single-nucleotide variants (SNVs) were detected with ctDNA analysis. For ctDNA profiles of CEA+ PCa, the most commonly amplified genes were AR, PIK3CA, MYC, CDK6, BRAF, MET; the most common clonal SNVs were in TP53, PTEN, APC, PIK3CA, and MET. Serial ctDNA analyses were done in 23 CEA+ PCa patients, of which 8 showed conversion from CEAnl to CEA+ PCa. This change was accompanied by emergence of new amplifications (62.5%; AR, MET, MYC, BRAF, EGFR, CDK6) or SNVs (tumor suppressor genes [ APC, TP53] or mitogen signaling pathways [ BRAF, ERBB2, KRAS, MET, PIK3CA]). Clonal mutations present in CEAnl PCa frequently persisted after emergence of a CEA+ phenotype. CEA+ PCa differed from CEAnl PCa by the higher prevalence of AR amplifications (p = 0.033), higher AR copy number (p = 0.004), and lower number of AR clonal mutations (p = 0.0017). AR amplification was significantly more frequent in CEA+ PCa (50%) than in another CEA+ malignancy, colon cancer (3%). AR amplification copy number was also much higher in CEA+ PCa than in colon cancer (p = 0.0023). Conclusions: ctDNA analysis shows AR amplifications as highly associated with CEA+ and neuroendocrine PCa. New amplifications occur during evolution from CEAnl to CEA+ PCa. Genomic profile obtained using ctDNA (within limits) is comparable to TCGA database. AR amplification is characteristic of CEA+ PCA and may distinguish this entity from other cancers with elevated CEA.