Prostate Ductal Adenocarcinoma Revisited: Clinicopathological and Genomic Characterization Identifies Heterogenous Group of Diseases with Implications for Patient Management

Prostate ductal adenocarcinoma (PDA) is an aggressive subtype of prostate adenocarcinoma (PA). It can be found either in the peripheral zone, typically associated with acinar PA, or centrally in or around the verumontanum as a urethral polyp. Whether centrally occurring PDAs are biologically and genetically different compared with peripheral PDA remains unknown. Thirty-five PDAs diagnosed on resection specimens were categorized into 3 groups based on PDA location (central [urethra] involvement only [PDA-C], both central and peripheral involvement [PDA-C&P], peripheral involvement only [PDA-P]) and analyzed for clinicopathological, genomic characteristics, and outcomes. Targeted next-generation DNA and RNA sequencing with full exon coverage of 1425 cancer-related genes was performed on 2 PDA-C, 8 PDA-C&P, and 12 PDA-P with a grossly dissectible population of viable PDA. In 11 PDA-P, the same patients' ductal and associated acinar components were sequenced separately. Of 35 PDAs, 2 (6%), 11 (31%), and 22 (63%) were PDA-C, PDA-C&P, and PDA-P, respectively. PDA-C&P compared with PDA-P presented with larger tumor size (median 45 mm vs 25 mm), % ductal component (100% vs 30%), ≥ pT3 disease (100% vs 64%), visceral metastasis (36% vs 0%), and cancer-specific mortality (27% vs 0%) (P < .05) and enrichment for at least 1 DNA damage and repair (DDR)-related gene alterations (BRCA2, ATM, CDK12, ERCC2) (63% vs 8%), and PI3K pathway alterations (37% vs none). PDA-Ps were enriched in FOXA1 alterations compared with PDA-C&P (75% vs 25%) including 5 (56%) having FOXA1 mutation in only ductal components. TMPRSS2::ERG fusion was present in only 1 patient with PDA-P in both ductal and acinar components. One patient with PDA-C and 3 with PDA-C&P exhibited novel gene fusion ACPP::FGFR2 and NF1::ADAP, FGFR2::POC1B, and RB1:TTTY3, respectively. In 2 patients with PDA-C, PDA was eradicated in transurethral resection with no residual disease in follow-up radical prostatectomy. PDA-C lacked alterations in DDR genes. Our findings suggest that PDAs are clinically and genetically heterogeneous diseases. Understanding the heterogeneity of PDA is critically important in determining its biological potential and facilitating optimal patient management.