Clinical implications of molecular alterations in intraductal carcinoma of the prostate.
Authors: Miron Benjamin , Wei Shuanzeng , Baca Yasmine , Herchenhorn Daniel , Cunha Isabela Werneck , Zarrabi Kevin Kayvan , Brown Jacqueline T , Oberley Matthew James , Nabhan Chadi , Antonarakis Emmanuel S. , Geynisman Daniel M. , McKay Rana R. 
Published: June 2023

5024 Background: Intraductal carcinoma of the prostate (IDC-P) is a recent addition to the 2016 WHO classification system and little is known about the nature of its true incidence and biology. Clinically, it has been observed to be associated with higher grade group tumors and a more aggressive disease course with a high risk of local recurrence and distant metastasis. However, the molecular underpinnings which define IDC-P are not well elucidated. Initial case series with molecular profiling have suggested an enrichment of alterations in DNA damage/repair (DDR), PI3K, WNT and MAPK pathways. We now present comprehensive molecular profiling data from the largest cohort of IDC-P reported to date in order to better characterize this relatively new histologic entity. Methods: Eligible patients included those with radical prostatectomy tumor tissue labeled as IDC-P on testing requisition with available tissue-based DNA and RNA sequencing utilizing a commercially available CLIA-certified assay (Caris Life Sciences). Prostatic tumor specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 genes and NovaSeq, WES). Digitized H&E slides underwent central pathological review by a board certified pathologist (SW) specializing in genitourinary malignancies to confirm presence of intraductal histology according to the 2022 WHO classification. Results: 31 of 44 submitted cases were confirmed to be IDC-P on central review. Median age of patients was 64 yrs (range 44-79). The majority of cases (26/31 - 84%) were Grade Group 5 and all were Grade Group 3 or higher. Overall the most frequently detected alterations were in TP53 (39%), TMPRSS2 fusion (39%), FOXA1 (16%), CDK12 (10%), PIK3CA (10%), SPOP (10%), ATM (7%), AKT1 (7%) and RB1 (5%). The most commonly altered pathways were in cell cycle regulators (50%), DDR ( BRCA1/2, ATM, CDK12) (23%), and PI3K/AKT/MTOR (23%) and WNT (10%). The FOXA1 mutation rate in this cohort was higher compared to the localized prostate cancer cohort from the TCGA (16% - 5/31 vs 6% - 82/1325). In the IDC-P cohort, there were no tumors which demonstrated mismatch-repair deficiency (dMMR) or microsatellite instability and none of the profiled tumors had a high tumor mutational burden (≥10 mutations/megabase). Conclusions: This data suggests that IDC-P harbors targetable molecular alterations in DDR genes ( BRCA1/2 and CDK12) with approved targeted agents (e.g. PARP inhibitors). These findings should underscore the importance of germline and somatic mutation testing when IDC-P is identified. We also found enrichment of oncogenic FOXA1 mutations in IDC-P which are associated with prostate cancer progression, castrate-resistance and an unfavorable prognosis. Further efforts are ongoing to expand this cohort of IDC-P cases and compare them with a matched cohort of pure adenocarcinoma cases and will include analysis of key RNA expression signatures.