Evaluating molecular alteration profiles to distinguish intraductal carcinoma of the prostate.

407 Background: Intraductal carcinoma of the prostate (IDC-P) is an intra-acinar and/or intraductal neoplastic epithelial proliferation that is a distinct entity in the 2016 WHO classification system for prostate cancer. Clinically, it is associated with higher grade tumors and a more aggressive disease course with a high risk of local recurrence and distant metastasis. However, the molecular underpinnings of IDC-P are not well elucidated. We present comprehensive molecular profiling data from the largest cohort of IDC-P cases reported to date, with direct comparison to a matched cohort of adenocarcinoma cases. Methods: We identified radical prostatectomy (RP) cases from Caris Life Sciences database, classified as prostatic adenocarcinoma with Grade Group 4-5 or had the words “cribriform”, “necrosis”, or “intraductal” in the pathology report, for which imaging files were available. Digitized H&E slides underwent central pathology review by a board-certified genitourinary pathologist (IW) to identify the presence of IDC-P according to the 2022 WHO classification. Cases with IDC-P were compared to cases without IDC-P on central review or lacked reference to “cribriform”, “necrosis”, or “intraductal” in the RP pathology report (non-IDC-P). Prostatic tumor specimens were sequenced at Caris Life Sciences via NextGen DNA Seq (592 gene panel or whole exome) and RNA Seq (whole transcriptome). Results: 4,880 cases were identified, of which 176 were confirmed to have IDC-P with median age of 63.5 years. 43% (76/176) of IDC-P cases were Grade Group 5 and 99% (175/176) were Grade Group 3 or higher. Compared to non-IDC-P cases, the IDC-P cohort had significantly more mutations in MUTYH (4.5% vs. 1.4%, p <0.01), FANCA (2.7% vs. 0.5%, p <0.01), NBN (2.5% vs. 0.6%, p <0.05), and MTOR (0.6% vs. 0.1%, p <0.05), and fewer alterations in AR (0% vs. 0.7%, p <0.01) and AR-V7 splice variants (5.5% vs. 6.2%, p <0.001). IDC-P tumors were enriched for DLL3 and CEACAM5 expression with lower expression of STEAP1, TROP2, ERBB2, and B7-H3 compared to non-IDC-P. Patients with IDC-P had significantly higher neuroendocrine prostate cancer (NEPC) signature scores, with similar AR signature scores compared to non-IDC-P. The tumor microenvironment of IDC-P tumors had significantly higher cell fractions of M2 macrophages and regulatory T cells, and fewer dendritic cells. Conclusions: Our findings demonstrate that IDC-P possesses a distinct molecular profile and immunologic phenotype. Specifically, we observed an increased prevalence of DNA repair alterations, including in the MUTYH gene. Furthermore, IDC-P showed an increased NEPC signature and a more immunosuppressive phenotype. This information is important for developing personalized treatment strategies for histologically distinct prostate cancer subsets.