Molecular alteration profiles characterize intraductal carcinoma of the prostate.

Abstract

Intraductal carcinoma of the prostate (IDC-P) is an intra-acinar and/or intraductal neoplastic epithelial proliferation that is a distinct histological entity according to the 2016 World Health Organization (WHO) classification system. Clinically, it is associated with higher grade tumors and a more aggressive disease course. However, the molecular underpinnings of IDC-P are not well elucidated. This study identified radical prostatectomy (RP) cases from the Caris Life Sciences database, classified as prostatic adenocarcinoma with grade group 4/5 or with the words "cribriform," "necrosis," or "intraductal" in the pathology report. Digitized hematoxylin-eosin slides underwent central pathology review by a board-certified genitourinary pathologist to identify the presence of IDC-P according to the 2022 WHO classification. IDC-P cases (n = 175) were compared to non-IDC-P cases (n = 5334). Prostatic tumor specimens were sequenced via next-generation DNA/RNA sequencing. Compared to non-IDC-P cases, the IDC-P cohort had significantly more mutations in MUTYH (4.5% vs. 1.4%; p < .01), FANCA (2.7% vs. 0.5%; p < .01), NBN (2.5% vs. 0.6%; p < .05), and MTOR (0.6% vs. 0.1%; p < .05). IDC-P tumors were enriched for DLL3 and CEACAM5 expression, with lower expression of STEAP1, TROP2, ERBB2, PSCA, and B7-H3, compared to non-IDC-P tumors. IDC-P had significantly higher neuroendocrine prostate cancer signature scores and IFN-γ signature scores, and similar androgen receptor signature scores, compared to non-IDC-P. The tumor microenvironment of IDC-P had significantly higher cell fractions of M2 macrophages and fewer dendritic cells. IDC-P possesses a distinct molecular and immunological profile. Understanding these molecular underpinnings is crucial for the development of personalized treatment strategies for histologically distinct prostate cancer subsets.