Genomic alterations in intraductal prostate cancer: Insights from the Genomic Umbrella Neoadjuvant study (GUNS) in high-risk localized disease.

417 Background: Intraductal carcinoma of the prostate (IDC) is an aggressive histological variant of prostate cancer, characterized by the presence of malignant cells within the prostatic ducts. Retrospective studies have shown IDC linked to higher tumor grades and odds of lymphatic metastasis and worse oncological outcomes. In patient derived xerograph models, IDC can persist after castration, with a subpopulation of castrate tolerant cells able to regenerate upon testosterone restoration. This suggests that IDC contributes to therapy resistance and highlights the need to understand molecular alterations of IDC. This study aims to evaluate genomic profiles of these tumors in the GUNS trial. Methods: From 9/2021 to 8/2024, GUNS enrolled 95 patients in Canada. Diagnostic biopsies underwent Tempus’ CLIA-certified 648-gene panel DNA sequencing. A total of 93 patients were evaluable for genomic alterations. Of those, 81 additionally had immunohistochemistry (IHC) staining for PTEN. All biopsy specimens were centrally reviewed by TvK. Associations between IDC and genomic alterations or PTEN IHC staining (positive vs. negative/heterogeneous) were assessed by Fisher’s exact test, and the false discovery rate (FDR) was controlled using the Benjamini-Hochberg method. Only genomic alterations annotated as biologically significant by Tempus were considered for analysis. Results: Of the 93 evaluable patients, 36 (39%) had IDC on biopsy. PTEN IHC status showed a significant association with IDC status, with negative or heterogeneous PTEN IHC staining being more prevalent among IDC-positive cases (p = 0.002; FDR q = 0.05). Specifically, PTEN IHC staining was negative/heterogeneous in 15/32 (47%) IDC-positive cases but only 7/49 (14%) IDC-negative cases. Genomic PTEN (22% vs. 7%) and TP53 (19% vs. 9%) alterations were also more common in IDC-positive cases than IDC-negative cases, although these trends were not statistically significant. Conversely, CDKN1B was exclusively altered in IDC-negative cases (0% vs. 9%), and BRCA2 alterations (germline or somatic) were also more frequent in IDC-negative cases (3% vs 11%), but these observations were also not statistically significant. Relatively low frequencies of genomic alterations were likely impediments to statistical significance, warranting larger sample sizes to assess these trends. Conclusions: Negative or heterogeneous PTEN IHC staining was more common in IDC-positive cases, consistent with the known association between PTEN loss and aggressive disease. PTEN IHC status, along with other genetic markers, may help to define subgroups within prostate cancer that differ in their underlying biology and response to neoadjuvant treatment. This highlights the importance of integrating molecular and histological data to better understand prostate cancer progression and to tailor therapeutic approaches.