ESTRO 2025 - Abstract Book

S2146

Clinical - Urology

ESTRO 2025

4644

Poster Discussion Genomic and Transcriptomic Analysis of Radiorecurrent Prostate Cancer

Beth K Neilsen 1 , Rong Rong Huang 2 , Luca F Valle 1 , James Proudfoot 3 , Elai Davicioni 3 , Una Ryg 4 , Melanie Schulz Jaavall 4 , Joanne B. Weidhaas 1 , Milisuryani Santoso 1 , Jeremie Calais 5 , Robert E. Reiter 6 , Matthew B. Rettig 6 , Michael L. Steinberg 1 , Anthony Sisk 2 , Wayne Brisbane 7 , Leonard S. Marks 7 , Paul C. Boutros 7 , Wolfgang H. Lilleby 4 , Amar U. Kishan 1 1 Radiation Oncology, University of California, Los Angeles, Los Angeles, USA. 2 Pathology, University of California, Los Angeles, Los Angeles, USA. 3 Veracyte, Veracyte Inc, San Diego, USA. 4 Urological Oncology, Oslo University Hospital, Oslo, Norway. 5 Nuclear Medicine, University of California, Los Angeles, Los Angeles, USA. 6 Medical Oncology, University of California, Los Angeles, Los Angeles, USA. 7 Urology, University of California, Los Angeles, Los Angeles, USA Purpose/Objective: Very little is known about the biological underpinnings of intraprostatic recurrences after definitive radiotherapy for prostate cancer. An understanding of their biology may have implications for the management of both recurrent and newly diagnosed prostate cancer. We hypothesize there are conserved molecular profiles associated with local radioresistance. Material/Methods: Forty-one locally radiorecurrent (LRR) prostate cancer tumors from 36 unique patients treated at two large academic centers were profiled using a targeted pan-cancer DNA sequencing panel as well as RNA expression (Veracyte, San Diego, CA). Genomic alteration frequencies within LRR PC were compared to alteration frequencies in treatment naïve PC from The Cancer Genome Atlas (TCGA). Significance was assessed using Chi-squared analysis. Transcriptomic data were compared to de-identified data from the Decipher Genomics Resource Information Database (GRID; NCT02609269, n = 146,865), which was accessed to create a subset (n=28,577) of patients identified by matching Gleason grade (GG) group with the LRR cohort. Standardized mean differences were used to assess for small (<0.4), moderate (0.4-0.7) and large (>0.7) differences between the cohorts. Results: The LRR cohort included patients with relatively aggressive disease including 17% with GG5, 20% with GG4, 15% GG3 and 20% unassigned. The LRR PC cohort demonstrated enrichment in PI3K pathway alterations compared to treatment naïve PC within TCGA with alteration frequencies in PTEN of 12% (5/41) vs 3%, (p = 0.005) and PIK3CA of 12% (5/41) vs 2% (p < 0.001). Other genetic alterations enriched in LRR PC include BRCA1 (10%, 4/41), PTCH1 (22%, 9/41), MSH3 (12%, 5/41), and STAG2 (34%, 14/41). However, no common genetic alteration was conserved across all samples. The LRR cohort had proportionately greater patients with Decipher high risk signatures (64% LRR vs. 55% for GG-matched GRID [SMD 0.42] and vs. 34% for the overall GRID cohort [SMD 0.85]). Lower AR-activity was enriched in LRR (52% vs 9%, SMD 1.05) as were basal subtype tumors (48% vs 20%, SMD 0.80) when compared with the GG-matched GRID cohort. Tumor suppressor gene signatures for p53 (45% vs 27%, SMD 0.36), Rb loss (9% vs 3%, SMD 0.27) and PTEN deletion (18% vs 12%, SMD 0.17) were also increased in the LRR PC cohort. Conclusion: Genetic profiling and transcriptomic analysis of LRR PC revealed that LRR disease had an enrichment in mutations associated with high grade disease as well as higher Decipher scores, lower AR activity, loss of tumor suppressors and basal subtypes, even after matching for GG.

Keywords: Molecular Profile, Radioresistance, Prostate