2866 - Genetic Profiling of Aggressive Prostate Cancer in Patients Undergoing High Dose Rate (HDR) Brachytherapy

B. K. Neilsen¹, S. T. Fitz-Gibbon², H. Winata², T. N. Yamaguchi², N. K. Wang², Y. Patel², L. B. Zaide¹, M. Lee¹, M. Kim¹, A. Lim³, A. Lee¹, P. S. Venkat¹, A. U. Kishan¹, P. C. Boutros², and A. J. Chang¹; ¹Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, ²University of California, Los Angeles, Los Angeles, CA, ³Department of Radiation Oncology, University of Southern California, Los Angeles, CA

Purpose/Objective(s): High Dose Rate (HDR) brachytherapy is a standard of care treatment option for men with localized prostate cancer. It is often utilized in patients with high risk or locally recurrent disease. Given the clinical aggressiveness of prostate cancer in these individuals, we hypothesized that multi-omic profiling using DNA and RNA sequencing would reveal specific mutations and biological pathways contributing to this aggressive phenotype. Materials/

Methods: At a single institution, prostate cancer tissue biopsies and/or serum blood samples (liquid biopsies) were obtained prior to HDR brachytherapy for TEMPUS profiling in 89 unique patients. TEMPUS xF (liquid biopsy, n = 19) was utilized to profile 105 genes via targeted DNA sequencing. TEMPUS xT (tissue biopsy, n = 84) was utilized to profile 648 cancer-associated genes via both DNA and RNA (where technically possible) sequencing. The DNA and RNA profiling was compared and correlated to traditional markers of disease aggressiveness including T category, PSA at time of diagnosis, Gleason score, and overall risk group stratification. Additionally, genetic profiling and frequency of specific gene alterations were evaluated in the context of de novo versus locally recurrent prostate cancer.
Results: In the liquid biopsies (xF), the most frequently mutated genes were TP53 (n = 9, 47.4%) and NOTCH1 (n = 2, 10.5%). Several additional mutations present in a single sample were found in the following genes: ATM, ATR, BRAF, BRCA1, IDH1, IDH2, JAK2, and SDHA (n = 1, 5.3% for each). In the tissue biopsies (xT), the most commonly mutated genes were FOXA1 (n = 16, 19%), SPOP (n = 11, 13.1%), TP53 (n = 9, 10.7%), ATM (n = 8, 9.5%), KMT2C (n = 8, 9.5%), and PTEN (n = 7, 8.3%). Mutations were identified in approximately 5% of samples in the following genes: APC (n = 4, 4.8%), BRCA1 (n = 4, 4.8%), CDKN1B (n = 4, 4.8%), CHEK2 (n = 4, 4.8%), and LRP1B (n = 5, 6%). Fourteen patients had both liquid and tissue biopsy samples profiled. The paired samples only shared one or more common mutation in two cases with the remaining having no shared mutations. Notably, in five paired samples, mutations in the TP53 gene were identified in the liquid biopsy sample, but not the tissue biopsy sample.
Conclusion: Mutations present in prostate cancer overall are highly variable with numerous possible drivers. This variability persists even in aggressive disease including within the subset of patients that elect to undergo HDR brachytherapy. Further, replicate tissue biopsies or paired liquid and tissue biopsies frequently identified different cancer-related mutations highlighting the potential benefit of repeat testing and the heterogeneous nature of prostate cancer. Additional tumor characterization with clinically available genetic and/or transcriptomic profiles provides the opportunity to further risk stratify patients and provide the necessary foundation to highlight the various pathways driving prostate cancer.