Abstract 5762: New perspective on racial disparities in prostate cancer: identification of new molecular subsets using whole-mount radical prostatectomy

Introduction: Prostate cancer is a heterogenous multifocal disease. We hypothesize that different tumor foci may harbor distinct driver molecular aberrations, making it a more complex disease and difficult to manage. To avoid overlooking smaller tumor foci with clinical and biological significance, we used an innovative approach to understand the genetic underpinnings of each tumor foci based on the molecular analysis of whole-mount radical prostatectomy specimens rather than a systematic sampling of dominant nodules alone. Our study aimed to identify distinct molecular subsets of prostate cancer, if any, and correlate them with clinical outcomes in Caucasians (CA) and African Americans (AA). Method: We randomly selected 834 whole-mount radical prostatectomy tissues including 463 (56%) CA and 371 (44%) AA. We used combined dual immunohistochemistry (IHC) for ERG and SPINK1 and dual RNA in-situ hybridization (ISH) for ETV1 and ETV4. The racial disparity in aberrant oncogene expression was analyzed by the Chi-squared test. The recurrence-free survival (RFS) of patients with distinct molecular subsets of prostate cancer was examined by the Kaplan-Meier method and cox-ph models. The Gleason’s grades of prostate biopsies were summarized by spaghetti plot and compared by linear mixed models. Results: Patients with localized prostate cancer expressing none, one, two, and three of four oncogenes were 16.4%, 58.4%, 21.7%, and 3.5%, respectively. The expression of ERG and SPINK1 was negatively correlated (odds ratio (OR)=0.38, 95% CI 0.29-0.51, p<.001). Compared with CA, AA had a lower incidence of ERG (38.8% vs 60.3%), a higher incidence of SPINK1 (63.3% vs 35.6%), and similar incidences of ETV1 (9.4% vs 9.3%) and ETV4 (4.6% vs 3.9%). Importantly, ETV1 expression was associated with a worse RFS in CAs (hazard ratio (HR)=2.49, 95% CI 1.15-5.38, p=.02). ETV4 expression was associated with a worse RFS in AA (HR=3.11, 95% CI 1.32-8.04, p=.01). In addition, ETV4 expression was associated with lymph node metastasis in AA (OR=4.0, 95% CI 1.06-12.44, p=.02) but not in CA (OR=0.56, 95% CI 0.03-2.85, p=.57). For those who had multiple biopsies before radical prostatectomy, Gleason’s grade increased with time in AA (0.23 per year, p<.001) but was unchanged in CA. ERG expression was associated with a lower Gleason grade (-0.20, p=.03). ETV4 was associated with a higher Gleason grade (0.50, p=.02). Conclusion: Our findings showed the molecular heterogeneity between CA and AA who had localized prostate cancer, and supported ETV1 and ETV4 as prognostic markers that can be incorporated into clinical practice to better predict prostate cancer recurrence after radical prostatectomy in CA and AA, respectively. Citation Format: Wei Zhao, Pin Li, Shannon Carskadon, Craig Rogers, James Peabody, Mani Menon, Dhananjay Chitale, Sean Williamson, Nilesh Gupta, Nallasivam Palanisamy. New perspective on racial disparities in prostate cancer: identification of new molecular subsets using whole-mount radical prostatectomy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5762.