Androgen-indifferent prostate cancer (AIPC) is increasingly common and particularly lethal. Data describing these tumors are sparse, and AIPC remains a poorly understood malignancy. Utilizing the Oncology Research Information Exchange Network (ORIEN) database, we enriched for tumors with features of AIPC using previously described characteristics. Our AIPC cohort included three subgroups: aggressive variant prostate cancer (AVPC), neuroendocrine PC (NEPC), and double-negative PC (DNPC). Of 1496 total PC patients available for analysis, we identified 323 (22%) as MCRPC. Of those, 39 (12%) met AIPC criteria (17 AVPC, 13 NEPC, 9 DNPC) and 284 (88%) were non-AIPC. Forty-three percent of AIPC patients had de novo metastatic disease vs. 15% for non-AIPC (p = 0.003). Homologous recombination deficiency (HRD) and tumor mutational burden (TMB) did not differ between cohorts, but microsatellite instability scores (MSI) were significantly higher in AIPC (p = 0.019). Using Gene Set Enrichment Analysis (GSEA), we found that genes defining response to androgens and genes involved in oxidative phosphorylation were the most downregulated, whereas genes involved in epithelial-mesenchymal transition (EMT) and immune signaling were significantly upregulated in AIPC vs. non-AIPC. Our study demonstrates the potential for predefined criteria that aim to enrich for AIPC and suggests opportunities for therapeutic investigation.
International journal of molecular sciences. 2025 Jan 15*** epublish ***
Jack Masur, Aakrosh Ratan, Krzysztof Wierbilowicz, Adanma Ayanambakkam, Michelle L Churchman, Laura S Graham, George Daniel Grass, Sumati Gupta, Sean Q Kern, Jennifer King, Zin Myint, Robert J Rounbehler, Bodour Salhia, Eric A Singer, Yousef Zakharia, Bryce M Paschal, Paul V Viscuse
Division of Hematology/Oncology, University of Virginia, Charlottesville, VA 22903, USA., Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA., Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA., Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA., Aster Insights, Hudson, FL 34667, USA., Department of Medicine, Division of Medical Oncology, University of Colorado Cancer Center Anschutz Medical Campus, Aurora, CO 80045, USA., H. Lee Moffitt Cancer Center, Department of Radiation Oncology, Tampa, FL 33612, USA., Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84103, USA., Murtha Cancer Center, Uniformed Services University, Bethesda, MD 20814, USA., Department of Medicine, Division of Hematology and Medical Oncology, Indiana University Health Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA., Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40546, USA., Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA., Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.