Transcriptomic Heterogeneity of Androgen Receptor Activity Defines a de novo low AR-Active Subclass in Treatment Naïve Primary Prostate Cancer

• Published in: Clinical cancer research Vol. 25; no. 22; pp. 6721 - 6730
• Main Authors: Spratt, Daniel E, Alshalalfa, Mohammed, Fishbane, Nick, Weiner, Adam B, Mehra, Rohit, Mahal, Brandon A, Lehrer, Jonathan, Liu, Yang, Zhao, Shuang G, Speers, Corey, Morgan, Todd M, Dicker, Adam P, Freedland, Stephen J, Karnes, R Jeffery, Weinmann, Sheila, Davicioni, Elai, Ross, Ashley E, Den, Robert B, Nguyen, Paul L, Feng, Felix Y, Lotan, Tamara L, Chinnaiyan, Arul M, Schaeffer, Edward M
• Format: Journal Article
• Language: English
• Published: United States 15.11.2019
• Subjects: Aged; Aged, 80 and over; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; Cohort Studies; Genetic Heterogeneity; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prostate - metabolism; Prostate - pathology; Prostate-Specific Antigen - blood; Prostatectomy - methods; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Prostatic Neoplasms, Castration-Resistant - therapy; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Transcriptome - genetics
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1587

The heterogeneity of androgen receptor (AR)-activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatment-naïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications. Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery ( = 5,239) and validation ( = 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data ( = 1,170), and The Cancer Genome Atlas ( = 333). A low AR-active subclass was identified, which comprised 9%-11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis [HR, 2.61; 95% confidence interval (CI), 1.22-5.60; = 0.014]. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21-0.80; = 0.008). Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation.