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

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 (n = 5,239) and validation (n = 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (n = 1,170), and The Cancer Genome Atlas (n = 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 ERG 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; P = 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; P = 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.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2019 Sep 12 [Epub]

Daniel E Spratt, Mohammed Alshalalfa, Nick Fishbane, Adam B Weiner, Rohit Mehra, Brandon A Mahal, Jonathan Lehrer, Yang Liu, Shuang G Zhao, Corey Speers, Todd M Morgan, Adam P Dicker, Stephen J Freedland, R Jeffery Karnes, Sheila Weinmann, Elai Davicioni, Ashley E Ross, Robert B Den, Paul L Nguyen, Felix Y Feng, Tamara L Lotan, Arul M Chinnaiyan, Edward M Schaeffer

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. ., Department of Radiation Oncology, University of California, San Francisco, San Francisco, California., Decipher Biosciences, San Diego, California., Department of Urology, Feinberg School of Medicine, Northwestern University, Illinois., Department of Pathology, University of Michigan, Ann Arbor, Michigan., Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School, Boston, Massachusetts., Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan., Department of Urology, Michigan Medicine, Ann Arbor, Michigan., Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania., Department of Surgery, Division of Urology, Cedars-Sinai Medical Center, Los Angeles, California., Department of Urology, Mayo Clinic, Rochester, Minnesota., Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon., Texas Urology Specialists, Dallas, Texas., Department of Pathology, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland., Department of Pathology, University of Michigan, Ann Arbor, Michigan. ., Department of Urology, Feinberg School of Medicine, Northwestern University, Illinois. .