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

Abstract

Purpose: 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 treatmentnaïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications.Experimental Design: 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 ¼ 5,239) and validation (n ¼ 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (n ¼ 1,170), and The Cancer Genome Atlas (n ¼ 333).Results: 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 ¼ 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 ¼ 0.008).Conclusions: 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.

Reduced KLK2 expression is a strong and independent predictor of poor prognosis in ERG‐negative prostate cancer

“…While KLK2 expression in IHC was typically at least weak to moderate in the cytoplasm of normal prostate epithelium, it was reduced or lost in a significant fraction of prostate cancers. This is in line with analyses of published transcriptome data describing lower mRNA expression in prostate cancer than in normal prostatic tissue (reviewed in 11,12 showing associations between low AR signaling and adverse patient outcome 30 and a comparably strong link of reduced expression of the KLK2 regulated PSA to unfavorable prognosis for our prostate cancer cohort. 28 These observations fit with results of Tremblay et al, 10 who also described associations of reduced KLK2 expression with unfavorable prostate cancer phenotype in their 70 cancers.…”

Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance

“…However, there were many gene sets activated in enzalutamide nonresponders in our trial-including those linked to EMT, stemness, and immune hallmarks-that were also activated in subsets of localized, hormone-naïve prostate cancer that had low AR activity in a recent report from our group (19). Importantly, low AR activity in that prior report was associated with shorter metastasis-free survival or time to biochemical recurrence, demonstrating the clinical significance of AR activitylow prostate cancers and the utility of this signature (the Spratt signature) (19). Therefore, we next measured AR function in RNA-seq data from our enzalutamide trial specimens using the Spratt signature.…”

“…Low AR activity has also been linked to immune pathways (19). Indeed, IFN-γ, IFN-α, allograft rejection, and inflammatory response were also among the top gene sets activated in nonresponders ( Fig.…”

“…Low AR activity has been linked to lineage plasticity, EMT, or stemness (19,(23)(24)(25)(26). Importantly, GSEA of differentially expressed genes identified 18 pathways (P < 0.05) that were activated in tumors from patients with de novo enzalutamide resistance-most notably pathways that are often linked to stemness, lineage plasticity, or EMT (32).…”

“…AR Activity Analysis. The Spratt AR activity scores were calculated based on nine genes described previously (19). To measure AR activity, we also used the VIPER R package (20).…”