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 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.

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 = 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).

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 = 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).

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.

Figure 1.

CONSORT Diagram.

Figure 2.

Transcriptomic profiling of treatment naïve primary prostate cancers demonstrates significant inter-individual diversity of AR gene and AR-activity expression. A. Heatmap representing the gene expression over the eight exons and intronic region probe sets of the AR, as well as summarized full length AR using the prospective discovery cohort. B. Heatmap of the gene expression of 9 canonical AR-target genes using the prospective discovery cohort. C. Distribution of AR-activity across five independent cohorts (TCGA, prospective discovery and validation cohorts, JHMI, and BWH; total n=19,470). D. Heat scatter plot of the relationship between serum pre-treatment PSA that is log2 transformed, to the AR-activity score for each tumor and the gene for PSA, KLK3. Abbreviations: PSA, prostate-specific antigen; TCGA, The Cancer Genome Atlas; JHMI, Johns Hopkins Medical Institute; BWH, Brigham and Women Hospital

Figure 3:

Biologic landscape in primary prostate cancer of low AR-active tumors. A. PAM50 subtypes of prostate cancer (Zhao et al; Basal, Luminal A, and Luminal B) by decile of AR-A. B. Analysis of AR-A decile and distribution of immune cell content, DNA repair, and neuroendocrine marker expression. Additional neuroendocrine markers shown in supplementary table S3. Abbreviations: DSBR, double strand break repair; MDSC, Myeloid derived suppressor cells; MMR, mismatch repair; NEPC, neuroendocrine prostate cancer; Treg, Regulatory T-cell

Figure 4:

Association of AR-activity with recurrence and metastases. Kaplan-Meier curves by AR-activity for A) recurrence-free survival within TCGA, B) metastasis-free survival within JHMI cohort and C) BWH cohort. Abbreviations: TCGA, The Cancer Genome Atlas; JHMI, Johns Hopkins Medical Institute; BWH, Brigham and Women Hospital

Figure 5:

Prognostic and predictive treatment implications of AR-A in primary prostate cancer. A. Multivariable competing risk analysis for the development of metastasis within the JHMI cohort. B. Logistic regression for pre-clinical in vitro drug sensitivity analysis and clinical validation using the JHMI cohort for treatment sensitivity to ADT by AR-A status. C. Logistic regression for pre-clinical in vitro drug sensitivity analysis to PARP inhibitor therapy, platinum chemotherapy, and taxane chemotherapy by AR-A. Abbreviations: ADT, androgen-deprivation therapy; AR-A, androgen receptor-activity; JHMI, Johns Hopkins Medical Institute