Transcriptomic heterogeneity of androgen receptor activity in primary prostate cancer: Identification and characterization of a low AR-active subclass.

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2 Background: Significant genomic diversity exists in the androgen receptor ( AR) and its activity (AR-A) in mCRPC. In localized prostate cancer, the biologic, prognostic, and therapeutic clinical implications of AR-A heterogeneity have yet to be interrogated Methods: Genome-wide expression profiles of FFPE RP or biopsy tumor samples were evaluated from a prospective registry cohort (n = 5,239, NCT02609269) and six retrospective institutional cohorts (n = 1,170). AR-A was calculated based on expression of 9 targets of AR.. Results: Utilizing 6,409 localized prostate adenocarcinomas with full transcriptomic data, we found there was marked inter-individual transcriptomic diversity in AR and AR-A expression, and weak correlation between them (r = 0.08 to 0.36 based on cohort), in contrast to mCRPC that has a strong correlation between AR and AR-A expression (r = 0.76). Additionally, serum PSA had no correlation to intratumoral AR-A (r = 0.06). Unsupervised hierarchical clustering identified a distinct subclass of low AR-A prostate tumors, which had increased markers of immunogenicity (decreased T-regs and MDSCs, and increased CD3 effector T-cells), increased neuroendocrine marker expression ( NCAM1, ENO2, and SCG2), and decreased DNA repair pathway expression (all p < 0.001). Clinically, low AR-A tumors had more rapid development of metastatic disease in three independent cohorts, were more prone to develop resistance to hormonal therapy and develop CRPC, and were found at an increased frequency in African-American men. Interrogating in vitro drug sensitivity analyses utilizing the NCI-60 panel, low AR-A tumors appear more sensitive to platinum chemotherapy and PARP inhibition, and less sensitive to hormone therapy and taxanes. Conclusions: The diversity in AR-signaling in localized prostate cancer represents important biological heterogeneity that is both prognostic and predictive of treatment response. These findings are provocative in that low AR-A tumors may be more susceptible to immunotherapy, PARP inhibition, platinum chemotherapy, and/or radiotherapy. Patients with low AR-A tumors warrant dedicated biomarker enhanced clinical trials.