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European urology

Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response.


PMID 27497761

Abstract

Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. To identify molecular subgroups of PC bone metastases of relevance for therapy. Fresh-frozen bone metastasis samples from men with CRPC (n=40), treatment-naïve PC (n=8), or other malignancies (n=12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription-polymerase chain reaction (RT-PCR) in an extended set of bone metastases (n=77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease (n=12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients (n=284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation. The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were non-AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3 Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.