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Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response.
Eur Urol. 2017 05; 71(5):776-787.EU

Abstract

BACKGROUND

Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation.

OBJECTIVES

To identify molecular subgroups of PC bone metastases of relevance for therapy.

DESIGN, SETTING, AND PARTICIPANTS

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.

RESULTS AND LIMITATIONS

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+ and CD68+ cells was lower in AR-driven than in non-AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient.

CONCLUSIONS

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.

PATIENT SUMMARY

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.

Authors+Show Affiliations

Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.Department of Surgery and Perioperative Sciences, Orthopedics, Umea University, Umea, Sweden.Section of Urology, Department of Surgical Science, Karolinska Institutet, Stockholm, Sweden.Department of Surgery and Perioperative Sciences, Urology & Andrology, Umea University, Umea, Sweden.Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden.Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden. Electronic address: pernilla.wikstrom@umu.se.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27497761

Citation

Ylitalo, Erik Bovinder, et al. "Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response." European Urology, vol. 71, no. 5, 2017, pp. 776-787.
Ylitalo EB, Thysell E, Jernberg E, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol. 2017;71(5):776-787.
Ylitalo, E. B., Thysell, E., Jernberg, E., Lundholm, M., Crnalic, S., Egevad, L., Stattin, P., Widmark, A., Bergh, A., & Wikström, P. (2017). Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. European Urology, 71(5), 776-787. https://doi.org/10.1016/j.eururo.2016.07.033
Ylitalo EB, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol. 2017;71(5):776-787. PubMed PMID: 27497761.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. AU - Ylitalo,Erik Bovinder, AU - Thysell,Elin, AU - Jernberg,Emma, AU - Lundholm,Marie, AU - Crnalic,Sead, AU - Egevad,Lars, AU - Stattin,Pär, AU - Widmark,Anders, AU - Bergh,Anders, AU - Wikström,Pernilla, Y1 - 2016/08/03/ PY - 2016/04/04/received PY - 2016/07/19/accepted PY - 2016/8/9/pubmed PY - 2018/2/13/medline PY - 2016/8/8/entrez KW - Bone metastasis KW - Castration-resistance KW - Immune response KW - Metabolism KW - Prostate cancer SP - 776 EP - 787 JF - European urology JO - Eur. Urol. VL - 71 IS - 5 N2 - BACKGROUND: Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. OBJECTIVES: To identify molecular subgroups of PC bone metastases of relevance for therapy. DESIGN, SETTING, AND PARTICIPANTS: 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. RESULTS AND LIMITATIONS: 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+ and CD68+ cells was lower in AR-driven than in non-AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient. CONCLUSIONS: 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. PATIENT SUMMARY: 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. SN - 1873-7560 UR - https://www.unboundmedicine.com/medline/citation/27497761/Subgroups_of_Castration_resistant_Prostate_Cancer_Bone_Metastases_Defined_Through_an_Inverse_Relationship_Between_Androgen_Receptor_Activity_and_Immune_Response_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0302-2838(16)30438-9 DB - PRIME DP - Unbound Medicine ER -