Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer

详细信息    查看全文

• 作者：Jonathan Welti^a ; ^&dagger ; ; Daniel Nava Rodrigues^a ; ^&dagger ; ; Adam Sharp^a ; ^&dagger ; ; Shihua Sun^b ; David Lorente^a ; ^c ; Ruth Riisnaes^a ; Ines Figueiredo^a ; Zafeiris Zafeiriou^a ; Pasquale Rescigno^a ; Johann S. de Bono^a ; ^&Dagger ; ; ^{johann.de-bono@icr.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Stephen R. Plymate^b ; ^&Dagger ; ; ^{splymate@uw.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Androgen receptor ; Androgen receptor variant-7 ; Castration-resistant prostate cancer ; Metastatic biopsy ; Treatment resistance ; Predictor of outcome
• 刊名：European Urology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：70
• 期：4
• 页码：599-608
• 全文大小：2523 K

文摘

The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide.

Objective

To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC.

Design, setting, and participants

Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis.

Outcome measurements and statistical analysis

Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined.

Results and limitations

Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5–90) compared to CRPC (HS 135, IQR 80–157.5; p < 0.0001), and in biopsy tissue taken before (HS 80, IQR 30–136.3) compared to after (HS 140, IQR 105–167.5; p = 0.007) abiraterone or enzalutamide treatment. Lower nuclear AR-V7 expression at CRPC biopsy was associated with longer OS (hazard ratio 1.012, 95% confidence interval 1.004–1.020; p = 0.003). While this monoclonal antibody primarily binds to AR-V7 in PC biopsy tissue, it may also bind to other proteins.

Conclusions

We provide the first evidence that nuclear AR-V7 expression increases with emerging CRPC and is prognostic for OS, unlike antibody staining for the AR N-terminal domain. These data indicate that AR-V7 is important in CRPC disease biology; agents targeting AR splice variants are needed to test this hypothesis and further improve patient outcome from CRPC.

Patient summary

In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time.