Androgen receptor splice variant 7 (AR-V7) and drug efficacy in castration-resistant prostate cancer: biomarker for treatment selection exclusion or inclusion? (original) (raw)
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Journal of Clinical Oncology
PURPOSE Androgen receptor splice variant 7 (AR-V7) results in a truncated receptor, which leads to ligand-independent constitutive activation that is not inhibited by anti-androgen therapies, including abiraterone or enzalutamide. Given that previous reports suggested that circulating tumor cell (CTC) AR-V7 detection is a poor prognostic indicator for the clinical efficacy of secondary hormone therapies, we conducted a prospective multicenter validation study. PATIENTS AND METHODS PROPHECY ( ClinicalTrials.gov identifier: NCT02269982) is a multicenter, prospective-blinded study of men with high-risk mCRPC starting abiraterone acetate or enzalutamide treatment. The primary objective was to validate the prognostic significance of baseline CTC AR-V7 on the basis of radiographic or clinical progression free-survival (PFS) by using the Johns Hopkins University modified-AdnaTest CTC AR-V7 mRNA assay and the Epic Sciences CTC nuclear-specific AR-V7 protein assay. Overall survival (OS) and ...
2022
BackgroundTherapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance as predictive biomarker in CSPC remains understudied.MethodsWe explored multiple approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines and patient-derived xenograft (PDX) models, in both publicly available and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein, and its association with clinical outcome.ResultsIn publicly available benign prostate, CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increas...
Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer
The Journal of clinical investigation, 2018
Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival (OS) from endocrine therapies in castration resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue. Following generation and validation of a novel AR-V7 antibody for immunohistochemistry, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, full length AR (AR-FL) expression, response to therapy, and gene expression was determined. We demonstrated that AR-V7 protein is rarely expressed (<1%) in primary PC but is frequently detected (75% of cases) following androgen deprivation therapy, with further significant (P = 0.020) increase in expression following abiraterone acetate or enzalutamide therapy. In CRPC, AR-V7 expression is predominantly (94% ...
European urology, 2016
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. 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. Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) 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. 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...
European Urology Oncology
Background: In metastatic castration-resistant prostate cancer (mCRPC), androgen receptor splice variant 7 (AR-V7) expression is associated with a low response to androgen receptor signaling (ARS) inhibitors such as abiraterone or enzalutamide. Objective: To perform a highly sensitive assay for detecting AR-V7 (hsAR-V7) in circulating tumor cells (CTCs) and evaluate its ability to predict response to ARS inhibitors. Design, setting, and participants: From 41 mCRPC patients, CTCs were prospectively enriched using AdnaTest platform and analyzed for AR-V7 with and without the highly sensitive assay. Outcome measurements and statistical analysis: The first objective of the study was to compare AR-V7 detection rates with and without the highly sensitive assay. Next, we investigated how AR-V7 (detected without the highly sensitive assay) and hsAR-V7 status influenced prostate-specific antigen (PSA) response and long-term clinical outcomes (PSA progression-free survival [PFS] and radiological PFS) after ARS-inhibitor treatment. Finally, discriminatory abilities of the assays were assessed by C-index to compare their impact on long-term clinical outcomes.
Background: androgen receptor variant 7 (AR-V7) has been suggested as potential marker for treatment selection in men with metastatic castration-resistant prostate cancer (mCRPC). The aim of the present review is to critically analyze: frequency of the AR-V7 expression in mCRPC cases-impact of AR-V7 expression on abiraterone, enzalutamide, and taxane therapy. Methods: we searched in the Medline and Cochrane Library database from the literature of the past 10 years. We critically evaluated the level of evidence according to the European Association of Urology (EAU) guidelines. Results: 12 clinical trials were selected. The determination of AR-V7 in peripheral blood using circulating tumor cells mRNA seems to be the preferred method. At baseline, the mean percentage of cases with AR-V7 positivity was 18.3% (range 17.8%-28.8%). All data on mCRPC submitted to enzalutamide or abiraterone reported a significantly (P <.05) lower clinical progression-free survival (CPFS) and overall survival (OS) in AR-V7+ than AR-V7À cases (CPFS hazard ratio [HR]: 2.3; 95% CI 1.1-4.9; OS HR: 3.0; 95% CI 1.4-6.3). In mCRPC cases submitted to chemotherapies data are not homogeneous and some studies showed no association between CPFS or OS and AR-V7 status (OS HR 1.6; 95% CI 0.6-4.4; P = .40). Conclusions: the suggestion is that taxane therapy is more efficacious than abiraterone or enzalutamide for men with AR-V7+ CRPC. On the contrary, clinical outcomes did not seem to differ significantly on the basis of the type of therapy used among AR-V7À cases. Abbreviations: ADT = androgen deprivation therapies, AR = androgen receptor, AR-V7 = androgen receptor variant 7, CPFS = clinical progression free survival, CRPC = castration resistant prostate cancer, HR = hazard ratio, mCRPC = metastatic castration resistant prostate cancer, OS = overall survival, PC = prostate cancer, PCR = polymerase chain reaction, PSA = prostate specific antigen.
Splice variants of androgen receptor and prostate cancer
Oncology Reviews, 2016
Over the last ten years, two new-generation hormonal drugs and two chemotherapeutic agents have been approved for the treatment of metastatic castration-resistant prostate cancer. Unfortunately, some patients have primary resistance to them and the others eventually develop secondary resistance. It has recently been suggested that the presence of androgen receptor splice variants plays a leading role in the primary and secondary resistance to the new hormonal drugs, whereas their presence seem to have only a partial effect on the activity of the chemotherapeutic agents. The aim of this paper is to review the published data concerning the role of androgen receptor splice variants in prostate cancer biology, and their potential use as biomarkers when making therapeutic decisions.
Journal of Clinical Investigation, 2010
Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (AR v567es ) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, AR v567es functioned as a constitutively active receptor, increased expression of full-length AR (AR fl ), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with AR v567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of AR v567es to AR fl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected AR v567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.
2019
Adam Sharp , Jon C. Welti , Maryou B.K. Lambros , David Dolling , Daniel Nava Rodrigues , Lorna Pope , Caterina Aversa , Ines Figueiredo , Jennifer Fraser , Zai Ahmad , Changxue Lu , Pasquale Rescigno , Michael Kolinsky , Claudia Bertan , George Seed , Ruth Riisnaes , Susana Miranda , Mateus Crespo , Rita Pereira , Ana Ferreira , Gemma Fowler , Berni Ebbs , Penny Flohr , Antje Neeb , Diletta Bianchini , Antonella Petremolo , Semini Sumanasuriya , Alec Paschalis , Joaquin Mateo , Nina Tunariu , Wei Yuan , Suzanne Carreira , Stephen R. Plymate , Jun Luo , Johann S. de Bono *
Data in Brief, 2021
These data include secondary analysis of publicly available RNA-seq data from castration-resistant prostate cancer (CRPC) patients as well as RT-qPCR and Western blotting analyses of patient-derived xenograft models and a CRPC cell line. We applied Spearman correlation analysis to assess the relationship between canonical androgen receptor (AR) splicing and alternative AR splicing. We also assessed the ratio of AR splice variants (AR-Vs) to the full-length AR (AR-FL) at the RNA and protein levels by absolute RT-qPCR and Western blotting, respectively. These data are critical for studying the mechanisms underlying upregulated expression of AR-Vs after AR-directed therapies and the importance of AR-Vs to castration-resistant progression of prostate cancer. Data presented here are related to the research article by Ma et al., "Increased transcription and high translation efficiency lead