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Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer.

ABSTRACT: We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown.To investigate whether AR-V7-positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men.We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men.We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates, PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone).Of 37 taxane-treated patients enrolled, 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7-positive and AR-V7-negative men (41% vs 65%; P?=?.19). Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0; P?=?.32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P?=?.11) were comparable in AR-V7-positive and AR-V7-negative patients. A significant interaction was observed between AR-V7 status and treatment type (P?

SUBMITTER: Antonarakis ES

PROVIDER: S-EPMC4537351 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer.

Antonarakis Emmanuel S ES Lu Changxue C Luber Brandon B Wang Hao H Chen Yan Y Nakazawa Mary M Nadal Rosa R Paller Channing J CJ Denmeade Samuel R SR Carducci Michael A MA Eisenberger Mario A MA Luo Jun J

JAMA oncology 20150801 5

<h4>Importance</h4>We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown.<h4>Objective</h4>To investigate whether AR-V7-positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a ...[more]

PMID: 26181238

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Project description:BackgroundThe prognostic value of androgen receptor splice variant 7 (AR-V7) for the treatment response of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we aimed to synthesize relevant studies that assessed the prognostic value of AR-V7 status for the treatment response of mCRPC patients treated with androgen receptor signalling inhibitors (ARSis) and chemotherapy.MethodsWe searched the PubMed, Embase, and MEDLINE databases by using the keywords AR-V7 and prostate cancer to identify relevant studies published before 25 September 2019. The main outcomes were prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS). Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale.ResultsA total of 1,545 patients from 21 studies were included. For the mCRPC patients treated with ARSis, AR-V7-positive patients had a lower PSA response rate (OR 6.01, 95% CI 2.88-12.51; P < 0.001), shorter PFS (HR 2.56, 95% CI 1.80-3.64; P < 0.001) and shorter OS (HR 4.28, 95% CI 2.92-6.27; P < 0.001) than AR-V7-negative patients. Although AR-V7-positive patients treated with chemotherapy also had a lower PSA response rate (OR 2.23, 95% CI 1.38-3.62; P = 0.001) and shorter OS than AR-V7-negative patients (HR 1.60, 95% CI 1.02-2.53; P = 0.043), there was no significant difference in PFS (HR 1.05, 95% CI 0.74-1.49; P = 0.796) between these groups. Furthermore, AR-V7-positive patients receiving ARSis had a shorter median OS than those receiving chemotherapy (HR 3.50, 95% CI 1.98-6.20; P < 0.001); There was no significant difference among AR-V7-negative patients (HR 1.30, 95% CI 0.64-2.62; P = 0.47).ConclusionsAR-V7 is a potential biomarker of treatment resistance in mCRPC patients. AR-V7-positive mCRPC patients had poorer treatment outcomes than AR-V7-nagetive patients when treated with ARSis. AR-V7-positive patients have better outcomes when treated with taxane than ARSis. Furthermore, the ability of AR-V7 status to predict treatment outcomes varies from different detection methods. The detection of AR-V7 before treatment is important for the selection of treatment modalities for mCRPC patients.

Project description:BACKGROUND: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.

Dataset Information

Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer.

Publications

Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer.

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