The Clinicopathological Characteristics of Androgen Receptor Splicing Variant 7 (AR-V7) Expression in Patients with Castration Resistance Prostate Cancer: A Systematic Review and Meta‐Analysis

Abstract

BACKGROUND Accumulating studies indicate AR-V7 may be related to the poor prognosis of castration resistance prostate cancer (CRPC), while the evidence of the clinicopathological characteristics of AR-V7 is rare.

METHODS To evaluate the clinicopathological features of AR-V7 in CRPC patients. A search of PubMed, Embase, and the Web of Science was performed using the keywords prostate cancer, prostate tumor, prostate neoplasm, prostate carcinoma; AR-V7, AR3, androgen receptor splicing variant-7, or androgen receptor-3. Twenty-four trials published due February 2020 were enrolled.

RESULTS The proportion of Gleason score ≥ 8 was significantly higher in AR-V7-positive CRPC (69.5%) than negative (54.9%) (OR 1.68, 95% CI 1.25–2.25, P<0.001), while the rate of T3/T4 stage (OR 1.16, 95% CI 0.60–2.24, P=0.65) and N1 stage (OR 0.99, 95% CI 0.65–1.51, P=0.96) were not statistically related to AR-V7 status. AR-V7-ositive patients had a significantly higher proportion of any site metastasis (61.3% versus 35.0%) (OR 2.19, 95% CI 1.57–3.05, P<0.001) and bone metastasis (81.7% versus 69.0%) (OR 1.97, 95% CI 1.44–2.69, P<0.001), and a trend close to significance was expected in visceral metastasis (28.8% versus 22.1%) (OR 1.29, 95% CI 0.96–1.74, P=0.09). The percentage of pain presence in AR-V7-positive CRPC (54.6%) was prominently higher than negative (28.1%) (OR 4.23, 95% CI 2.52–7.10, P<0.001), line with worse ECOG performance status (56.7% versus 35.0%, OR 2.18, 95% CI 1.51–3.16, P<0.001). Limitations of the study include the differences in study sample size and design, AR-V7 detection assay, and disease characteristics.

CONCLUSIONS AR-V7 positivity was associated with higher Gleason score, bone or any site metastasis, presence of pain and worse ECOG performance score in CRPC, but not related to tumor stage or lymph node metastasis. More studies are needed to confirm these findings.

1 Introduction

Prostate cancer is the most common cancer among American men according to the recent study published in 2019 [1]. Unfortunately, most prostate cancer eventually experience progression to metastatic castration-resistant prostate cancer (mCRPC) [2, 3]. Predictive biomarkers are urgently warranted to identify the patients with worse prognosis and optimize more precise treatment selection. The androgen receptor (AR) signal pathway is the primary therapeutic target of prostate cancer because AR axis is still a major driver for tumor progression [4, 5]. Either blocking AR [6, 7] or inhibiting ligand production [8, 9] can suppress AR signaling and extends the survival of men with metastatic castration resistant prostate cancer (mCRPC). Whereas the appearance of Androgen receptor variants (AR-Vs), spliced isoforms of the AR and encode truncated AR proteins lacking the C-terminal ligand-binding domain but retaining the trans-activating N-terminal domain, may lead to the AR signal based therapy resistance [10, 11].

Accumulating evidence suggested that AR variant 7 (AR-V7), one of the most abundant AR-Vs in CRPC, are associated with prostate cancer aggressiveness, castration-resistant prostate cancer (CRPC) development [4, 12] and primary resistance to Enzalutamide and Abiraterone therapy in men with CRPC [13–15]. Despite incompetent to bind ligand, AR-V7 remains constitutively active in a ligand-independent manner and capable of driving CRPC growth [12, 16]. Therefore, AR-V7 may guide treatment decisions in CRPC patients and serve as a predictive biomarker [17, 18].

Although the prognosis value of AR-V7 has been revealed in CRPC, the clinicopathological characteristics of AR-V7 expression still remain unclear and controversial [13, 14, 19–21]. Some studies indicated AR-V7 positivity was associated with clinicopathological characteristics; however, others were not [13, 21–23]. To our knowledge, there is no systematic review investigating this topic which has been published so far and a meta-analysis is expected to a robust conclusion. Our study aimed to analysis the relation between AR-V7 expression and clinicopathological features including Gleason score, tumor stage, node stage, metastasis status, presence of pain and ECOG performance status score in CRPC. 24 studies were enrolled to evaluate the clinicopathological significance of AR-V7 expression in CRPC patients.

2 Methods

3 Results

4 Discussion

We processed a meta-analysis to verify the hypothesis that AR-V7 positivity was associated with worse clinicopathological features. Biomarker of clinical utility should provide reliable information to the doctors with the potential to optimize precision treatment for patients. AR-V7 is taken for the most common AR splice variant, which was first found in advanced stage patients [25–29]. AR-V7 positive may be a particular type of prostate cancer subtype due to its worse clinicopathological characteristics. As various researches have indicated that AR-V7 was a novel AR splice variant which was capable of initiating and promoting CRPC progress [6, 7, 9], the AR-V7 positive CRPC needs to be considered as a novel subtype of CRPC with specific clinicopathological characteristics and resistance to AR signal targeted therapy.

AR-V7 positive has been associated with unfavorable baseline characteristics; therefore, it may reflect a larger neoplasm burden [20, 30, 31]. We compared the association between Gleason score and different AR-V7 status. Gleason score was obviously higher in AR-V7-positive than negative CRPC. We concluded that AR-V7 status is associated with clinicopathological characteristics for CRPC patients. However, recent trials showed insignificant relation between AR-V7-positive and higher Gleason score [14], some even implied AR-V7-negative patients had higher Gleason score [13]. Our results indicated AR-V7 positive patients had significant higher Gleason score, which was inconsistent with the previous findings that AR-V7 positivity was not related to higher Gleason score in metastatic CRPC [13]. Further researches about the relation between AR-V7 and Gleason score are still urgently expected.

Recent researches indicated that AR-V7-positive men would suffer higher T stage and lower N stage respectively [20, 21]. In this analysis, we assess the relevance between AR-V7 expression and clinicopathological features of CRPC patients. According to the merged results, we offered trustworthy evidence that the correlations between AR-V7 with T stage and lymph node metastasis were not statistically significant.

Bone or any site metastasis, presence of pain and ECOG performance score were compared in CRPC respectively with different AR-V7 status. AR-V7-positive patients had an elevated risk of any site metastasis, pain sufferance and worse ECOG performance score compared with AR-V7-negative CRPC. Although there were few studies about the clinicopathological features of AR-V7, it has been a hot-spot role of clinical decision-making and potential therapeutic target of CRPC. Existing evidence validated that expression of AR-V7 protein in circulating tumor cells nuclear was related with superior survival on taxane therapy in clinical practice as a specific treatment biomarker in men with mCRPC [18]. Accordingly, AR-V7 targeted therapy strategies are necessary and AR-V7 should be continuously surveilled during treatment. Same conclusion as before, AR-V7 is related to faster disease progression in CRPC [32–35]. Considering the prognosis value and the specific clinicopathological characteristics of AR-V7 in CRPC, AR-V7-positive CRPC should be taken as a novel subtype of prostate cancer which requires more aggressive, personalized and AR-V7 targeted therapy strategy. Further prospective studies are certainly needed to validate the role of AR-V7 positive as a particular type of prostate cancer subtype in CRPC.

There are several advantages in our systematic review. First of all, this is the first meta-analysis that indicates the clinicopathological characteristics of AR-V7 in CRPC patients to our knowledge. Second, our research offers a scientific basis to support for individualized estimations of clinicopathological features for CRPC patients, identifies more aggressive CRPC patients. In this way, doctors may conduct precision medicine and individualized treatment for CRPC patients. A challenge in the near future will be to correctly classify patients according to AR-V7 status within a suitable time for clinical practice [36]. In addition, this study may promote researchers to design additional clinical studies with larger sample sizes to validate these findings.

Notably, we did the best to perform this meta-analysis but there were still a few limitations in this systematic review. The sample size is rather small and limits its statistical power, which ranged from 3 to 953 participants. And the number of published studies was not sufficiently large for more accurate results due to the limited number of studies included. It is certain that smaller sample sizes were less reliable and tended to have publication bias. Thus, more large-cohort clinical trials are warranted to more accurate provide evidence for the clinicopathological features in CRPC patients. Second, the standards of study designs were not unified. Many studies caused an uncertain selection bias due to enrolled patients from a single center. Others reported patients in single or multicenter clinical trials, where patients enrolled might be highly selected by different criteria. Third, only references published in English were included in our meta-analysis. Fourth, the cut-off values distinguishing positive and negative AR-V7 expression differed in studies. And the various detection assays and antibodies used in the included researches might impact the sensitivity and specificity of AR-V7 positivity [37–40]. Therefore, consensus on the analytical method of testing and cut-off value are needed [41], generalized to more large multicenter researches, will provide more precise and credible results. Moreover, the clinicopathological features of CRPC patients including T stage, N stage and M stage, the definition of PSA and alkaline phosphatase response, and Gleason score vary among different studies, which might be responsible for the heterogeneity. Last but not the least, we admitted that AR-V7 was not extensively and sufficiently studied in CRPC patients, which would most likely draw controversial conclusions.

Several important efforts we made to deal with these drawbacks. Firstly, we performed a comprehensive, systematic, and repeatable search strategy for the most relevant references in multiple online databases which based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. To be honest, selection bias couldn’t be eliminated, but could be minimized by our strict screening of inclusion eligibility in the meta-analysis. Secondly, details of the study design, method of AR-V7 detection, types of therapy, Gleason score, tumor stage, node stage, metastasis status, presence of pain and ECOG performance status score in CRPC, and follow-up period were tabulated and available for further analysis and reference. Thirdly, fixed or random effect model was arranged according to different heterogeneity for more authentic and credible results. Additionally, the publication bias was evaluated and small-study effect was assessed by funnel plot listed in the supplement.

5 Conclusions

In conclusion, this meta-analysis clearly indicated that AR-V7 expression was significantly associated with Gleason score, bone or any site metastasis, pain presence and ECOG performance status, but not statistically related to tumor stage or lymph node metastasis. Specific clinicopathological features of AR-V7-postive CRPC were expected with higher Gleason score, more metastasis and pain presence, and worse ECOG performance status. Considering the prognostic value of AR-V7 in resistance to Abiraterone and Enzalutamide treatment for CRPC patients, our results may guide clinicians in identifying patients with more aggressive cancers, and selecting suitable patients that would derive durable clinical benefit from more active anti-tumor therapy. However, heterogeneous among study sample size and design, assays for AR-V7 detection assessment, and cut-off values definition for positive versus negative expression were evident within the included studies. More cross-institutional large-cohort prospective studies are warranted to confirm these findings and the clinical utility of AR-V7 as a biomarker in CRPC are expected.

Abbreviations

AR-V7: Androgen receptor splicing variant 7 

CRPC: Castration resistance prostate cancer

mCRPC: Metastatic castration-resistant prostate cancer

AR: Androgen receptor

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

T: Tumor

N: Node

M: Metastasis

ECGO: Eastern Cooperative Oncology Group

HSPC: Hormone sensitive prostate cancer

PSA: Prostate specific antigen

OR: Odds ratio

CI: Confidence interval

IQR: Inter quartile range

SD: Standard deviation

CTC: Circulating tumor cell

ADT: Androgen deprivation therapy

NHT: Novel hormonal therapy

LHRH: Luteinizing hormone releasing hormone

PCa: Prostate cancer

ABT: Abiraterone

ENZ: Enzalutamide

IHC: Immunohistochemistry;

Declarations

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Acknowledgment

We appreciate the technical supports of laboratory members.

Funding

None.

Authors' contributions

Project administration: ZW. Data curation: HS. Formal analysis: CW. Writing original draft: QL. Investigation: ZW. Writing revised: ZW and LX. All authors read and approved the final manuscript.

Ethics Statement

The studies involving human participants were reviewed and approved by First Affiliated Hospital of Zhejiang University.

Consent for publication

All authors have authorized the publication of this manuscript.

Conflicts of interest

Authors declare no conflicts of interest in this study.

Funding support

There was no funding source for this review. All authors had full access to all the data and the corresponding author had final responsibility for the decision to submit for publication.

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