Role of androgen receptor splice variants, their clinical relevance and treatment options

Wach, Sven; Täubert, Helge; Cronauer, Marcus V.

doi:10.1007/s00345-018-02619-0

Cited by 27 publications

(24 citation statements)

References 59 publications

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“…Next, we were interested in why AR-V7 granular staining could be associated with a longer RFS. AR-V7 participates in endocrine resistance [12]. Therefore, it was unexpected to see its association with a longer RFS.…”

Section: Discussionmentioning

confidence: 99%

“…The AR is the most important hormone receptor in PCa, and its splice variants, mainly AR-V7, can participate in endocrine resistance [12]. Here, the protein expression of AR and AR-V7 in tumors from 410 PCa patients was analyzed and correlated with clinicopathological parameters and survival data.…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, the tumor develops therapeutic resistance to AR-targeted therapies due to AR mutations, AR amplification or AR splice variants [9][10][11]. Among the more than 30 AR splice variants [12], AR-V7 appears to be the most clinically relevant variant [11]. Its protein expression in tumor tissue or circulating tumor cells (CTCs) has been associated with shorter overall survival (OS), disease-specific survival (DSS) and/or recurrence-free survival (RFS) [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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Expression of AR-V7 (Androgen Receptor Variant 7) Protein in Granular Cytoplasmic Structures Is an Independent Prognostic Factor in Prostate Cancer Patients

König

Eckstein

Jung

et al. 2020

Cancers

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Prostate cancer (PCa) is the second most common cancer, causing morbidity and mortality among men world-wide. The expression of the androgen receptor (AR) and its splice variants is a crucial factor of prostate cancer biology that has not been comprehensively studied in PCa tumors. The aim of this study was to characterize the protein expression of the AR and its splice variant, AR-V7, and their subcellular distributions in PCa by immunohistochemistry and to correlate the results to the clinicopathological data and prognosis. Immunohistochemical staining for AR and AR-V7 was performed on a tissue microarray (TMA) with specimens from 410 PCa patients using an immunoreactive score (IRS) or only the percentage of AR-V7 staining in cytoplasmic granules. Nuclear or cytoplasmic AR staining was not associated with prognosis. AR-V7 staining was only occasionally observed in the nucleus. However, AR-V7 staining in the cytoplasm or in cytoplasmic granules was associated with relapse-free survival (RFS). AR-V7 staining of the cytoplasm was associated with a shorter RFS, whereas AR-V7 staining of cytoplasmic granules was associated with a longer RFS. In a multivariate Cox’s regression analysis, only negative (<5%) AR-V7 staining of cytoplasmic granules remained an independent prognostic factor for RFS (HR = 5.3; p = 0.006). In a further subgroup analysis by multivariate Cox’s regression analysis, AR-V7 was an independent prognostic factor in the following groups: age ≤ 65 (HR = 9.7; p = 0.029), negative CK20 staining (HR = 7.0; p = 0.008), and positive perineural invasion (HR = 3.7; p = 0.034). Altogether, AR-V7 protein in granular cytoplasmic structures is an independent prognostic factor for RFS in PCa patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of AR-V7 (Androgen Receptor Variant 7) Protein in Granular Cytoplasmic Structures Is an Independent Prognostic Factor in Prostate Cancer Patients

König

Eckstein

Jung

et al. 2020

Cancers

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“…In this context, it is not fully understood how AR splicing is regulated. One hypothesis suggests that high availability of AR mRNA might be the predominant factor for the generation of AR-V7 [ 38 , 39 , 40 ]. Our data suggest that AR gain might be a basic mechanism increasing AR-FL expression and, hence, the presence of AR-V7 mRNA.…”

Section: Discussionmentioning

confidence: 99%

A Multi-Analyte Approach for Improved Sensitivity of Liquid Biopsies in Prostate Cancer

Hofmann

Sallinger

Haudum

et al. 2020

Cancers

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Novel androgen receptor (AR) signaling inhibitors have improved the treatment of castration-resistant prostate cancer (CRPC). Nonetheless, the effect of these drugs is often time-limited and eventually most patients become resistant due to various AR alterations. Although liquid biopsy approaches are powerful tools for early detection of such therapy resistances, most assays investigate only a single resistance mechanism. In combination with the typically low abundance of circulating biomarkers, liquid biopsy assays are therefore informative only in a subset of patients. In this pilot study, we aimed to increase overall sensitivity for tumor-related information by combining three liquid biopsy approaches into a multi-analyte approach. In a cohort of 19 CRPC patients, we (1) enumerated and characterized circulating tumor cells (CTCs) by mRNA-based in situ padlock probe analysis, (2) used RT-qPCR to detect cancer-associated transcripts (e.g., AR and AR-splice variant 7) in lysed whole blood, and (3) conducted shallow whole-genome plasma sequencing to detect AR amplification. Although 44–53% of patient samples were informative for each assay, a combination of all three approaches led to improved diagnostic sensitivity, providing tumor-related information in 89% of patients. Additionally, distinct resistance mechanisms co-occurred in two patients, further reinforcing the implementation of multi-analyte liquid biopsy approaches.

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“…Quite a few scholars believe that one reason for the resistant to ADT is the generation of AR splice variants. Until now, more than 30 distinct AR splice variants have been identi ed [26]. Among these variants, AR-V7 is the most common one [27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Splice Variant 7 Detected by Immunohistochemical Is an Independent Poor Prognostic Marker in Men Receiving Adjuvant Androgen-Deprivation Therapy After Radical Prostatectomy

Ouyang

Zhang

Long

et al. 2020

Preprint

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Background: To evaluate the predictive value of AR-V7 expression detected by immunohistochemical (IHC) in the prognosis of prostate cancer patients receiving adjuvant hormonal therapy (AHT) following by radical prostatectomy (RP).Methods: We retrospectively collected data of 110 patients with prostate cancer receiving RP, followed by AHT, from Tongji hospital. IHC analysis of AR-V7 expression was performed in a retrospective cohort. Results: In total, 110 patients were enrolled, of whom 21 patients (19.1%) were AR-V7-positive and 89 patients (80.9%) were AR-V7-negative. No significant differences in baseline characteristics were found between the two groups. AR-V7-positive patients had shorter progression‑free survival (PFS) (HR: 4.26; 95% CI, 1.55 to 11.68; P=0.003), shorter (cancer-special survival) CSS (HR: 22.47; 95% CI, 2.912 to 173.4; P=0.003) and shorter overall survival (OS ) (HR: 6.61; 95% CI, 1.40 to 31.20; P=0.017) compared to AR-V7-negative patients. In multivariate analysis, AR-V7 is an independent risk factor for shorter PFS (HR, 3.76; 95% CI, 1.63 to 8.70; P=0.002), shorter CSS (HR: 9.17; 95% CI, 1.48 to 55.56; P=0.017) and shorter OS (HR: 4.81; 95% CI, 1.28 to 17.86; P=0.020).Conclusion: The presence of AR-V7 in prostate cancer tissue is independently associated with an unfavorable prognosis for PFS, OS and CSS in patients who received AHT.

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Role of androgen receptor splice variants, their clinical relevance and treatment options

Cited by 27 publications

References 59 publications

Expression of AR-V7 (Androgen Receptor Variant 7) Protein in Granular Cytoplasmic Structures Is an Independent Prognostic Factor in Prostate Cancer Patients

Expression of AR-V7 (Androgen Receptor Variant 7) Protein in Granular Cytoplasmic Structures Is an Independent Prognostic Factor in Prostate Cancer Patients

A Multi-Analyte Approach for Improved Sensitivity of Liquid Biopsies in Prostate Cancer

Androgen Receptor Splice Variant 7 Detected by Immunohistochemical Is an Independent Poor Prognostic Marker in Men Receiving Adjuvant Androgen-Deprivation Therapy After Radical Prostatectomy

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