Dataset Information

Taxane-based Chemotherapy Induced Androgen Receptor Splice Variant 7 in Patients with Castration-Resistant Prostate Cancer: A Tissue-based Analysis.

ABSTRACT: In total, 95 prostate cancer (Pca) patients who underwent transurethral resection of the prostate from 2000 to 2013 were assigned to four groups: Group 1, hormone-naïve and T1a or T1b Pca (n?=?17); Group 2, hormone-sensitive and metastatic Pca (n?=?33); Group 3, chemo-naïve castration-resistant Pca (CRPC), (n?=?18); and Group 4, CRPC with chemotherapy (n?=?27). Full-length androgen receptor (ARfl) transcript levels significantly increased from Group 1 through to Group 3 (p?=?0.045), but decreased from Group 3 through to Group 4. AR splice variant 7 (ARV7) and glucocorticoid receptor (GR) transcript levels significantly increased from Group 1 through to Group 4 (p?=?0.002 and 0.049, respectively). Kaplan-Meier curve revealed that the high transcript level of these three receptors resulted in significantly poorer cancer-specific survival (CSS) than that by low transcript level, although Cox regression analysis revealed that the ARV7 level alone was an independent prognostic factor for CSS in CRPC patients (high vs. low: hazard ratio, 1.897; 95% confidence interval, 1.102-3.625; p?=?0.042). In conclusion, ARV7 and GR transcript levels significantly increase as Pca progresses to CRPC.

SUBMITTER: Shim M

PROVIDER: S-EPMC6856155 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Taxane-based Chemotherapy Induced Androgen Receptor Splice Variant 7 in Patients with Castration-Resistant Prostate Cancer: A Tissue-based Analysis.

Shim Myungsun M Kim Yunlim Y Park Yangsoon Y Ahn Hanjong H

Scientific reports 20191114 1

In total, 95 prostate cancer (Pca) patients who underwent transurethral resection of the prostate from 2000 to 2013 were assigned to four groups: Group 1, hormone-naïve and T1a or T1b Pca (n = 17); Group 2, hormone-sensitive and metastatic Pca (n = 33); Group 3, chemo-naïve castration-resistant Pca (CRPC), (n = 18); and Group 4, CRPC with chemotherapy (n = 27). Full-length androgen receptor (ARfl) transcript levels significantly increased from Group 1 through to Group 3 (p = 0.045), but decrease ...[more]

PMID: 31727962

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Project description:ImportanceWe 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.ObjectiveTo 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.Design, setting, and participantsWe 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.Main outcomes and measuresWe 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).ResultsOf 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 < .001). Clinical outcomes were superior with taxanes compared with enzalutamide or abiraterone therapy in AR-V7-positive men, whereas outcomes did not differ by treatment type in AR-V7-negative men. In AR-V7-positive patients, PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003).Conclusions and relevanceDetection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7-positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7-negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. Circulating tumor cell-based AR-V7 detection may serve as a treatment selection biomarker in CRPC.

Project description:BackgroundLiquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival 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.MethodsFollowing generation and validation of a potentially novel AR-V7 antibody for IHC, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, full-length androgen receptor (AR-FL) expression, response to therapy, and gene expression were determined.ResultsWe 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% of cases) nuclear and correlates with AR-FL expression (P ≤ 0.001) and AR copy number (P = 0.026). However, dissociation of expression was observed, suggesting that mRNA splicing remains crucial for AR-V7 generation. AR-V7 expression was heterogeneous between different metastases from a patient, although AR-V7 expression was similar within a metastasis. Moreover, AR-V7 expression correlated with a unique 59-gene signature in CRPC, including HOXB13, a critical coregulator of AR-V7 function. Finally, AR-V7-negative disease associated with better prostate-specific antigen (PSA) responses (100% vs. 54%, P = 0.03) and overall survival (74.3 vs. 25.2 months, hazard ratio 0.23 [0.07-0.79], P = 0.02) from endocrine therapies (pre-chemotherapy).ConclusionThis study provides impetus to develop therapies that abrogate AR-V7 signaling to improve our understanding of AR-V7 biology and to confirm the clinical significance of AR-V7.FundingWork at the University of Washington and in the Plymate and Nelson laboratories is supported by the Department of Defense Prostate Cancer Research Program (W81XWH-14-2-0183, W81XWH-12-PCRP-TIA, W81XWH-15-1-0430, and W81XWH-13-2-0070), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the Institute for Prostate Cancer Research, the Veterans Affairs Research Program, the NIH/National Cancer Institute (P01CA163227), and the Prostate Cancer Foundation. Work in the de Bono laboratory was supported by funding from the Movember Foundation/Prostate Cancer UK (CEO13-2-002), the US Department of Defense (W81XWH-13-2-0093), the Prostate Cancer Foundation (20131017 and 20131017-1), Stand Up To Cancer (SU2C-AACR-DT0712), Cancer Research UK (CRM108X-A25144), and the UK Department of Health through an Experimental Cancer Medicine Centre grant (ECMC-CRM064X).

Dataset Information

Taxane-based Chemotherapy Induced Androgen Receptor Splice Variant 7 in Patients with Castration-Resistant Prostate Cancer: A Tissue-based Analysis.

Publications

Taxane-based Chemotherapy Induced Androgen Receptor Splice Variant 7 in Patients with Castration-Resistant Prostate Cancer: A Tissue-based Analysis.

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