Androgen Receptor Splice Variant 7 Predicts Shorter Response in Patients with Metastatic Hormone-sensitive Prostate Cancer Receiving Androgen Deprivation Therapy

Li, Heng; Zhang, Yucong; Li, Dong; Ma, Xin; Xu, Kai; Ding, Beichen; Li, Hongzhao; Wang, Zhize; Ouyang, Wei; Long, Gongwei; Zeng, Jin; Liu, Haoran; Yan, Libin; Zhang, Yangjun; Liu, Zheng; Guan, Wei; Hu, Zhiquan; Liu, Cong; Wan, Jie; Wang, Guoping; Pu, Xiao‐Yong; Zhang, Minghui; Guo, Linlang; An, Ruihua; Qi, Jiping; Guo, Aitao; Ye, Zhangqun; Liu, Jiumin; Zhang, Xu; Xu, Hua

doi:10.1016/j.eururo.2021.01.037

Cited by 26 publications

(21 citation statements)

References 27 publications

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“…This is in line with previous results from literature; results from SWOG S1216 trial showed that Baseline CTC detection in mHSPC was associated with higher prostate-specific antigen (PSA), extensive disease, and bony metastasis [16]. Moreover, Li et al recently showed in a multicenter prospective cohort study that AR-V7 expression in primary cancer tissue is correlated with poor prognosis for mHSPC patients receiving ADT, confirming the role of this biomarker in an earlier scenario [17]. Our data did not confirm impact of CTC detection on biochemical response to I line ARTA therapy.…”

Section: Discussionsupporting

confidence: 90%

Prospective assessment of AR splice variant and PSMA detection on circulating tumor cells of mCRPC patients: preliminary analysis of patients enrolled in PRIMERA trial (NCT04188275)

Loi

Salvestrini

Mangoni

et al. 2021

Clin Exp Metastasis

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In our institution, a prospective observational trial testing micro-RNA (miRNA) and ARV7 mutational status in metastatic, castration resistant prostate cancer (mCRPC), is currently recruiting (PRIMERA trial, NCT04188275). A pre-planned interim analysis was performed when 50% of the planned accrual was reached. In this report, we explored the predictive value of Circulating Tumor Cell (CTC) detection in mCRPC patients undergoing 1st line therapy. Moreover, ARV7, ARFL, PSMA and PSA expression on CTC was reported to explore potential correlation with patient prognosis and response to therapy. PRIMERA is a prospective observational trial enrolling mCRPC patients undergoing standard treatment (ARTA + ADT) after I line ADT failure. Clinical and pathological features were collected. Outcomes selected for this preliminary analysis were time to castration resistance (TTCR), PSA at 8 weeks after ARTA therapy start, PSA drop at 8 weeks, Overall PSA drop, PSA nadir. Correlation between these outcomes and CTC detection was tested. Expression of ARV7, ARFL, PSA and PSMA was explored in CTC+ patients to assess their prevalence in this cohort and their impact on selected outcomes. Median TTCR was significantly shorter in CTC+ vs CTC− patients (32.3 vs 75 months, respectively, p = 0.03) and in ARFL+ vs ARFL− patients (30.2 vs 51.1 months, respectively, p = 0.02). ARV7, PSMA and PSA expression on CTC had no impact on median TTCR, nor on biochemical response to therapy. Patients in whom CTC and ARFL expression were detected had significant reduced TTCR. However, PSA response was not influenced by CTCs detection and specific biomarkers expression.

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Section: Discussionsupporting

confidence: 90%

Prospective assessment of AR splice variant and PSMA detection on circulating tumor cells of mCRPC patients: preliminary analysis of patients enrolled in PRIMERA trial (NCT04188275)

Loi

Salvestrini

Mangoni

et al. 2021

Clin Exp Metastasis

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“…6f lanes 10, 13) and FOXA1 antibody also precipitated AR and AR-V7 (Fig. 6f lanes 12,15) To test whether AR overexpression overcomes the effects of FOXA1 depletion on AR mediated transcription, LNCaP AR cells were treated with control or FOXA1 siRNA followed by induction of AR isoforms and treatment with R1881. Although overexpression altered levels of gene expression, it did not alter the sensitivity of any of the genes to FOXA1 depletion suggesting that preference likely is not due to FOXA1 sequestering a limiting amount of AR (Fig.…”

Section: A Role For Foxa1 In Ar Isoform Specific Gene Expressionmentioning

confidence: 99%

“…1a). Its expression has been correlated with resistance to second generation ADT in some, but not all studies [10][11][12][13] . Studies seeking to evaluate the role of AR-V7 in prostate cancer, whether it can function independent of full length AR (AR), and whether it only regulates a sub-set of AR targets or also has unique targets have yielded conflicting results 11,[14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Cistrome and transcriptome analysis identifies unique androgen receptor (AR) and AR- V7 splice variant chromatin binding and transcriptional activities

Basil

Robertson

Bingman

et al. 2021

Preprint

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The constitutively active androgen receptor (AR) splice variant, AR-V7, plays an important role in resistance to androgen deprivation therapy in castration resistant prostate cancer (CRPC). Studies seeking to determine whether AR-V7 is a partial mimic of the AR, or also has unique activities, and whether the AR-V7 cistrome contains unique binding sites have yielded conflicting results. One limitation in many studies has been the low level of AR variant compared to AR. Here, LNCaP and VCaP cell lines in which AR-V7 expression can be induced to match the level of AR, were used to compare the activities of AR and AR-V7. The two AR isoforms shared many targets, but overall had distinct transcriptomes. Optimal induction of novel targets sometimes required more receptor isoform than classical targets such as PSA. The isoforms displayed remarkably different cistromes with numerous differential binding sites. Some of the unique AR-V7 sites were located proximal to the transcription start sites (TSS). A de novo binding motif similar to a half ARE was identified in many AR-V7 preferential sites and, in contrast to conventional half ARE sites that bind AR-V7, FOXA1 was not enriched at these sites. This supports the concept that the AR isoforms have unique actions with the potential to serve as biomarkers or novel therapeutic targets.

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“…MHSPC are sensitive by definition to androgen deprivation [ 28 , 29 , 30 , 31 ], and thus suppression of testosterone to castrate levels by either orchiectomy or a long-acting LHRH agonist, results in a reduction in tumor cell division and metabolic activity. Combining the cytotoxic chemotherapy docetaxel with hormonal therapy resulted in a better OS in the STAMPEDE [ 13 , 14 ] and CHAARTED [ 11 ] trails.…”

Section: Discussionmentioning

confidence: 99%

Administering Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer 1–6 Days Compared to More Than 14 Days after the Start of LHRH Agonist Is Associated with Better Clinical Outcomes Due to Androgen Flare

Nasser

Sun

Scanlon

et al. 2022

Cancers

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Docetaxel, when given at the beginning of androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (MHSPC), results in significantly longer overall survival than ADT alone. We aimed to investigate if the delivery of the first dose of docetaxel during the testosterone flare associated with LHRH initiation results in better clinical outcomes, as testosterone induces mitosis of prostate cancer cells, and docetaxel specifically targets cells in mitosis. We analyzed data from the CHAARTED trial which randomized MHSPC patients to ADT alone or ADT plus docetaxel. We included only patients treated with LHRH agonist and docetaxel (n = 379). The only cutoff that resulted in differences in treatment outcomes was between patients who started docetaxel 1–6 days (n = 18) compared to more than 14 days from LHRH initiation (n = 297). Actuarial median overall survival was 72 versus 57 months (p = 0.2); progression-free survival was 49 versus 17 months (p = 0.06), and freedom from castrate-resistant prostate cancer was 51 versus 18 months (p = 0.04) for patients who started docetaxel 1–6 days compared to more than 14 days from LHRH initiation, respectively. Administering docetaxel 1–6 days from the initiation of LHRH agonist for patients with MHSPC could be associated with improved clinical outcomes.

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Androgen Receptor Splice Variant 7 Predicts Shorter Response in Patients with Metastatic Hormone-sensitive Prostate Cancer Receiving Androgen Deprivation Therapy

Cited by 26 publications

References 27 publications

Prospective assessment of AR splice variant and PSMA detection on circulating tumor cells of mCRPC patients: preliminary analysis of patients enrolled in PRIMERA trial (NCT04188275)

Prospective assessment of AR splice variant and PSMA detection on circulating tumor cells of mCRPC patients: preliminary analysis of patients enrolled in PRIMERA trial (NCT04188275)

Cistrome and transcriptome analysis identifies unique androgen receptor (AR) and AR- V7 splice variant chromatin binding and transcriptional activities

Administering Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer 1–6 Days Compared to More Than 14 Days after the Start of LHRH Agonist Is Associated with Better Clinical Outcomes Due to Androgen Flare

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