Dataset Information

Clinical Utility of the Nuclear-localized AR-V7 Biomarker in Circulating Tumor Cells in Improving Physician Treatment Choice in Castration-resistant Prostate Cancer.

ABSTRACT:

Background

Proof of the clinical utility of a biomarker is when its use informs a management decision and improves patient outcomes relative to when it is not used.

Objective

To model the clinical benefit of the nuclear-localized androgen receptor splice variant 7 (AR-V7) test for men with progressing metastatic castration-resistant prostate cancer (mCRPC) at the second line of therapy or greater to inform the choice of an androgen receptor signaling inhibitor (ARSI) or a taxane.

Design, setting, and participants

The study population was a cross-sectional cohort of 193 unique patients with progressing mCRPC from whom 255 samples were drawn at the time of the second line or later treatment decision who then received an ARSI or taxane, with up to 3?yr of additional follow-up Circulating tumor cells (CTCs) were identified from blood samples and tested for AR-V7. Physicians were blinded to AR-V7 status and the testing laboratory was blinded to outcomes.

Outcome measurements and statistical analyses

We measured physician propensity for choosing an ARSI or taxane based on patient prognosis. We also measured overall survival (OS) adjusted for physician propensity by drug class; OS data were analyzed both without and with knowledge of nuclear-localized AR-V7 status.

Results and limitations

Treating physicians had a propensity for choosing a taxane over an ARSI for patients with more advanced disease or who received an ARSI as the immediate prior therapy. After adjusting for physician propensity, discernible OS differences were not observed between taxane- and ARSI-treated patients (median 15.6 vs 14.4 mo; p?=0.11). Patients with detectable nuclear-localized AR-V7 in CTCs had superior survival with taxanes over ARSIs (median 9.8 vs 5.7 mo; p?=?0.041). AR-V7-negative patients had superior survival on ARSIs over taxanes (p?=?0.033) but overlapping curves limit the interpretation. Mutivariable models showed a robust interaction between AR-V7 status and drug, and a lower risk of death on taxanes for AR-V7-positive men.

Conclusions

Use of the nuclear-localized AR-V7 CTC test to inform treatment choice can improve patient outcomes relative to decisions based solely on standard-of-care measures.

Patient summary

Men with metastatic prostate cancer who test positive for AR-V7 protein in circulating tumor cells are likely to live longer if taxane chemotherapy is used.

SUBMITTER: Graf RP

PROVIDER: S-EPMC7472426 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Clinical Utility of the Nuclear-localized AR-V7 Biomarker in Circulating Tumor Cells in Improving Physician Treatment Choice in Castration-resistant Prostate Cancer.

Graf Ryon P RP Hullings Melanie M Barnett Ethan S ES Carbone Emily E Dittamore Ryan R Scher Howard I HI

European urology 20191021 2

<h4>Background</h4>Proof of the clinical utility of a biomarker is when its use informs a management decision and improves patient outcomes relative to when it is not used.<h4>Objective</h4>To model the clinical benefit of the nuclear-localized androgen receptor splice variant 7 (AR-V7) test for men with progressing metastatic castration-resistant prostate cancer (mCRPC) at the second line of therapy or greater to inform the choice of an androgen receptor signaling inhibitor (ARSI) or a taxane.< ...[more]

PMID: 31648903

Similar Datasets

Project description:ImportanceA critical decision in the management of metastatic castration-resistant prostate cancer (mCRPC) is when to administer an androgen receptor signaling (ARS) inhibitor or a taxane.ObjectiveTo determine if pretherapy nuclear androgen-receptor splice variant 7 (AR-V7) protein expression and localization on circulating tumor cells (CTCs) is a treatment-specific marker for response and outcomes between ARS inhibitors and taxanes.Design, setting, and participantsFor this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center, 265 men with progressive mCRPC undergoing a change in treatment were considered; 86 were excluded because they were not initiating ARS or taxane therapy; and 18 were excluded for processing time constraints, leaving 161 patients for analysis. Between December 2012 and March 2015, blood was collected and processed from patients with progressive mCRPC immediately prior to new line of systemic therapy. Patients were followed up to 3 years.Main outcomes and measuresProstate-specific antigen (PSA) response, time receiving therapy, radiographic progression-free survival (rPFS), and overall survival (OS).ResultsOverall, of 193 prospectively collected blood samples from 161 men with mCRPC, 191 were evaluable (128 pre-ARS inhibitor and 63 pretaxane). AR-V7-positive CTCs were found in 34 samples (18%), including 3% of first-line, 18% of second-line, and 31% of third- or greater line samples. Patients whose samples had AR-V7-positive CTCs before ARS inhibition had resistant posttherapy PSA changes (PTPC), shorter rPFS, shorter time on therapy, and shorter OS than those without AR-V7-positive CTCs. Overall, resistant PTPC were seen in 65 of 112 samples (58%) without detectable AR-V7-positive CTCs prior to ARS inhibition. There were statistically significant differences in OS but not in PTPC, time on therapy, or rPFS for patients with or without pretherapy AR-V7-positive CTCs treated with a taxane. A multivariable model adjusting for baseline factors associated with survival showed superior OS with taxanes relative to ARS inhibitors when AR-V7-positive CTCs were detected pretherapy (hazard ratio, 0.24; 95% CI, 0.10-0.57; P = .035).Conclusions and relevanceThe results validate CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker that is associated with superior survival on taxane therapy over ARS-directed therapy in a clinical practice setting. Continued examination of this biomarker in prospective studies will further aid clinical utility.

Project description:BackgroundAndrogen receptor (AR) splice variants (AR-Vs) have been discussed as a biomarker in prostate cancer (PC). However, some reports question the predictive property of AR-Vs. From a mechanistic perspective, the connection between AR full length (AR-FL) and AR-Vs is not fully understood. Here, we aimed to investigate the dependence of AR-FL and AR-V expression levels on AR gene activity. Additionally, we intended to comprehensively analyze presence of AR-FL and three clinically relevant AR-Vs (AR-V3, AR-V7 and AR-V9) in different stages of disease, especially with respect to clinical utility in PC patients undergoing AR targeted agent (ARTA) treatment.MethodsAR-FL and AR-V levels were analyzed in PC and non-PC cell lines upon artificial increase of AR pre-mRNA using either drug treatment or AR gene activation. Furthermore, expression of AR-FL and AR-Vs was determined in PC specimen at distinct stages of disease (primary (n = 10) and metastatic tissues (n = 20), liquid biopsy samples (n = 422), mCRPC liquid biopsy samples of n = 96 patients starting novel treatment). Finally, baseline AR-FL and AR-V status was correlated with clinical outcome in a defined cohort of n = 65 mCRPC patients undergoing ARTA treatment.ResultsWe revealed rising levels of AR-FL accompanied with appearance and increase of AR-Vs in dependence of elevated AR pre-mRNA levels. We also noticed increase in AR-FL and AR-V levels throughout disease progression. AR-V expression was always associated with high AR-FL levels without any sample being solely AR-V positive. In patients undergoing ARTA treatment, AR-FL did show prognostic, yet not predictive validity. Additionally, we observed a substantial clinical response to ARTA treatment even in AR-V positive patients. Accordingly, multivariate analysis did not demonstrate independent significance of AR-Vs in neither predictive nor prognostic clinical utility.ConclusionWe demonstrate a correlation between AR-FL and AR-V expression during PC progression; with AR-V expression being a side-effect of elevated AR pre-mRNA levels. Clinically, AR-V positivity relies on high levels of AR-FL, making cells still vulnerable to ARTA treatment, as demonstrated by AR-FL and AR-V positive patients responding to ARTA treatment. Thus, AR-FL and AR-V might be considered as a prognostic, yet not predictive biomarker in mCRPC patients.

Dataset Information

Clinical Utility of the Nuclear-localized AR-V7 Biomarker in Circulating Tumor Cells in Improving Physician Treatment Choice in Castration-resistant Prostate Cancer.

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analyses

Results and limitations

Conclusions

Patient summary

Publications

Clinical Utility of the Nuclear-localized AR-V7 Biomarker in Circulating Tumor Cells in Improving Physician Treatment Choice in Castration-resistant Prostate Cancer.

Similar Datasets

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