AR-V7 Transcripts in Whole Blood RNA of Patients with Metastatic Castration Resistant Prostate Cancer Correlate with Response to Abiraterone Acetate

Tilman Todenhöfer, Arun Azad, Craig Stewart, Jian Gao, Bernhard J. Eigl, Martin E. Gleave, Anthony M. Joshua, Peter C. Black, Kim N. Chi

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose The expression of AR-V7 (androgen receptor splice variant) 7 in circulating tumor cells has been associated with resistance to abiraterone and enzalutamide in patients with metastatic castration resistant prostate cancer. We used a sensitive, whole blood reverse transcriptase-polymerase chain reaction assay that does not require circulating tumor cell enrichment to correlate outcomes of abiraterone with whole blood expression of AR-V7 and other prostate cancer associated transcripts. Materials and Methods We assessed the expression of AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3 and TMPRSS2:ERG mRNA in 2.5 ml whole blood from each of 27 patients with metastatic castration resistant prostate cancer and 33 controls without cancer as the discovery cohort. Cycle threshold values of controls with the highest gene expression were set as the threshold for a positive test. Thresholds were then applied to a validation cohort of 37 patients with metastatic castration resistant prostate cancer who were commencing abiraterone. Gene expression was correlated with the prostate specific antigen response rate using the chi-square test, and with time to prostate specific antigen progression and overall survival using the log rank test. Results In the discovery cohort 3 of 27 patients (11.1%) with metastatic castration resistant prostate cancer were AR-V7 positive vs 4 of 37 (10.8%) in the validation cohort. In the validation cohort patients with a positive AR-V7 test had a lower prostate specific antigen response rate (0% vs 42%, p = 0.27) together with shorter median prostate specific antigen progression (0.7 vs 4.0 months, p <0.001) and median overall survival (5.5 vs 22.1 months, p <0.001). Conclusions Reverse transcriptase-polymerase chain reaction detection of AR-V7 transcripts in whole blood was associated with inferior outcomes in patients treated with abiraterone. These results reinforce the potential usefulness of AR-V7 as a prognostic and predictive biomarker for metastatic castration resistant prostate cancer.

Original languageEnglish
Pages (from-to)135-142
Number of pages8
JournalJournal of Urology
Volume197
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • abiraterone
  • androgen
  • biomarkers
  • castration-resistant
  • neoplasm metastasis
  • prostatic neoplasms
  • receptors
  • tumor

Cite this

Todenhöfer, Tilman ; Azad, Arun ; Stewart, Craig ; Gao, Jian ; Eigl, Bernhard J. ; Gleave, Martin E. ; Joshua, Anthony M. ; Black, Peter C. ; Chi, Kim N. / AR-V7 Transcripts in Whole Blood RNA of Patients with Metastatic Castration Resistant Prostate Cancer Correlate with Response to Abiraterone Acetate. In: Journal of Urology. 2017 ; Vol. 197, No. 1. pp. 135-142.
@article{f991d6c0ecf94c96824228aa30282525,
title = "AR-V7 Transcripts in Whole Blood RNA of Patients with Metastatic Castration Resistant Prostate Cancer Correlate with Response to Abiraterone Acetate",
abstract = "Purpose The expression of AR-V7 (androgen receptor splice variant) 7 in circulating tumor cells has been associated with resistance to abiraterone and enzalutamide in patients with metastatic castration resistant prostate cancer. We used a sensitive, whole blood reverse transcriptase-polymerase chain reaction assay that does not require circulating tumor cell enrichment to correlate outcomes of abiraterone with whole blood expression of AR-V7 and other prostate cancer associated transcripts. Materials and Methods We assessed the expression of AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3 and TMPRSS2:ERG mRNA in 2.5 ml whole blood from each of 27 patients with metastatic castration resistant prostate cancer and 33 controls without cancer as the discovery cohort. Cycle threshold values of controls with the highest gene expression were set as the threshold for a positive test. Thresholds were then applied to a validation cohort of 37 patients with metastatic castration resistant prostate cancer who were commencing abiraterone. Gene expression was correlated with the prostate specific antigen response rate using the chi-square test, and with time to prostate specific antigen progression and overall survival using the log rank test. Results In the discovery cohort 3 of 27 patients (11.1{\%}) with metastatic castration resistant prostate cancer were AR-V7 positive vs 4 of 37 (10.8{\%}) in the validation cohort. In the validation cohort patients with a positive AR-V7 test had a lower prostate specific antigen response rate (0{\%} vs 42{\%}, p = 0.27) together with shorter median prostate specific antigen progression (0.7 vs 4.0 months, p <0.001) and median overall survival (5.5 vs 22.1 months, p <0.001). Conclusions Reverse transcriptase-polymerase chain reaction detection of AR-V7 transcripts in whole blood was associated with inferior outcomes in patients treated with abiraterone. These results reinforce the potential usefulness of AR-V7 as a prognostic and predictive biomarker for metastatic castration resistant prostate cancer.",
keywords = "abiraterone, androgen, biomarkers, castration-resistant, neoplasm metastasis, prostatic neoplasms, receptors, tumor",
author = "Tilman Todenh{\"o}fer and Arun Azad and Craig Stewart and Jian Gao and Eigl, {Bernhard J.} and Gleave, {Martin E.} and Joshua, {Anthony M.} and Black, {Peter C.} and Chi, {Kim N.}",
year = "2017",
month = "1",
day = "1",
doi = "10.1016/j.juro.2016.06.094",
language = "English",
volume = "197",
pages = "135--142",
journal = "Journal of Urology",
issn = "0022-5347",
publisher = "American Urological Association",
number = "1",

}

AR-V7 Transcripts in Whole Blood RNA of Patients with Metastatic Castration Resistant Prostate Cancer Correlate with Response to Abiraterone Acetate. / Todenhöfer, Tilman; Azad, Arun; Stewart, Craig; Gao, Jian; Eigl, Bernhard J.; Gleave, Martin E.; Joshua, Anthony M.; Black, Peter C.; Chi, Kim N.

In: Journal of Urology, Vol. 197, No. 1, 01.01.2017, p. 135-142.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - AR-V7 Transcripts in Whole Blood RNA of Patients with Metastatic Castration Resistant Prostate Cancer Correlate with Response to Abiraterone Acetate

AU - Todenhöfer, Tilman

AU - Azad, Arun

AU - Stewart, Craig

AU - Gao, Jian

AU - Eigl, Bernhard J.

AU - Gleave, Martin E.

AU - Joshua, Anthony M.

AU - Black, Peter C.

AU - Chi, Kim N.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Purpose The expression of AR-V7 (androgen receptor splice variant) 7 in circulating tumor cells has been associated with resistance to abiraterone and enzalutamide in patients with metastatic castration resistant prostate cancer. We used a sensitive, whole blood reverse transcriptase-polymerase chain reaction assay that does not require circulating tumor cell enrichment to correlate outcomes of abiraterone with whole blood expression of AR-V7 and other prostate cancer associated transcripts. Materials and Methods We assessed the expression of AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3 and TMPRSS2:ERG mRNA in 2.5 ml whole blood from each of 27 patients with metastatic castration resistant prostate cancer and 33 controls without cancer as the discovery cohort. Cycle threshold values of controls with the highest gene expression were set as the threshold for a positive test. Thresholds were then applied to a validation cohort of 37 patients with metastatic castration resistant prostate cancer who were commencing abiraterone. Gene expression was correlated with the prostate specific antigen response rate using the chi-square test, and with time to prostate specific antigen progression and overall survival using the log rank test. Results In the discovery cohort 3 of 27 patients (11.1%) with metastatic castration resistant prostate cancer were AR-V7 positive vs 4 of 37 (10.8%) in the validation cohort. In the validation cohort patients with a positive AR-V7 test had a lower prostate specific antigen response rate (0% vs 42%, p = 0.27) together with shorter median prostate specific antigen progression (0.7 vs 4.0 months, p <0.001) and median overall survival (5.5 vs 22.1 months, p <0.001). Conclusions Reverse transcriptase-polymerase chain reaction detection of AR-V7 transcripts in whole blood was associated with inferior outcomes in patients treated with abiraterone. These results reinforce the potential usefulness of AR-V7 as a prognostic and predictive biomarker for metastatic castration resistant prostate cancer.

AB - Purpose The expression of AR-V7 (androgen receptor splice variant) 7 in circulating tumor cells has been associated with resistance to abiraterone and enzalutamide in patients with metastatic castration resistant prostate cancer. We used a sensitive, whole blood reverse transcriptase-polymerase chain reaction assay that does not require circulating tumor cell enrichment to correlate outcomes of abiraterone with whole blood expression of AR-V7 and other prostate cancer associated transcripts. Materials and Methods We assessed the expression of AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3 and TMPRSS2:ERG mRNA in 2.5 ml whole blood from each of 27 patients with metastatic castration resistant prostate cancer and 33 controls without cancer as the discovery cohort. Cycle threshold values of controls with the highest gene expression were set as the threshold for a positive test. Thresholds were then applied to a validation cohort of 37 patients with metastatic castration resistant prostate cancer who were commencing abiraterone. Gene expression was correlated with the prostate specific antigen response rate using the chi-square test, and with time to prostate specific antigen progression and overall survival using the log rank test. Results In the discovery cohort 3 of 27 patients (11.1%) with metastatic castration resistant prostate cancer were AR-V7 positive vs 4 of 37 (10.8%) in the validation cohort. In the validation cohort patients with a positive AR-V7 test had a lower prostate specific antigen response rate (0% vs 42%, p = 0.27) together with shorter median prostate specific antigen progression (0.7 vs 4.0 months, p <0.001) and median overall survival (5.5 vs 22.1 months, p <0.001). Conclusions Reverse transcriptase-polymerase chain reaction detection of AR-V7 transcripts in whole blood was associated with inferior outcomes in patients treated with abiraterone. These results reinforce the potential usefulness of AR-V7 as a prognostic and predictive biomarker for metastatic castration resistant prostate cancer.

KW - abiraterone

KW - androgen

KW - biomarkers

KW - castration-resistant

KW - neoplasm metastasis

KW - prostatic neoplasms

KW - receptors

KW - tumor

UR - http://www.scopus.com/inward/record.url?scp=85003583757&partnerID=8YFLogxK

U2 - 10.1016/j.juro.2016.06.094

DO - 10.1016/j.juro.2016.06.094

M3 - Article

VL - 197

SP - 135

EP - 142

JO - Journal of Urology

JF - Journal of Urology

SN - 0022-5347

IS - 1

ER -