Expression of AR-V7 and ARV 567Es in circulating tumor cells correlates with outcomes to taxane therapy in men with metastatic prostate cancer treated in taxynergy

Scott T. Tagawa, Emmanuel Antonarakis, Ada Gjyrezi, Giuseppe Galletti, Seaho Kim, Daniel Worroll, John Stewart, Atef Zaher, Ted P. Szatrowski, Karla V. Ballman, Katsuhiro Kita, Shinsuke Tasaki, Yang Bai, Luigi Portella, Brian J. Kirby, Fred Saad, Mario Eisenberger, David M. Nanus, Paraskevi Giannakakou

Research output: Contribution to journalArticle

Abstract

Purpose: Biomarkers aiding treatment optimization in metastatic castration-resistant prostate cancer (mCRPC) are scarce. The presence or absence of androgen receptor (AR) splice variants, AR-V7 and AR v567es , in mCRPC patient circulating tumor cells (CTC) may be associated with taxane treatment outcomes. Experimental Design: A novel digital droplet PCR (ddPCR) assay assessed AR-splice variant expression in CTCs from patients receiving docetaxel or cabazitaxel in TAXYNERGY (NCT01718353). Patient outcomes were examined according to AR-splice variant expression, including prostate-specific antigen (PSA) 50 response and progression-free survival (PFS). Results: Of the 54 evaluable patients, 36 (67%) were AR-V7 þ , 42 (78%) were AR v567esþ , 29 (54%) were double positive, and 5 (9%) were double negative. PSA 50 response rates at any time were numerically higher for AR-V7 versus AR-V7 þ (78% vs. 58%; P ¼ 0.23) and for AR v567es versus AR v567esþ (92% vs. 57%; P ¼ 0.04) patients. When AR-V mRNA status was correlated with change in nuclear AR from cycle 1 day 1 to day 8 (n ¼ 24), AR-V7 þ patients (n ¼ 16) had a 0.4% decrease versus a 12.9% and 26.7% decrease in AR-V7/AR v567es (n ¼ 3) and AR-V7/AR v567esþ (n ¼ 5) patients, respectively, suggesting a dominant role for AR-V7 over AR v567es . Median PFS was 12.02 versus 8.48 months for AR-V7 versus AR-V7 þ (HR ¼ 0.38; P ¼ 0.01), and 12.71 versus 7.29 months for AR v567es versus AR v567esþ (HR ¼ 0.37; P ¼ 0.02). For AR-V7 þ , AR-V7/AR v567esþ , and AR-V7/ AR v567es patients, median PFS was 8.48, 11.17, and 16.62 months, respectively (P ¼ 0.0013 for trend). Conclusions: Although detection of both CTC-specific AR-V7 and AR v567es by ddPCR influenced taxane outcomes, AR-V7 primarily mediated the prognostic impact. The absence of both variants was associated with the best response and PFS with taxane treatment.

Original languageEnglish (US)
Pages (from-to)1880-1888
Number of pages9
JournalClinical Cancer Research
Volume25
Issue number6
DOIs
StatePublished - Jan 1 2019

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Circulating Neoplastic Cells
Androgen Receptors
Prostatic Neoplasms
Therapeutics
taxane
Disease-Free Survival
Castration
docetaxel

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Expression of AR-V7 and ARV 567Es in circulating tumor cells correlates with outcomes to taxane therapy in men with metastatic prostate cancer treated in taxynergy . / Tagawa, Scott T.; Antonarakis, Emmanuel; Gjyrezi, Ada; Galletti, Giuseppe; Kim, Seaho; Worroll, Daniel; Stewart, John; Zaher, Atef; Szatrowski, Ted P.; Ballman, Karla V.; Kita, Katsuhiro; Tasaki, Shinsuke; Bai, Yang; Portella, Luigi; Kirby, Brian J.; Saad, Fred; Eisenberger, Mario; Nanus, David M.; Giannakakou, Paraskevi.

In: Clinical Cancer Research, Vol. 25, No. 6, 01.01.2019, p. 1880-1888.

Research output: Contribution to journalArticle

Tagawa, ST, Antonarakis, E, Gjyrezi, A, Galletti, G, Kim, S, Worroll, D, Stewart, J, Zaher, A, Szatrowski, TP, Ballman, KV, Kita, K, Tasaki, S, Bai, Y, Portella, L, Kirby, BJ, Saad, F, Eisenberger, M, Nanus, DM & Giannakakou, P 2019, ' Expression of AR-V7 and ARV 567Es in circulating tumor cells correlates with outcomes to taxane therapy in men with metastatic prostate cancer treated in taxynergy ', Clinical Cancer Research, vol. 25, no. 6, pp. 1880-1888. https://doi.org/10.1158/1078-0432.CCR-18-0320
Tagawa, Scott T. ; Antonarakis, Emmanuel ; Gjyrezi, Ada ; Galletti, Giuseppe ; Kim, Seaho ; Worroll, Daniel ; Stewart, John ; Zaher, Atef ; Szatrowski, Ted P. ; Ballman, Karla V. ; Kita, Katsuhiro ; Tasaki, Shinsuke ; Bai, Yang ; Portella, Luigi ; Kirby, Brian J. ; Saad, Fred ; Eisenberger, Mario ; Nanus, David M. ; Giannakakou, Paraskevi. / Expression of AR-V7 and ARV 567Es in circulating tumor cells correlates with outcomes to taxane therapy in men with metastatic prostate cancer treated in taxynergy In: Clinical Cancer Research. 2019 ; Vol. 25, No. 6. pp. 1880-1888.
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title = "Expression of AR-V7 and ARV 567Es in circulating tumor cells correlates with outcomes to taxane therapy in men with metastatic prostate cancer treated in taxynergy",
abstract = "Purpose: Biomarkers aiding treatment optimization in metastatic castration-resistant prostate cancer (mCRPC) are scarce. The presence or absence of androgen receptor (AR) splice variants, AR-V7 and AR v567es , in mCRPC patient circulating tumor cells (CTC) may be associated with taxane treatment outcomes. Experimental Design: A novel digital droplet PCR (ddPCR) assay assessed AR-splice variant expression in CTCs from patients receiving docetaxel or cabazitaxel in TAXYNERGY (NCT01718353). Patient outcomes were examined according to AR-splice variant expression, including prostate-specific antigen (PSA) 50 response and progression-free survival (PFS). Results: Of the 54 evaluable patients, 36 (67{\%}) were AR-V7 {\th} , 42 (78{\%}) were AR v567es{\th} , 29 (54{\%}) were double positive, and 5 (9{\%}) were double negative. PSA 50 response rates at any time were numerically higher for AR-V7 versus AR-V7 {\th} (78{\%} vs. 58{\%}; P ¼ 0.23) and for AR v567es versus AR v567es{\th} (92{\%} vs. 57{\%}; P ¼ 0.04) patients. When AR-V mRNA status was correlated with change in nuclear AR from cycle 1 day 1 to day 8 (n ¼ 24), AR-V7 {\th} patients (n ¼ 16) had a 0.4{\%} decrease versus a 12.9{\%} and 26.7{\%} decrease in AR-V7/AR v567es (n ¼ 3) and AR-V7/AR v567es{\th} (n ¼ 5) patients, respectively, suggesting a dominant role for AR-V7 over AR v567es . Median PFS was 12.02 versus 8.48 months for AR-V7 versus AR-V7 {\th} (HR ¼ 0.38; P ¼ 0.01), and 12.71 versus 7.29 months for AR v567es versus AR v567es{\th} (HR ¼ 0.37; P ¼ 0.02). For AR-V7 {\th} , AR-V7/AR v567es{\th} , and AR-V7/ AR v567es patients, median PFS was 8.48, 11.17, and 16.62 months, respectively (P ¼ 0.0013 for trend). Conclusions: Although detection of both CTC-specific AR-V7 and AR v567es by ddPCR influenced taxane outcomes, AR-V7 primarily mediated the prognostic impact. The absence of both variants was associated with the best response and PFS with taxane treatment.",
author = "Tagawa, {Scott T.} and Emmanuel Antonarakis and Ada Gjyrezi and Giuseppe Galletti and Seaho Kim and Daniel Worroll and John Stewart and Atef Zaher and Szatrowski, {Ted P.} and Ballman, {Karla V.} and Katsuhiro Kita and Shinsuke Tasaki and Yang Bai and Luigi Portella and Kirby, {Brian J.} and Fred Saad and Mario Eisenberger and Nanus, {David M.} and Paraskevi Giannakakou",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/1078-0432.CCR-18-0320",
language = "English (US)",
volume = "25",
pages = "1880--1888",
journal = "Clinical Cancer Research",
issn = "1078-0432",
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}

TY - JOUR

T1 - Expression of AR-V7 and ARV 567Es in circulating tumor cells correlates with outcomes to taxane therapy in men with metastatic prostate cancer treated in taxynergy

AU - Tagawa, Scott T.

AU - Antonarakis, Emmanuel

AU - Gjyrezi, Ada

AU - Galletti, Giuseppe

AU - Kim, Seaho

AU - Worroll, Daniel

AU - Stewart, John

AU - Zaher, Atef

AU - Szatrowski, Ted P.

AU - Ballman, Karla V.

AU - Kita, Katsuhiro

AU - Tasaki, Shinsuke

AU - Bai, Yang

AU - Portella, Luigi

AU - Kirby, Brian J.

AU - Saad, Fred

AU - Eisenberger, Mario

AU - Nanus, David M.

AU - Giannakakou, Paraskevi

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Biomarkers aiding treatment optimization in metastatic castration-resistant prostate cancer (mCRPC) are scarce. The presence or absence of androgen receptor (AR) splice variants, AR-V7 and AR v567es , in mCRPC patient circulating tumor cells (CTC) may be associated with taxane treatment outcomes. Experimental Design: A novel digital droplet PCR (ddPCR) assay assessed AR-splice variant expression in CTCs from patients receiving docetaxel or cabazitaxel in TAXYNERGY (NCT01718353). Patient outcomes were examined according to AR-splice variant expression, including prostate-specific antigen (PSA) 50 response and progression-free survival (PFS). Results: Of the 54 evaluable patients, 36 (67%) were AR-V7 þ , 42 (78%) were AR v567esþ , 29 (54%) were double positive, and 5 (9%) were double negative. PSA 50 response rates at any time were numerically higher for AR-V7 versus AR-V7 þ (78% vs. 58%; P ¼ 0.23) and for AR v567es versus AR v567esþ (92% vs. 57%; P ¼ 0.04) patients. When AR-V mRNA status was correlated with change in nuclear AR from cycle 1 day 1 to day 8 (n ¼ 24), AR-V7 þ patients (n ¼ 16) had a 0.4% decrease versus a 12.9% and 26.7% decrease in AR-V7/AR v567es (n ¼ 3) and AR-V7/AR v567esþ (n ¼ 5) patients, respectively, suggesting a dominant role for AR-V7 over AR v567es . Median PFS was 12.02 versus 8.48 months for AR-V7 versus AR-V7 þ (HR ¼ 0.38; P ¼ 0.01), and 12.71 versus 7.29 months for AR v567es versus AR v567esþ (HR ¼ 0.37; P ¼ 0.02). For AR-V7 þ , AR-V7/AR v567esþ , and AR-V7/ AR v567es patients, median PFS was 8.48, 11.17, and 16.62 months, respectively (P ¼ 0.0013 for trend). Conclusions: Although detection of both CTC-specific AR-V7 and AR v567es by ddPCR influenced taxane outcomes, AR-V7 primarily mediated the prognostic impact. The absence of both variants was associated with the best response and PFS with taxane treatment.

AB - Purpose: Biomarkers aiding treatment optimization in metastatic castration-resistant prostate cancer (mCRPC) are scarce. The presence or absence of androgen receptor (AR) splice variants, AR-V7 and AR v567es , in mCRPC patient circulating tumor cells (CTC) may be associated with taxane treatment outcomes. Experimental Design: A novel digital droplet PCR (ddPCR) assay assessed AR-splice variant expression in CTCs from patients receiving docetaxel or cabazitaxel in TAXYNERGY (NCT01718353). Patient outcomes were examined according to AR-splice variant expression, including prostate-specific antigen (PSA) 50 response and progression-free survival (PFS). Results: Of the 54 evaluable patients, 36 (67%) were AR-V7 þ , 42 (78%) were AR v567esþ , 29 (54%) were double positive, and 5 (9%) were double negative. PSA 50 response rates at any time were numerically higher for AR-V7 versus AR-V7 þ (78% vs. 58%; P ¼ 0.23) and for AR v567es versus AR v567esþ (92% vs. 57%; P ¼ 0.04) patients. When AR-V mRNA status was correlated with change in nuclear AR from cycle 1 day 1 to day 8 (n ¼ 24), AR-V7 þ patients (n ¼ 16) had a 0.4% decrease versus a 12.9% and 26.7% decrease in AR-V7/AR v567es (n ¼ 3) and AR-V7/AR v567esþ (n ¼ 5) patients, respectively, suggesting a dominant role for AR-V7 over AR v567es . Median PFS was 12.02 versus 8.48 months for AR-V7 versus AR-V7 þ (HR ¼ 0.38; P ¼ 0.01), and 12.71 versus 7.29 months for AR v567es versus AR v567esþ (HR ¼ 0.37; P ¼ 0.02). For AR-V7 þ , AR-V7/AR v567esþ , and AR-V7/ AR v567es patients, median PFS was 8.48, 11.17, and 16.62 months, respectively (P ¼ 0.0013 for trend). Conclusions: Although detection of both CTC-specific AR-V7 and AR v567es by ddPCR influenced taxane outcomes, AR-V7 primarily mediated the prognostic impact. The absence of both variants was associated with the best response and PFS with taxane treatment.

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U2 - 10.1158/1078-0432.CCR-18-0320

DO - 10.1158/1078-0432.CCR-18-0320

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SP - 1880

EP - 1888

JO - Clinical Cancer Research

JF - Clinical Cancer Research

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