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 S.
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 A.
AU - Nanus, David M.
AU - Giannakakou, Paraskevi
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019
Y1 - 2019
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
M3 - Article
C2 - 30301829
AN - SCOPUS:85055454847
SN - 1078-0432
VL - 25
SP - 1880
EP - 1888
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -