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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.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Mar 15; Vol. 25 (6), pp. 1880-1888. Date of Electronic Publication: 2018 Oct 09. - Publication Year :
- 2019
-
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 <superscript>v567es</superscript> , 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) <subscript>50</subscript> response and progression-free survival (PFS).<br />Results: Of the 54 evaluable patients, 36 (67%) were AR-V7 <superscript>+</superscript> , 42 (78%) were AR <superscript>v567es+</superscript> , 29 (54%) were double positive, and 5 (9%) were double negative. PSA <subscript>50</subscript> response rates at any time were numerically higher for AR-V7 <superscript>-</superscript> versus AR-V7 <superscript>+</superscript> (78% vs. 58%; P = 0.23) and for AR <superscript>v567es-</superscript> versus AR <superscript>v567es+</superscript> (92% vs. 57%; P = 0.04) patients. When AR-V mRNA status was correlated with change in nuclear AR from cycle 1 day 1 to day 8 ( n = 24), AR-V7 <superscript>+</superscript> patients ( n = 16) had a 0.4% decrease versus a 12.9% and 26.7% decrease in AR-V7 <superscript>-</superscript> /AR <superscript>v567es-</superscript> ( n = 3) and AR-V7 <superscript>-</superscript> /AR <superscript>v567es+</superscript> ( n = 5) patients, respectively, suggesting a dominant role for AR-V7 over AR <superscript>v567es</superscript> . Median PFS was 12.02 versus 8.48 months for AR-V7 <superscript>-</superscript> versus AR-V7 <superscript>+</superscript> (HR = 0.38; P = 0.01), and 12.71 versus 7.29 months for AR <superscript>v567es-</superscript> versus AR <superscript>v567es+</superscript> (HR = 0.37; P = 0.02). For AR-V7 <superscript>+</superscript> , AR-V7 <superscript>-</superscript> /AR <superscript>v567es+</superscript> , and AR-V7 <superscript>-</superscript> /AR <superscript>v567es-</superscript> patients, median PFS was 8.48, 11.17, and 16.62 months, respectively ( P = 0.0013 for trend).<br />Conclusions: Although detection of both CTC-specific AR-V7 and AR <superscript>v567es</superscript> 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.See related commentary by Dehm et al., p. 1696.<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Biomarkers, Tumor metabolism
Docetaxel pharmacology
Docetaxel therapeutic use
Humans
Kallikreins blood
Male
Middle Aged
Prednisone pharmacology
Prednisone therapeutic use
Progression-Free Survival
Prostate-Specific Antigen blood
Prostatic Neoplasms, Castration-Resistant blood
Prostatic Neoplasms, Castration-Resistant mortality
Prostatic Neoplasms, Castration-Resistant pathology
Protein Isoforms genetics
Protein Isoforms metabolism
Receptors, Androgen metabolism
Taxoids pharmacology
Taxoids therapeutic use
Treatment Outcome
Antineoplastic Combined Chemotherapy Protocols pharmacology
Biomarkers, Tumor genetics
Drug Resistance, Neoplasm genetics
Neoplastic Cells, Circulating metabolism
Prostatic Neoplasms, Castration-Resistant drug therapy
Receptors, Androgen genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 25
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 30301829
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-18-0320