TY - JOUR
T1 - Cell-free DNA alterations in the AR enhancer and locus predict resistance to AR-directed therapy in patients with metastatic prostate cancer
AU - Dang, Ha X.
AU - Chauhan, Pradeep S.
AU - Ellis, Haley
AU - Feng, Wenjia
AU - Harris, Peter K.
AU - Smith, Grace
AU - Qiao, Mark
AU - Dienstbach, Katherine
AU - Beck, Rachel
AU - Atkocius, Andrew
AU - Qaium, Faridi
AU - Luo, Jingqin
AU - Michalski, Jeff M.
AU - Picus, Joel
AU - Pachynski, Russell K.
AU - Maher, Christopher A.
AU - Chaudhuri, Aadel A.
N1 - Funding Information:
Supported by the Alvin J. Siteman Cancer Research Fund at Washington University in St Louis (A.A.C., C.A.M., R.K.P.), the National Cancer Institute of the National Institutes of Health under award number K08CA238711 (A.A.C.), the Cancer Research Foundation Young Investigator Award (A.A.C.), the American Cancer Society Institutional Research Grant under award number IRG-18-158-61 (H.X.D.), the Prostate Cancer Foundation Young Investigator Award (R.K.P.), the Sidney Kimmel Scholar Award (R.K.P.), and the Galen Hoskin and Dina Wolkoff Giving Fund (R.K.P.).
Publisher Copyright:
© 2020 by American Society of Clinical Oncology.
PY - 2020
Y1 - 2020
N2 - PURPOSE Cell-free DNA (cfDNA) and circulating tumor cell (CTC)-based liquid biopsies have emerged as potential tools to predict responses to androgen receptor (AR)-directed therapy in metastatic prostate cancer. However, because of complex mechanisms and incomplete understanding of genomic events involved in metastatic prostate cancer resistance, current assays (eg, CTC AR-V7) demonstrate low sensitivity and remain underutilized. The recent discovery of AR enhancer amplification in > 80% of patients with metastatic disease and its association with disease resistance presents an opportunity to improve on current assays. We hypothesized that tracking AR/enhancer genomic alterations in plasma cfDNA would detect resistance with high sensitivity and specificity. PATIENTS AND METHODS We developed a targeted sequencing and analysis method as part of a new assay called Enhancer and Neighboring Loci of Androgen Receptor Sequencing (EnhanceAR-Seq). We applied EnhanceARSeq to plasma collected from 40 patients with metastatic prostate cancer treated with AR-directed therapy to monitor AR/enhancer genomic alterations and correlated these events with therapy resistance, progression-free survival (PFS), and overall survival (OS). RESULTS EnhanceAR-Seq identified genomic alterations in the AR/enhancer locus in 45% of cases, including a 40% rate of AR enhancer amplification. Patients with AR/enhancer alterations had significantly worse PFS and OS than those without (6-month PFS, 30% v 71%; P = .0002; 6-month OS, 59% v 100%; P = .0015). AR/enhancer alterations in plasma cfDNA detected 18 of 23 resistant cases (78%) and outperformed the CTC ARV7 assay, which was also run on a subset of patients. CONCLUSION cfDNA-based AR locus alterations, including of the enhancer, are strongly associated with resistance to AR-directed therapy and significantly worse survival. cfDNA analysis using EnhanceAR-Seq may enable more precise risk stratification and personalized therapeutic approaches for metastatic prostate cancer.
AB - PURPOSE Cell-free DNA (cfDNA) and circulating tumor cell (CTC)-based liquid biopsies have emerged as potential tools to predict responses to androgen receptor (AR)-directed therapy in metastatic prostate cancer. However, because of complex mechanisms and incomplete understanding of genomic events involved in metastatic prostate cancer resistance, current assays (eg, CTC AR-V7) demonstrate low sensitivity and remain underutilized. The recent discovery of AR enhancer amplification in > 80% of patients with metastatic disease and its association with disease resistance presents an opportunity to improve on current assays. We hypothesized that tracking AR/enhancer genomic alterations in plasma cfDNA would detect resistance with high sensitivity and specificity. PATIENTS AND METHODS We developed a targeted sequencing and analysis method as part of a new assay called Enhancer and Neighboring Loci of Androgen Receptor Sequencing (EnhanceAR-Seq). We applied EnhanceARSeq to plasma collected from 40 patients with metastatic prostate cancer treated with AR-directed therapy to monitor AR/enhancer genomic alterations and correlated these events with therapy resistance, progression-free survival (PFS), and overall survival (OS). RESULTS EnhanceAR-Seq identified genomic alterations in the AR/enhancer locus in 45% of cases, including a 40% rate of AR enhancer amplification. Patients with AR/enhancer alterations had significantly worse PFS and OS than those without (6-month PFS, 30% v 71%; P = .0002; 6-month OS, 59% v 100%; P = .0015). AR/enhancer alterations in plasma cfDNA detected 18 of 23 resistant cases (78%) and outperformed the CTC ARV7 assay, which was also run on a subset of patients. CONCLUSION cfDNA-based AR locus alterations, including of the enhancer, are strongly associated with resistance to AR-directed therapy and significantly worse survival. cfDNA analysis using EnhanceAR-Seq may enable more precise risk stratification and personalized therapeutic approaches for metastatic prostate cancer.
UR - http://www.scopus.com/inward/record.url?scp=85088949279&partnerID=8YFLogxK
U2 - 10.1200/PO.20.00047
DO - 10.1200/PO.20.00047
M3 - Article
AN - SCOPUS:85088949279
SN - 2473-4284
VL - 4
SP - 680
EP - 713
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -